ic Microangiopathy and the Kidney

Update for the Clinician

2
Katrina M. Wood,3 and David Kavanagh1,2

ngiopathy
giopathy can manifestand the
in a diverse rangeKidney
of diseases and is characterized by th
Clinical Journal of American Society of Nephrology

emolytic anemia, and1,2organ injury, including AKI. It can be associated with

Rajnish Mehrotra MD, MS

Gary C. Curhan, MD, ScD
EDITORS-IN-CHIEF
Michel B. Chonchol, MD
Paul M. Palevsky, MD
DEPUTY EDITORS
Carla M. Nester, MD
Ronald J. Falk, MD
SERIES EDITORS
Glomerular Diseases

and David
ality, but a Kavanagh
systematic approach to investigation and prompt initiation of su
some cases, effective specific treatment can result in good outcomes. This rev
 CJASN
Clinical Journal of the American Society of Nephrology

Glomerular Diseases: Update for the Clinician

Article 1 Introduction: Glomerular Disease Update for the Clinician

Carla M. Nester and Ronald J. Falk
Article 2 The Players: Cells Involved in Glomerular Disease
A. Richard Kitching and Holly L. Hutton
Article 3 All Things Complement
Joshua M. Thurman and Carla M. Nester
Article 4 Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach
in Nephrology
Laura H. Mariani, William F. Pendergraft III, and Matthias Kretzler
Article 5 Glomerular Diseases: Registries and Clinical Trials
Marva M. Moxey-Mims, Michael F. Flessner, Lawrence Holzman, Frederick Kaskel, John R. Sedor,
William E. Smoyer, Aliza M. Thompson, and Lynne Yao
Article 6 Patient-Reported Outcomes in Glomerular Disease
David T. Selewski, Aliza Thompson, Sarrit Kovacs, Elektra J. Papadopoulos, Noelle E. Carlozzi,
Howard Trachtman, Jonathan P. Troost, Peter A. Merkel, and Debbie S. Gipson
Article 7 Minimal Change Disease
Marina Vivarelli, Laura Massella, Barbara Ruggiero, and Francesco Emma
Article 8 Focal Segmental Glomerulosclerosis
Avi Z. Rosenberg and Jeffrey B. Kopp
Article 9 IgA Nephropathy
Jennifer C. Rodrigues, Mark Haas, and Heather N. Reich
Article 10 Update on Lupus Nephritis
Salem Almaani, Alexa Meara, and Brad H. Rovin
Article 11 Primary Membranous Nephropathy
William G. Couser
Article 12 Anti-Glomerular Basement Membrane Disease
Stephen P. McAdoo and Charles D. Pusey
Article 13 Viral-Associated GN: Hepatitis C and HIV
Warren L. Kupin
Article 14 Viral-Associated GN: Hepatitis B and Other Viral Infections
Warren L. Kupin
Article 15 ANCA Glomerulonephritis and Vasculitis
J. Charles Jennette and Patrick H. Nachman
Article 16 Pregnancy and Glomerular Disease: A Systematic Review of the Literature with
Management Guidelines
Kimberly Blom, Ayodele Odutayo, Kate Bramham, and Michelle A. Hladunewich
Article 17 Diabetic Kidney Disease: Challenges, Progress, and Possibilities
Radica Z. Alicic, Michele T. Rooney, and Katherine R. Tuttle
Article 18 Dysproteinemias and Glomerular Disease
Nelson Leung, Maria E. Drosou, and Samih H. Nasr
Article 19 Thrombotic Microangiopathy and the Kidney
Vicky Brocklebank, Katrina M. Wood, and David Kavanagh
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 Glomerular Diseases: Update for the Clinician

Introduction: Glomerular Disease Update for the

Clinician
Carla M. Nester* and Ronald J. Falk†
Clin J Am Soc Nephrol 11: 1662–1663, 2016. doi: 10.2215/CJN.07430716

Introduction specialized role of mesangial cells, endothelial cells,

*Stead Family
With this issue, the Clinical Journal of the American podocytes, and parietal epithelial cells within the glo- Department of
Society of Nephrology launches the latest in its educa- merulus. Next, the role of complement in glomerular Pediatrics and
tional series: a Glomerular Disease Update for the Cli- disease is considered, with examples of how comple- Department of
nician. Substantial progress has been made in our Internal Medicine, The
ment may mediate glomerular disease and become a
University of Iowa,
understanding of the underlying disease mechanism target for therapeutic intervention. A subsequent arti- Iowa City, Iowa; and
for a number of glomerular diseases. These advances cle considers the “omics” and state of the art bioinfor- †
Division of
have, in turn, set the stage for improved diagnostic matics tools that have pushed the study of glomerular Nephrology,
Department of
and treatment considerations. To illustrate these disease further into the 21st century. The introductory
Internal Medicine,
advances, a panel of distinguished authors have section closes with two important patient-centered re- University of North
composed a suite of comprehensive reviews (Table 1) views. The first review addresses the issues pertaining Carolina, Chapel Hill,
that we expect will serve as both an update for the to performing clinical trials in rare disease and how North Carolina
seasoned clinician, and as educational insight for patient registries may be leveraged. The second patient-
Correspondence:
trainees. centered review discusses the role of patient-reported
Dr. Carla M. Nester,
The series begins with five introductory pieces outcomes (PRO) in the study of glomerular disease. Stead Family
designed to highlight the elements driving prog- The authors review whether PROs are appropriate in Department of
ress in the field. The initial review is an overview the study of glomerular disease and highlight oppor- Pediatrics and
Department of
discussing the cells or “players” involved in glomer- tunities for incorporating PRO measures into clinical
Internal Medicine, The
ular pathology and disease. The authors discuss the care and research. University of Iowa,
200 Hawkins Drive,
4036BT, Iowa City, IA
52241. Email:
carla-nester@uiowa.
Table 1. Reviews included in the Glomerular Disease Update for the Clinician series edu

Introductory overviews
The Players: Cells Involved in Glomerular Disease
All Things Complement
Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach
in Nephrology
Primary Glomerular Disease: Registries and Clinical Trials
Patient Reported Outcomes in Glomerular Disease
Primary glomerular disease
Minimal Change Disease
Focal and Segmental Glomerulosclerosis
Membranous nephropathy
IgA Nephropathy
C3 Glomerulopathy
Secondary glomerular disease
Lupus Nephritis
ANCA Vasculitis
Anti-Glomerular Basement Membrane Disease
Viral Glomerulonephritides
Glomerular Disease During Pregnancy
Diabetic Nephropathy
Dysproteinemias and Glomerular Disease
TMA and the Kidney

TMA, thrombotic microangiopathy.

1662 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 September, 2016
Clin J Am Soc Nephrol 11: 1662–1663, September, 2016 GN Update 1663

In subsequent issues, 12 individual glomerular diseases Acknowledgments

are reviewed with attention to both epidemiology and
pathology. Pertinent clinical controversies are discussed, as
well as the most current, best approach to diagnosis and
management.
This series highlights the remarkable progress that has
been made in our understanding of the glomerular dis-
eases. It is the editors’ hope that it will also serve as a
springboard for a discussion on future directions as we
move toward optimal care for patients with glomerular
disease.
We wish to thank Dr. Danniele Gomes Holanda, Department of
Pathology–Renal Pathology, University of Iowa Hospitals & Clinics, for
providing the photomicrographs on the series banner.
C.M.N. is a representative of the American Society of Nephrol-
ogy’s Glomerular Disease Advisory Group.
Disclosures
None.
Published online ahead of print. Publication date available at www.
cjasn.org.
 The Players: Cells Involved in Glomerular Disease
A. Richard Kitching*†‡ and Holly L. Hutton*†

Abstract
Glomerular diseases are common and important. They can arise from systemic inflammatory or metabolic
diseases that affect the kidney. Alternately, they are caused primarily by local glomerular abnormalities, including
genetic diseases. Both intrinsic glomerular cells and leukocytes are critical to the healthy glomerulus and to
glomerular dysregulation in disease. Mesangial cells, endothelial cells, podocytes, and parietal epithelial cells
*Centre for
within the glomerulus all play unique and specialized roles. Although a specific disease often primarily affects a Inflammatory
particular cell type, the close proximity, and interdependent functions and interactions between cells mean that Diseases, Department
even diseases affecting one cell type usually indirectly influence others. In addition to those cells intrinsic to the of Medicine, School of
glomerulus, leukocytes patrol the glomerulus in health and mediate injury in disease. Distinct leukocyte types and Clinical Sciences,
Monash University,
subsets are present, with some being involved in different ways in an individual glomerular disease. Cells of the Clayton, Victoria,
innate and adaptive immune systems are important, directing systemic immune and inflammatory responses, Australia;
locally mediating injury, and potentially dampening inflammation and facilitating repair. The advent of new †
Department of
genetic and molecular techniques, and new disease models means that we better understand both the basic Nephrology, and
‡
biology of the glomerulus and the pathogenesis of glomerular disease. This understanding should lead to better Department of
Pediatric Nephrology,
diagnostic techniques, biomarkers, and predictors of prognosis, disease severity, and relapse. With this knowledge Monash Medical
comes the promise of better therapies in the future, directed toward halting pathways of injury and fibrosis, or Centre, Clayton,
interrupting the underlying pathophysiology of the individual diseases that lead to significant and progressive Victoria, Australia
glomerular disease.
Clin J Am Soc Nephrol 11: 1664–1674, 2016. doi: 10.2215/CJN.13791215 Correspondence:
Prof. A. Richard
Kitching, Centre for
Inflammatory
Introduction reactive segmental scarring. Immune deposits (Ig, Diseases, Department
The glomerulus is a spherical mass of specialized complement, or other material) can accumulate. Ad- of Medicine, Monash
capillaries fed by an afferent arteriole and draining Medical Centre, 246
ditional glomerular extracellular matrix (ECM) can ac- Clayton Road,
into an efferent arteriole. The urinary space (Bowman’s cumulate, and with severe or prolonged disease, Clayton, VIC 3168,
space) is surrounded by Bowman’s capsule, a base- glomeruli sclerose. Until relatively recently, syn- Australia. Email:
ment membrane to which a layer of glomerular dromic combinations of clinical and histologic fea- richard.kitching@
parietal epithelial cells (PECs) adheres (Figure 1A) monash.edu
tures have been the bedrock of the nomenclature of
(1). Mesangial cells and mesangial matrix form the glomerular disease. However, advances in our under-
central, tuft-like structure on which the glomerular standing of glomerular biology and disease pathogen-
microvasculature lies (1). The glomerular filtration esis suggest that we need to progress beyond
barrier (GFB), specialized to permit substantial filtra- standard histopathology to describe and classify glo-
tion of water and solutes, is composed of three lay- merular disease in the most meaningful manner.
ers: glomerular endothelial cells (with glycocalyx), Within glomeruli, podocytes, mesangial cells, and
the glomerular basement membrane (GBM), and endothelial cells engage in multidirectional cross talk
podocytes, within Bowman’s space (Figure 1B). Stud- among themselves and with leukocytes (3). For exam-
ies in white adult males without known kidney dis- ple, podocyte injury may induce mesangial cell pro-
ease have shown a median of 940,000 nephrons per liferation, and mesangial cell injury can lead to
individual and a glomerular volume of 2.43106 mm3, podocyte foot process effacement and fusion. Signals
with glomeruli possessing a median of 558 podo- from mesangial and endothelial cells are necessary
cytes, 367 PECs, and 1383 nonpodocyte cells within for normal podocyte function (4). In some cases,
the glomerular tuft (2). cell-specific, conditional knockout systems have de-
Glomerular cells are critical to normal physiology fined the mechanisms underpinning these observa-
but are targets of a range of injurious processes in tions, but in other situations the mechanisms of this
disease, including immune, metabolic, vascular, and cellular cross talk remain to be elucidated (3). Glo-
malignant disorders. While the clinical manifestations merular cells respond to injury depending on the
of glomerular disease are variable in severity, they are nature, magnitude, and duration of the insult. An
relatively limited in nature. Histologically, in “prolif- overview of typical responses of intrinsic cells to in-
erative” disease, intrinsic glomerular cells proliferate jury is presented in Table 1. This article will set the
and leukocytes accumulate. Cell death leads to histo- scene for later articles in this series (Glomerular Dis-
logically visible areas of necrosis or cell loss with eases: Update for the Clinician) by describing the key

1664 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 September, 2016
Clin J Am Soc Nephrol 11: 1664–1674, September, 2016 Cells Involved in Glomerular Disease 1665

Figure 1. | Basic structure of the glomerulus and the glomerular filtration barrier. (A) Each glomerulus is composed of an afferent arteriole,
which supplies the glomerular capillaries, and an efferent arteriole, into which they drain. Mesangial cells and mesangial matrix provide
structural support for the glomerular capillaries, lined by specialized fenestrated endothelium, and then the glomerular basement membrane.
On the urinary side of the glomerular basement membrane are podocytes, with foot processes that wrap around the glomerular capillaries. The
urinary space is lined by a cup-like layer of parietal epithelial cells which adhere to the basement membrane of Bowman’s capsule. (B) The
glomerular filtration barrier is a specialized molecular sieve, with properties that aid filtration of small solutes from the blood to the urine, while
limiting the passage of macromolecules such as albumin.

cellular players in glomerular disease, using selected
illustrative examples. Figure 2 summarizes some of
the ways in which glomerular injury can occur, with
individual diseases that will be discussed below and
in later articles in this series.
The Cellular Composition of the Glomerulus: Intrinsic
Glomerular Cells
Mesangial Cells: Matrix Homeostasis and a Glomerular
Scaffold
Mesangial cells provide support for the glomerular cap-
illary network and help maintain the homeostasis of the
mesangial matrix by secreting soluble factors. When injured,
mesangial cells can develop an activated phenotype or die
(via apoptosis or other mechanisms) (5). Circulating soluble
factors or metabolites can induce these responses directly, or
cause mesangial cells to secrete factors that elicit these
responses in an autocrine manner (6). In a process analogous
to wound healing, mesangial cell injury without ongoing
injurious stimuli may result in healthy remodelling of the
glomerulus, with mesangial cell migration, proliferation of
mesangial cell precursors in the juxta-glomerular apparatus,
and production of appropriate mesangial matrix (7).
Mesangial cell activation commonly results in hyper-
trophy and proliferation, excessive matrix production, and
the production of reactive oxygen species (5). Activated
mesangial cells produce chemokines and cytokines, which
act on mesangial cells themselves and on other resident
glomerular cells or leukocytes. These nearby cells in turn
secrete mediators that act on mesangial cells, forming a
paracrine loop (3). PDGFB is a potent mesangial cell mito-
gen. Its production by glomerular endothelial cells is es-
sential for mesangial cell development (5) and its
expression is upregulated in IgA nephropathy and other
proliferative forms of GN (8). Mesangial matrix expansion
1666 Clinical Journal of the American Society of Nephrology

Table 1. Key functions and responses of intrinsic glomerular cells

Normal Function and Relevant Glomerular

Cell Type Responses to Injury
Features Diseases (Examples)

Mesangial Maintain structural architecture Lysis with healthy remodeling IgA nephropathy
cells of glomerulus Apoptosis Diabetic nephropathy
Mesangial matrix homeostasis Hypertrophy
Regulate filtration surface area Proliferation and matrix expansion
Phagocytose apoptotic cells leading to glomerulosclerosis
Glomerular Fenestrations and glycocalyx Apoptosis ANCA-associated GN
endothelial facilitate selective permeability Loss of fenestrations Lupus nephritis
cells and filtration Widening of cell-cell junctions, (class 3 and 4)
transcellular holes Hemolytic uremic
Glycocalyx damage, loss of GAG
syndrome
synthesis
Diabetic nephropathy
Podocytes Foot processes wrap around Apoptosis Minimal change disease
capillaries Foot process effacement FSGS
Adherence to GBM Detachment from GBM, podocyte Diabetic nephropathy
Slit diaphragm regulates filtration loss
Loss of slit diaphragm
Parietal Line Bowman’s capsule Apoptosis Crescentic GN
epithelial Several subsets of cells likely Migration to glomerular tuft, FSGS
cells with different functions production of ECM proteins
Subset of cells may be able to leading to glomerulosclerosis
differentiate into podocytes Proliferation leading to crescent and
and play a reparative function pseudocrescent formation

GAG, glycosaminoglycan; GBM, glomerular basement membrane; ECM, extracellular matrix.

and the release of vasoactive mediators results in de-
creased glomerular surface area and altered glomerular
hemodynamics, with decreased GFR (3,5). If mesangial
cell activation is ongoing, ECM accumulation in the inter-
stitial space leads to interstitial fibrosis, followed by glo-
merulosclerosis (9).
Mesangial cells are targets both in immunologic injury
and in metabolic disease. Mesangial IgA deposition is the
hallmark of IgA nephropathy. In this disease, current models
imply a multihit pathogenesis with immune complexes
of anti-glycan autoantibodies and galactose-deficient
IgA1 being deposited in the mesangium, resulting in
mesangial cell injury and proliferation (10). Mesangial cell
hypertrophy and matrix expansion are histologic fea-
tures of diabetic nephropathy, mediated by metabolic
and hemodynamic changes in the setting of diabetes.
These include hyperglycemia, advanced glycation end
products, oxidized free fatty acids, and angiotensin II
(5). Acquired or genetic abnormalities of the GBM may
also influence the phenotype and activation status of
mesangial cells, with mesangial matrix expansion and
subsequent glomerular sclerosis, as in experimental Alport
disease (11).
Glomerular Endothelial Cells: Adapted for Selective
Permeability
Glomerular endothelial cells are uniquely adapted for
selective permeability and filtration. Although the glomerular
endothelium is continuous, it contains fenestrations, which
cover up to 50% of the glomerular surface area (12). On
conventional electron microscopy these fenestrations
appear as ovoid transcellular “holes”, 60–70 nm in
diameter (12). However, the fenestrations (and the glo-
merular endothelium itself) are covered by glycocalyx, a
carbohydrate-rich, gel-like mesh with important roles in
capillary permeability, regulation of the interactions be-
tween leukocytes and endothelial cells, and transduction
of shear stress (12).
In some disease states, endothelial injury leads to altered
microvascular permeability and albuminuria. Inflamma-
tory stimuli increase permeability by widening endothelial
cell-cell junctions, and in some instances, inducing trans-
cellular holes (13). Endothelial disease is a feature of rap-
idly progressive forms of GN, including ANCA-associated
GN, anti-GBM GN, and class 3 and 4 lupus nephritis.
However, reduced GFR also occurs in association with a
loss of endothelial fenestral area in other diseases, such as
preeclampsia (14) and diabetic nephropathy (15). Glomerular
endothelial cells are particularly vulnerable to injury medi-
ated by complement dysregulation, for example in atypical
hemolytic uremic syndrome (16). Podocyte-derived
vascular endothelial growth factor (VEGF) is critical
to the maintenance of endothelial cell structure and
function. Anti-VEGF therapies are associated with pro-
teinuria in humans, and mice with a podocyte-
specific VEGF deletion develop proteinuria (17). The
glomerular endotheliosis and proteinuria seen in preeclamp-
sia is associated with increased placental production of
soluble fms-like tyrosine kinase-1, an endogenous VEGF
antagonist (18).
The endothelial glycocalyx is predominantly composed
of proteoglycans, with their negatively charged glycos-
aminoglycan (GAG) chains covalently bound to the cell
surface, and sialoproteins, with adsorbed components
Clin J Am Soc Nephrol 11: 1664–1674, September, 2016 Cells Involved in Glomerular Disease 1667

Figure 2. | Simplified diagrammatic representation of a selection of mechanisms of glomerular injury. (A) Antibody-mediated glomerular
injury. From left to right, (i) neutrophils (shown) and macrophages induce injury after anti-a3(IV)NC1 autoantibodies bind to the GBM in anti-
GBM GN; (ii) in membranous glomerulopathy autoantibodies against PLA2R1 (and other antigens) on podocytes are deposited subepithelially,
with the involvement of complement; (iii) antibodies can bind to antigens lodged in the glomerulus (grey dots) with recruitment of macrophages
(shown) and neutrophils, and the activation of complement; (iv) circulating immune complexes can be deposited in glomeruli, activate
complement, and recruit leukocytes; (v) ANCA, (with complement) activates neutrophils and enables their recruitment to the glomerulus. Not
shown, but important, is IgA deposition in mesangial areas. (B) Cell-mediated immune mechanisms. (i) Effector CD41 cells (often Th1 or Th17
type) recognize antigens that can be intrinsic to or planted in the glomeruli. This occurs via their T cell receptor recognizing MHC class II
peptide complexes (several cell types could possibly be involved in this process). Activated T cells produce cytokines (IL-17A and IFN-g as
examples) that have direct effects on intrinsic kidney cells and activate, together with costimulatory molecules (e.g., CD154/CD40), innate
leukocytes such as macrophages. Not shown are interactions between intrinsic renal cells and T cells that include costimulation and cytokines.
(ii) CD81 cells can recognize antigenic peptides with MHC class I on intrinsic cells and secrete cytokines or induce cell death. (C) Metabolic,
vascular, and other mechanisms of injury. Podocyte and foot process injury and dysfunction occurs due to (i) genetic abnormalities of slit
diaphragm proteins and (ii) in minimal change disease and FSGS due to circulating permeability factors. Metabolic factors such as (iii) systemic
and intraglomerular hypertension and (iv) hyperglycemia and its consequences are common, and affect both the cells and the structural
components of the glomerulus. Both glomerular endothelial cell and podocyte injury are important consequences of preeclampsia, involved a
number of mediators including soluble fms-like tyrosine kinase-1. C3 glomerulopathy, as well as some types of atypical hemolytic uremic
syndrome (vi), can be induced by autoantibodies to, or genetic abnormalities in, complement regulatory proteins, resulting in complement
activation. a3(IV)NC1, the non-collagenous domain of the a3 chain of type IV collagen; FLT1, fms-like tyrosine kinase-1; GBM, glomerular
basement membrane; Mac, macrophage; M-type PLA2R1, phospholipase A2 receptor 1; Th, T helper; VEGF, vascular endothelial growth
factor.
1668 Clinical Journal of the American Society of Nephrology
such as albumin (12). The net negative charge of the glyco-
calyx is thought to play a role in the charge selectivity of
the GFB, helping restrict the passage of the negatively
charged macromolecule, albumin (12). While some data
does not support this ‘charge selectivity’ theory (19), it is
likely that the glycocalyx, functioning as a hydrogel,
forms a physical barrier that is important for permselectiv-
ity (12,20). The development of albuminuria in experimen-
tal models of diabetes is associated with changes in the
glycocalyx, including loss of GAGs (12), which may occur
due to hyperglycemia-induced disruption of GAG synthe-
sis (21). Damage to any of the three layers of the GFB (en-
dothelium, GBM, or podocyte) can result in the presence of
high molecular weight proteins in the urine (22). However,
because changes in component of the GFB often affect the
other elements, the contribution of each individual com-
ponent to the filtration barrier is not easy to discern (22).
Additionally, even in health, a significant amount of al-
bumin may pass through the GFB and be retrieved by the
proximal tubule, mediated by the neonatal Fc receptor,
FcRn (19,23). The relative importance of these two
pathways in glomerular diseases remains the subject
of debate and may differ in individual diseases and
patients (23).
Glomerular endothelial cell injury may promote tubu-
lointerstitial fibrosis, leading to ESRD in CKD (24). Shear
stress is necessary for glomerular endothelial function and
with poor glomerular perfusion, decreased survival sig-
nals from endothelial cells induce regression and rarefac-
tion of the peritubular capillary network (24). This reduced
microvascular blood flow results in chronic tubulointersti-
tial hypoxia and fibrosis, with inflammation from damaged
tubular epithelial cells propagating further endothelial cell
injury (24).
Podocytes: Critical to Maintaining the Filtration Barrier
Podocytes possess multiple foot processes that wrap
around the glomerular capillaries, with filtration slits
between adjacent processes (25). Although sometimes de-
scribed as a specialized epithelial cell, the podocyte is a
uniquely differentiated cell with some mesenchymal fea-
tures (4,26). Diseased podocytes may exhibit actin cytoskel-
etal rearrangement, loss of the slit diaphragm, a more
cuboidal morphology (27), and may dedifferentiate in dis-
ease along epithelial or mesenchymal pathways, termed
‘podocyte disease transformation’ (26). Podocytes have lim-
ited capacity for repair or regeneration, with podocyte loss
being a feature of many conditions that lead to glomerulo-
sclerosis (28). As podocytes are lost from glomeruli, the
GFB is compromised; experimentally, when .20% of po-
docytes are lost, progressive glomerulosclerosis ensues
(29). Evidence that the extent of podocyte loss determines
outcome is consistent with the “podocyte depletion” hy-
pothesis (30). This hypothesis unifies a variety of glomeru-
lar diseases by postulating that the degree of podocyte
depletion induced by injurious processes is a critical deter-
minant of progression to glomerulosclerosis.
The term ‘podocytopathy’ describes disease that feature
podocyte dysfunction as the primary manifestation of the
disease process and that result in significant proteinuria.
Podocytopathies commonly occur due to circulating fac-
tors or inherited deficiencies of podocyte genes (4,31), and
include minimal change disease and FSGS. However, po-
docyte injury and loss can also occur due to other envi-
ronmental cues, including indirectly, due to abnormalities
in the paracrine, ECM, and GBM-mediated signaling nec-
essary for normal podocyte function (4,25). Both intact
junctions between podocyte foot processes at the slit di-
aphragm and adhesion of podocytes to the GBM are es-
sential for the function of the GFB (25). Podocyte
detachment occurs due to increased shear stress either in
glomerular hypertension or hyperfiltration, or to impaired
podocyte adhesion, more commonly occurring in inflam-
matory glomerular diseases (28). Podocyte adhesion to the
GBM involves a range of regulatory and scaffold proteins.
As well as serving as a mechanical anchor, adhesion is
an interface for the bidirectional transmission of signals
concerning cell growth, differentiation, and survival (32).
Podocyte transmembrane receptors bind to the GBM, with
the extracellular domain binding to a specific GBM protein
(e.g., collagen or laminin), and the intracellular domain re-
cruiting effector proteins linked to components of the podo-
cyte cytoskeleton, most commonly actin. Integrins are a
major family of such transmembrane receptors, with muta-
tions in integrins and changes in activation status implicated
in a number of diseases, including FSGS (33,34).
Podocyte foot processes are connected by the podocyte
intercellular junction, commonly called the slit diaphragm
due to its appearance on electron microscopy. This junction
is a necessary component of the GFB that determines
glomerular permeability characteristics. Within the kid-
ney, nephrin and podocin are unique to the podocyte and
essential for its function (25). Inactivating mutations of the
genes encoding nephrin and podocin causes nephrotic
syndrome with diffuse collapse of podocyte foot processes
(35,36). Both proteins are also involved in signal transduc-
tion (37), and signaling via adaptor proteins has a major
influence on the function of the podocyte actin cytoskele-
ton (25). Lastly, podocytes may act as “immune cells” (38)
that under some circumstances, present antigenic pep-
tides to CD41 T cells (39).
Glomerular PECs: Not Merely Lining Cells
PECs adhere in a monolayer to Bowman’s capsule, and
in humans are morphologically similar to squamous epi-
thelial cells (1). Several subpopulations of PECs exist in
humans, expressing combinations of podocyte, progenitor,
or tubular markers, although no consensus has been
reached on the nomenclature and function of these cell
types (1). Although podocytes and PECs are derived
from a common mesenchymal progenitor, PECs proliferate
under normal conditions, whereas terminally differenti-
ated podocytes have limited ability to regenerate (1).
Some studies suggest that some PECs can differentiate
into podocytes (1,40), supported by in vivo imaging studies
in mice showing not only migration of PECs to the visceral
layer of the glomerular tuft, but also nanotube “bridges”
between podocytes and PECs, and podocyte migration to
the Bowman’s capsule epithelial layer (41). While PECs
may be able to play a reparative role, they can also con-
tribute to injury after conversion. Activated PECs can pro-
liferate and contribute to crescent formation in rapidly
progressive GN (1), or participate in the formation of pseu-
docrescents and sclerotic lesions, as in certain forms of
Clin J Am Soc Nephrol 11: 1664–1674, September, 2016 Cells Involved in Glomerular Disease 1669

FSGS, with PECs migrating to the glomerular tuft and pro- could also promote renal and glomerular inflammation
ducing ECM matrix proteins (1). by sensing danger (48).

Glomerular Leukocyte Recruitment: Specialized and

Leukocytes and the Glomerulus in Health and Disease
Leukocytes participate in many forms of glomerular
disease. They can influence disease by inducing, damp-
ening, or resolving systemic immune responses that lead to
glomerular disease. Alternately, leukocytes may act locally
within the glomerulus to mediate inflammation, or poten-
tially to resolve inflammation and mediate repair, or
contribute to homeostasis within normal glomeruli. Fig-
ure 3 shows leukocytes within glomeruli in GN. The sys-
temic actions of a range of innate and adaptive leukocytes
are critical to glomerular diseases discussed in articles
later in this series. The pathogenesis of these diseases
are intimately related to leukocyte behavior and activity
systemically, for example, the loss of tolerance and the
generation of nephritogenic autoimmunity in secondary
lymphoid organs (42–46).
Leukocytes in the Normal Glomerulus
Cross-sections of glomeruli from humans without renal
disease show few leukocytes, suggesting that the glomerulus
may not, under steady state conditions, support substantial
leukocyte recruitment. However, viewing normal mouse
glomeruli in vivo in three dimensions over time shows that
leukocytes patrol the normal glomerulus (Figure 4A) (47).
Patrolling monocytes in glomeruli are phenotypically sim-
ilar to monocytes that survey other blood vessels, and
although they may have homeostatic functions, they
Potentially Damaging
A variety of leukocytes are recruited to glomeruli in
inflammatory glomerular disease. Generally speaking,
leukocyte recruitment is mediated by adhesion molecules
and chemokines (Figure 4B). Adhesion of leukocytes in glo-
merular capillaries does not follow the traditional selectin-
mediated rolling paradigm that exists in postcapillary
venules in other tissues. On recruitment, leukocytes halt
suddenly in glomerular capillaries (49), with some re-
maining static and others migrating bidirectionally (47).
The specific adhesion molecules that mediate this arrest
and migration are context-dependent, both in terms of
the leukocyte type involved and the process inducing the
recruitment. Also critical to leukocyte recruitment are
chemokines, with some specialization in that specific
chemokines are associated with specific chemokine
receptor-expressing leukocytes (e.g., CXCL8/IL-8 and
CXCR2-expressing neutrophils). Activated products of
complement, C3a and C5a, are chemoattractants, while
other mediators are more specialized, e.g., leukocytes that
express Fcg receptors, monocyte/macrophages, and neutro-
phils, are recruited via IgG deposited in glomeruli (50).
Neutrophils and the Glomerulus: First Responders with a
Damaging Phenotype
Neutrophils, the most abundant immune cells, are first-
line responders in inflammation and in a variety of

Figure 3. | Leukocytes in glomeruli of patients with rapidly progressive GN. High powered photomicrographs as illustrative examples of
leukocytes within glomeruli in ANCA-associated GN. In all panels cell nuclei are stained with 49,6-diamidino-2-phenylindole (blue). (A) CD451 cells
(green, CD45 is a common leukocyte marker) in the glomerulus, (B) CD31 T cells (green), (C) CD681 macrophages (green), and (D) myeloperoxidase
(red) expressing leukocytes (neutrophils or macrophages) in a segmental glomerular lesion with local loss of CD34 (green), an endothelial cell lesion.
Nephrin (marking podocytes) is in white. Magnification: (A), (C ) and (D) x400; (B) x600. Photomicrographs from Ms. Kim O’Sullivan.
1670 Clinical Journal of the American Society of Nephrology

Figure 4. | Leukocyte recruitment and behavior in the glomerulus. (A) In health, neutrophils and monocytes (and potentially other leukocytes)
patrol the glomerulus. While some are static, the majority migrate bidirectionally within glomerular capillaries. (B) In acute disease, leukocytes
can be recruited and retained in glomeruli via a number of molecular processes. Examples are given with reference to the neutrophil (from left
to right). Neutrophils can be recruited via direct FcgR-Fc interactions. Adhesion molecules participate in recruitment, migration, and retention,
with, for example, Mac-1 (CD11b/CD18) on neutrophils slowing migration and inducing retention. P-selectins is not constitutively expressed
by glomerular endothelial cells, but in some situations P-selectin can participate in forming bridges with recruited platelets (pink oval) to
recruit neutrophils. Lastly, chemokines, for example CXCL8 (IL-8) secreted by endothelial cells, podocytes, mesangial cells (not shown), or
other leukocytes (not shown), attract leukocytes expressing appropriate chemokine receptors down a concentration gradient. Other
mechanisms, for example complement (not shown), can also attract leukocytes to the glomerulus. FcgR, Fcg receptor; ICAM-1, intercellular
adhesion molecule 1.

glomerular diseases. On activation, neutrophils produce
and release reactive oxygen species, proteases, cytokines,
and chemokines. Neutrophils are activated systemically
(51,52), or locally by proinflammatory mediators gener-
ated or deposited in the kidney, such as immune com-
plexes (47). Proinflammatory products of neutrophils
directly damage the GFB. In addition, in some forms of
GN (such as ANCA-associated GN and lupus nephritis)
neutrophils generate neutrophil extracellular traps, web-like
structures of histones decorated with proteases, peptides,
and enzymes that are also likely to be injurious (53). In
vivo microscopy reveals that a neutrophil can influence in-
jury over a considerable proportion of the glomerulus by
crawling within glomerular capillaries, in one disease
model covering an average of 150 mm/hour (47).
Monocytes, Macrophages, and the Glomerulus: Diverse
and Important
Innate cells of the monocyte/macrophage lineage have
multiple roles in tissues. Macrophages can adopt proin-
flammatory (M1) or anti-inflammatory (M2) phenotypes,
although these phenotypes exist on a continuum (46).
These phenotypes are plastic in vivo, with macrophages
responding to cues in the tissue microenvironment. In
the initial phases of experimental AKI, due to ischemia
reperfusion injury, macrophages in the interstitium are
proinflammatory and damaging (54). After the injurious
stimulus subsides, the same cells take on a healing and
reparative role (54). There is no intrinsic reason why intra-
glomerular leukocytes, in some situations, are not also
anti-inflammatory. While these reparative roles are
healthy if injury is self-limited, when pathologic processes
are ongoing, macrophages function as “frustrated” healing
cells and contribute to progressive fibrotic injury. In auto-
immune kidney disease, both humoral and cell-mediated
effector responses use macrophages as effector cells. Glo-
merular IgG activates macrophages via Fc-FcgR interac-
tions, while effector T helper 1 (Th1) and T helper 17
(Th17) cells activate these cells both by cytokines and via
cell-cell contact.
Clin J Am Soc Nephrol 11: 1664–1674, September, 2016
Dendritic Cells: The Interstitium, and the Glomerulus As
Well?
Systemically, dendritic cells (DCs), specialized leuko-
cytes that present antigen to T cells, play a key role in
adaptive immune responses that cause GN. In the kidney,
DCs form an extensive interstitial network (55), where they
help maintain tolerance to filtered self-peptides (56) and
act innately as pro- or anti-inflammatory renal mononu-
clear phagocytes. These interstitial DCs are largely acutely
protective. However, in inflammatory states, recruited in-
flammatory monocytes differentiate into proinflammatory
DCs, while activated resident DCs carry antigen to drain-
ing lymph nodes and activate naïve T cells. In contrast to
the interstitial DC network, DCs are rarely present in nor-
mal glomeruli (57) and only uncommonly in acute disease.
While human biopsy studies are divided as to the presence
of DCs in glomeruli in more established injury, in estab-
lished rapidly progressive GN, DCs within injured glo-
meruli may participate in T cell recruitment and
activation (43).
Mast Cells: More than Just Mediators of Allergy
While mast cells traditionally are considered as media-
tors of anaphylaxis and allergy, they are tunable cells that
contribute to, and regulate inflammation and autoimmu-
nity. In addition to histamine and other mediators of
allergy, mast cells secrete both stored and newly synthe-
sized pro- and anti-inflammatory cytokines. Mast cells
are present within the kidney in GN in both the tubuloin-
terstitium and the glomerulus. Intrarenal mast cells are
proinflammatory, with the capacity to degranulate (58),
while in secondary lymphoid organs they are anti-
inflammatory, acting with regulatory T cells to help maintain
tolerance (59,60).
T Lymphocytes: Subsets Directing Immunity and
Glomerular Disease
Conventional CD41 and CD81 T lymphocytes have a
wide range of ab T cell receptors that can recognize a huge
variety of antigenic peptides. T cells are instrumental in
protection from infectious threats but in disease, T cells
mediate a number of forms of inflammatory and autoim-
mune glomerular disease. CD41 cells orchestrate adaptive
immunity, differentiating into subsets that direct the sub-
sequent components of the immune response. These sub-
sets, while somewhat plastic, are definable by their
signature cytokines, transcription factors, and to some
degree, chemokine receptors (44). In glomerular disease,
T follicular helper cells promote T cell–dependent anti-
body production. In contrast, Th1 and Th17 cells recognize
antigens intrinsic to, or planted in glomeruli, and act as
local effectors of glomerular injury in experimental rapidly
progressive forms of GN (61). Th1 cells are particularly
associated with macrophage activation, and Th17 cells
are associated with neutrophil recruitment and activation.
Temporally, at least in responding to foreign antigens,
Th17 cells act earlier in immune responses and over time
convert to a mixed Th1/Th17 or Th1 phenotype (44). Th2
cells support eosinophils, important in allergic interstitial
nephritis and in glomerular disease in sub-Saharan Africa
(62). CD81 cells are cytotoxic, killing cells that express
Cells Involved in Glomerular Disease 1671
their cognate peptide with MHC class 1, but also secrete
cytokines and may act in a proinflammatory manner (63).
B Lymphocytes: Antibodies As Key Mediators of Glomerular
Disease
B cells and their terminally differentiated progeny, antibody-
secreting plasma cells, are critical cells in humoral im-
munity. Within lymphoid organs, they produce antibodies
that impact the glomerulus in different ways in many forms
of GN. In autoimmunity and after some infections, Igs can
form circulating immune complexes that are deposited in
glomeruli, including IgA1 complexes in IgA nephropathy.
Alternately, in situ immune complexes form when anti-
bodies bind to antigens that are intrinsic to the glomerulus
or antigens that have been “planted” in the glomerulus. In
malignant conditions, such as multiple myeloma, single
clones of antibodies or light chains can be deposited in
glomeruli, while cryoglobulins (both IgM and IgG) lodge
in glomeruli in infectious, autoimmune, and malignant
diseases. Antibody production by the B cell/plasma cell
lineage is not the only possible role for B cells. In GN, B cell
aggregates in the interstitium could secrete cytokines and,
especially in established autoimmune responses, autoreactive
B cells may assist in antigen recognition by concentrating
autoantigenic peptides derived from autoantigens internalized
by their own cognate B cell receptor (64).
Immunoregulatory Immune Cells: T Cells, Macrophages,
and More
A variety of immune cells, including some CD41 and
CD81 T cells, macrophages, and DCs, dampen both sys-
temic immunity and local inflammation. The best de-
scribed subset is the CD41CD251foxp31 regulatory T
cell (Treg) that maintains tolerance and dampens inflam-
mation via soluble mediators and cell-cell contact. Both
endogenous and exogenous Tregs regulate experimental
glomerular disease (65,66) by inhibiting systemic immu-
nity, and probably also via local effects. Studies using reg-
ulatory CD81 T cells in experimental membranous
nephropathy illustrate their anti-inflammatory role (67),
with transfer of regulatory macrophages and DCs also lim-
iting experimental glomerular disease (68,69), including
progressive and chronic fibrotic injury. Given the potential
plasticity of many of these cells, future cell therapy trials
would need to consider the question of the stability of
transferred immune cells.
Innate Lymphoid Cells and Other T Lymphocytes:
Unconventional and Interesting
Other potentially important leukocytes include natural
killer (NK) cells, other innate lymphoid cells, and un-
conventional T cells: gd T cells, NK T cells, MR1-restricted
mucosal associated invariant T cells, and MHC class
1b–reactive T cells (70). Some unconventional T cells inter-
act with MHC class I/II-peptide complexes, but in a manner
distinct to that of classical T cells, while others recognize
glycolipids, vitamin B metabolites, and modified peptides.
Unlike conventional ab cells, whose T cell receptors un-
dergo somatic recombination, unconventional T cells have
relatively restricted patterns of antigen recognition (70).
Little is known about these cells in glomerular disease.
1672 Clinical Journal of the American Society of Nephrology
However, for example, NK cells and their ligands are pre-
sent in the kidney in human lupus nephritis (71). Experi-
mentally, deficiency of invariant natural killer T cells
exacerbated GN (72,73), while proinflammatory gd T cells
are present in kidneys after passive antibody transfer (74).
Some of these subsets are particularly relevant to mucosal
immunity, with clear potential relevance not only for IgA
nephropathy but also for other forms of glomerular disease.
Intrinsic Glomerular Cells and Leukocytes Interact in
Glomerular Disease
Interactions between leukocytes and resident glomerular
cells in immune glomerular disease are dynamic and sub-
stantial, going beyond the simplistic paradigm of glomerular
cells merely being the target of leukocyte-mediated injury.
Cytokines, chemokines, and costimulatory molecules from
intrinsic glomerular cells activate (and regulate) leukocytes
locally, and it is possible that effector T cells recognize
antigenic peptides displayed by intrinsic glomerular cells.
There are many examples of these interactions: chemokines
derived from toll-like receptor 4–expressing glomerular
endothelial cells recruit neutrophils in experimental
ANCA-associated GN (75), while cytokines and costimula-
tory molecules expressed by intrinsic renal cells participate
in local activation of effector CD41 T cells in experimental
GN (76,77).
Summary and Conclusions
The glomerulus is vulnerable to injury from inflamma-
tory, metabolic, and other disease processes, which not
uncommonly involve the “dark side” of innate and adap-
tive immunity. In recent years we have made great prog-
ress in understanding glomerular disease. We now better
understand systemic disease processes that direct glomer-
ular injury; the local cellular, humoral, metabolic, genetic,
and molecular responses that induce injury; the detail of
the pathologic appearances of human glomerular disease;
and some of the prognostic indicators. This knowledge
allows us to take a more integrated view of glomerular
disease. Key challenges in the future include not only
identifying common local pathways for intervention and
regulating systemic processes that mediate glomerular
disease, but also developing more specific and less toxic
therapies specific to individual glomerular diseases, and
subsets of patients (or even individual patients) with a
specific disease.
Acknowledgments
Ms. Kim O’Sullivan is thanked for the photomicrographs in
Figure 3. We apologize to the many excellent researchers whose
work we have not discussed and cited.
Research performed by A.R.K in glomerular disease is funded by
Project Grants from the National Health and Medical Research
Council of Australia (NHMRC) (nos. 1048575, 1045065, 1046585,
1064112, and 1084869). H.L.H. is funded by an NHMRC Post-
graduate Scholarship (no. 1075304).
Disclosures
A.R.K. has been a member of an advisory board for Roche
Products, Australia. No Roche studies (that the authors are aware
of) are reported or discussed in the manuscript. H.L.H. declares no
conflicts of interest.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Glomerular Diseases

All Things Complement

Joshua M. Thurman* and Carla M. Nester†‡

Abstract
The complement (C) cascade is an ancient system of proteins whose primary role is to initiate and modulate
immune responses. During C activation, circulating proteins are cleaved and nascent cleavage fragments
participate in a broad range of downstream innate and adaptive immune functions. Although the majority of these
functions are either homeostatic or protective, a large body of experimental and clinical evidence also highlights a
*Department of
central role for the C system in the pathogenesis of many types of glomerular disease. From classic pathway Medicine, University
activation in lupus nephritis to alternative pathway dysregulation in C3 glomerulopathy, our understanding of the of Colorado School of
spectrum of C involvement in kidney disease has expanded greatly in recent years. However, the characteristics Medicine, Anschutz
that make the glomerulus so uniquely susceptible to C-mediated injury are not fully understood, and this remains Medical Campus,
Aurora, Colorado; and
an area of ongoing investigation. Several C inhibitors have been approved for clinical use, and additional C †
Stead Family
inhibitory drugs are in development. The use of these drugs in patients with kidney disease will expand our Department of
understanding of the benefits and limitations of C inhibition. Pediatrics and
‡
Clin J Am Soc Nephrol 11: 1856–1866, 2016. doi: 10.2215/CJN.01710216 Department of
Internal Medicine,
University of Iowa,
Iowa City, Iowa
Introduction pathways (Figure 1) (3). Multiple different molecules
The complement (C) system is a complex group of inter- can trigger C activation. IgG (particularly the IgG3 Correspondence: Dr.
acting proteins that play a critical role in host immune and IgG1 isotypes), IgM, C-reactive protein, and serum Joshua M. Thurman,
surveillance and defense. C activation results in the gener- Division of Renal
amyloid P activate the CP. The mannose binding lectin
Diseases and
ation of multiple protein fragments that mediate biologic pathway is activated when circulating lectin binds to Hypertension, 1775
processes integral to both health and disease (Table 1) (1). sugar moieties on pathogens. C4b is deposited on tissues Aurora Court, M20-
In addition to the well described homeostatic functions of after activation of the CP or mannose binding lectin 3103, Aurora, CO
C, a pathologic role for C activation has emerged for a pathway, and it composes part of the CP C3-convertase 80045. Email: Joshua.
number of the glomerular diseases (Table 2). In many of Thurman@ucdenver.
(Figure 2). edu
these diseases, immune-complexes (ICs) trigger activation The CP is not simply a downstream effector of
of the classic pathway (CP). Other diseases, such as atyp- tissue injury in IC-mediated diseases, but it also
ical hemolytic uremic syndrome (aHUS) and C3 glomer- functions to prevent the development of autoimmu-
ulopathy (C3G), are associated with defective regulation nity. In fact, congenital deficiencies of the early CP
and/or enhanced activation of the alternative pathway proteins (C1q, C2, and C4) are among the strongest
(AP). Additional details regarding the role of C in mem- risk factors for developing lupus (4). This association
branous nephropathy, antiglomerular basement mem- may be due to impaired phagocytosis of apoptotic
brane (GBM) disease, and antineutrophil cytoplasmic cells and nuclear debris in the absence of the CP
antibody (ANCA)–associated vasculitis were dis- (Table 1) (5). The risk of developing autoimmunity
cussed in a recent Clinical Journal of the American Society to these nuclear antigens increases because of their
of Nephrology educational review (2). Other glomerular prolonged presence outside of cells (5). Opsonization of
diseases in which C activation likely plays a critical role antigens with C also lowers the activation threshold
will be reviewed in subsequent articles in this series. of B cells, and C deficiencies may hinder the elimina-
Although the mechanisms of C activation and C-mediated tion of autoreactive B cells (5). Thus, the CP reduces
injury may vary, the critical role of the C system in the risk of autoimmunity, but also mediates tissue
glomerular diseases of such diverse etiologies indicates injury caused by autoantibodies.
a unique susceptibility of the kidney to the injurious Some molecules, such as IgA, can directly activate
effects of C. In this review we present an overview of the the AP (6), but this pathway does not require specific
C cascade and evidence that C plays a role in glomerular protein–protein interactions and is constitutively ac-
disease, and we discuss recent advances in C biology tive as a result of spontaneous hydrolysis of C3. Ad-
that inform the treatment of glomerular disease. ditional details of the molecular interactions involved
in C activation are described in an excellent recent
review (2).
Overview of the C Cascade Activation through any of the C pathways leads to
C Activation Pathways the proteolytic cleavage and activation of C3 (3). Ac-
The C cascade is comprised of .30 circulating pro- tivated C3, referred to as C3b, is central to all three
teins that are activated through one of three initiation pathways. C3b contains a thioester bond that can

1856 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 October, 2016
Clin J Am Soc Nephrol 11: 1856–1866, October, 2016
Table 1. Functions of the C cascade
Adaptive Functions of C
Opsonize target cells (pathogens and injured cells)
Trigger vascular changes and inflammatory cell
chemotaxis
Lyse pathogens
Provide costimulation and proliferation signals for
immune cells
Remove immune-complexes and cellular debris
Maladaptive Functions of C
Promote tissue inflammation
Directly cause injury to host cells
Mediate cancer cell immune-evasion
form covalent amide or ester bonds with amino and hydroxyl
groups on cell surfaces. C3b is also a key component of the
AP C3-convertase, an enzyme that cleaves additional C3
(Figures 1 and 2). As a result, C activation through any of
the initiation pathways rapidly self-amplifies as C3b fosters
the generation of yet more C3b, and millions of the mole-
cules can be formed and deposited on target surfaces
within minutes (7). The addition of a C3b molecule to
the C3-convertases generates C5-convertases, enzymes that
cleave the protein C5.
C activation causes kidney injury through direct effects
on renal cells and through interactions with cells of the
innate and adaptive immune systems. Receptors for C3b
are expressed on erythrocytes, leukocytes, and nonhema-
tologic cells, and engagement of these receptors mediates
cell activation and phagocytosis (2). Small soluble peptides
referred to as anaphylotoxins (C3a and C5a) are also gen-
erated during C activation. C3a and C5a receptors are
expressed on leukocytes, endothelial cells, mesangial cells,
and tubular epithelial cells (2). These fragments trigger
systemic inflammatory responses through their receptors,
including vascular changes and the chemotaxis of immune
cells. C3a directly induces mesangial cells to proliferate
and secrete extracellular matrix (8), and it causes tubular
epithelial cells to produce proinflammatory chemokines
(9). Finally, full activation of the C pathways generates
C5b-9 (the membrane attack complex) a multimeric struc-
ture that forms pores in the membranes of target cells,
causing cell activation and lysis. C5b-9 causes endothelial
cells to release mitogens that promote mesangial prolifer-
ation (10). When C5b-9 is generated directly on the surface
of mesangial cells it triggers production of prostaglandins,
cytokines, and reactive oxygen species (11,12). Formation
of C5b-9 on podocytes is an important cause of glomerular
injury in membranous disease (13).
C Regulatory Proteins
To protect host cells from uncontrolled C activation,
several C regulatory proteins are expressed on the surface
of cells and also circulate in plasma (14). These proteins
inactivate the C convertases by dissociating them or by
cleaving C3b to form iC3b (Figure 2; see also Mathern
and Heeger [2]). Further degradation of iC3b yields C3d,
which remains covalently attached to target surfaces. Like
C3b, the C4b protein has an internal thioester bond that
Complement and Glomerulonephritis, Thurman et al. 1857
can form covalent bonds with tissue surfaces (15). Inacti-
vation (cleavage) of C4b by regulatory proteins yields C4d,
which also remains attached to tissues (Figure 2).
Factor H is a soluble regulator of the AP that is par-
ticularly important for protecting the kidney. Although it
is only one of several C regulators that function in the glo-
merulus, a large body of evidence indicates that defects in
the function of factor H are sufficient to cause glomerular
injury (16). Factor H is comprised of 20 repeating struc-
tural domains (short consensus repeats, or SCRs). The C
regulatory function of factor H is performed by the first
four SCRs, whereas several other regions of the protein
mediate binding of the protein to tissue surfaces. The
carboxy terminus of factor H (SCRs 19–20) binds to C3b
and glycosaminoglycans (17) and confers the ability to bind
and protect endothelial cells. Five C factor H–related pro-
teins (CFHRs) arose through gene reduplication and share
structural similarities to factor H (18). These proteins each
contain the SCR 19–20 binding domain, but they do not
contain the SCR 1–4 C regulatory domain. The function of
the CFHRs is controversial. Experiments have shown that
they can regulate C activation in some settings, but the
binding domains may also competitively inhibit factor H
from functioning on some surfaces (14,18).
The degree to which C is activated in a given tissue is
a dynamic process and depends on a number of factors.
Cell injury may reduce the surface expression of regulatory
proteins (19) and stimulate local production of C proteins
by renal cells (20). Both of these cellular responses promote
C activation. Other biologic systems also interact with the
C cascade. Notable examples include the activation of C5
by thrombin (21), and local impairment of factor H by the
protein annexin A2 (22).
Evidence That the C System is Involved in Glomerular
Diseases
As early as the 1960s it was understood that the C system
was involved in antibody-mediated glomerular injury
(23), and by the 1970s C proteins were detected in renal
biopsy specimens from patients with GN (24). Experi-
mental evidence in both animal models and in patients
links the C system with a large number of glomerular diseases
(Table 2).
Clinical Biomarkers of C Activation
Tissue Staining. Activation of the C cascade generates
several soluble and tissue bound protein fragments, and
these fragments can be employed as biomarkers of tissue
inflammation. Kidney biopsies are routinely immunostained
for deposits of C3 and C4 fragments. Tissue staining for
C3 is usually performed using an antibody to C3c, which
detects tissue-bound C3b and iC3b (Figure 2). Because C3b
is deposited on target tissues by all three activation path-
ways, detection of these fragments is interpreted as a catch-
all marker of C activation. The C4d fragment remains
attached to surfaces after C4 inactivation. Detection of C4d
is now routinely used as a marker of antibody-mediated
rejection, but is also an indicator of active disease in
IC-mediated GN (25). Biopsies are also sometimes
immunostained for C1q, which is another marker of CP
activation. In IC-mediated GN, Ig, C3 fragments, and C4
1858 Clinical Journal of the American Society of Nephrology

Table 2. Evidence that the C system is involved in glomerular diseases

Clinical
Plasma Autoantibodies C Gene Variants
C Protein Use of
Disease Complement to Complement Associated with
Depositsa Complement
Protein Level Proteins Disease
Inhibitors

Atypical hemolytic C3 and C5b-9 ↓C3 Factor H Factor H ✓

uremic syndrome deposits ↑C5a, ↑sC5b-9 Factor I
have been C3
reported (94) Factor B
C1q, C4d, CD46
C5b-9, MBL, CHFR1
and IgM CFHR3
reported in CFHR5
some cases Thrombomodulin
(62)
C3 Glomerulopathy Dominant C3 ↓C3, ↓factor B, C3Nefs (.75%) Factor H ✓
two orders of ↓properdin, C3b Factor I
magnitude ↓C5, ↓C7 Factor H C3
greater than ↑Ba, ↑Bb, Factor B
C8
that for Ig ↑C3d, ↑C5a, Factor B
↑sC5b-9 CHFR1
CFHR2
CFHR3
CFHR5
CR1
Lupus nephritis C3, C4, C1q ↓C3, ↓C4, C1q, C3 C1q, C1r/s, ✓
↓C1q C2, C4
Membranoproliferative C3, C4, IgG, ↓C3, ↓C4 C3Nefs Factor H
GN IgM Factor I
CD46
Catastrophic ↓C3, ↓C4 ✓
antiphospholipid ↑C3a, ↑C4a
antibody syndrome
IgA nephropathy C3, properdin, ↑C3a, ↑C3d Factor H ✓
6C4, 6MBL CFHR1
CFHR3
ANCA associated C3 and Ig can ↑C3a, ↑C5a, ✓
vasculitis be seen (95) ↑sC5b-9, ↑Bb
Postinfectious GN C3, 6C4 ↓C3, ↓C5,
↓properdin
Tubulointerstitial C3 on brush Urine iC3b, Bb,
diseases border C5b-9
a
Deposits seen in renal biopsy tissue. CFHR, complement factor H related proteins. Check marks represent diseases where patients
treated with C inhibitors have been reported.

fragments generally colocalize (26). The detection of C3
in the absence of Ig or C4 is a sign of an AP-mediated
process (Figure 1), and is the basis of the diagnosis of
C3G (27).
C Protein Levels. Decreased levels of plasma C3 and C4
have long been associated with active inflammation in
patients with autoimmune and systemic inflammatory di-
seases (28). The levels of these proteins are determined by
their rate of synthesis (primarily in the liver, but also by
renal cells) and the rate of consumption. They are sensitive
indicators of activity in some diseases, such as diffuse pro-
liferative lupus nephritis (28). Conditions in which hepatic
production of C proteins is altered can confound the inter-
pretation of low C levels. Production of the C proteins in-
creases in pregnancy, for example, whereas it decreases
in patients with cirrhosis (28). Furthermore, the levels
remain normal in many C-mediated diseases. This may
be because local C activation can cause significant tissue
injury without depleting the plasma pool of C3, or that
activation is driven by locally produced C3 (20). In con-
trast, it was reported that C3 levels remained depressed
in a patient with membranoproliferative GN who under-
went bilateral nephrectomy, demonstrating that the con-
sumption of C3 can occur in the plasma or tissues outside
of the kidneys (29).
Several clinical studies have measured C activation frag-
ments in plasma and urine as biomarkers of active kidney
disease. C activation fragments may be useful for predict-
ing disease flares in patients with lupus, particularly if the
level of intact C3 is confounded by pregnancy or other
clinical conditions (30). Urinary C3d and C5b-9 are bio-
markers of immunologic glomerular injury in patients
Clin J Am Soc Nephrol 11: 1856–1866, October, 2016 Complement and Glomerulonephritis, Thurman et al. 1859

Figure 1. | Overview of the C cascade. The C cascade can be activated through the classic pathway, the alternative pathway, and the mannose
binding lectin pathway. Activation through each of these pathways generates C3-convertases (shown in blue font), enzyme complexes that cleave C3
and generate C3b. Further amplification of C activation through the alternative pathway generates additional C3b. C3b combines with the
C3-convertases to create C5-convertases (shown in green font), enzyme complexes that cleave C5. Full activation of the C cascade generates several
proinflammatory fragments: C3a, C3b, C5a, and C5b-9 (shown in red font). Although the C system is activated in most forms of glomerular disease,
the mechanisms of activation and the pathways involved are distinct. Some of the diseases in which each pathway is involved are listed.

with membranous nephropathy (31). Given that the drug
eculizumab blocks the cleavage of C5, it is logical that de-
tection of sC5b-9 would be a useful guide to eculizumab
therapy, but local C activation may not always cause de-
tectable increases in the systemic levels of sC5b-9 (32). In
addition, the C proteins are labile, and measurement of the
activation fragments is sensitive to sample handling. These is-
sues must be considered when interpreting biomarker findings.
Animal Models
Both naturally occurring and laboratory-generated ani-
mal models have been instrumental in our understanding

Figure 2. | Fate C3 and C4 fragments on cell surfaces. The cleavage of C3 and C4 allows the covalent attachment to cell and tissue surfaces of
C3b and C4b, respectively. Deposited C3b composes part of the alternative pathway C3-convertase. This complex is stabilized by properdin
and generates additional C3b unless the convertase decays or C3b is inactivated (cleaved) by the plasma protease factor I, generating iC3b. The
decay of the convertase is accelerated by some regulatory proteins (not shown in this figure). To inactivate C3b, factor I requires cofactor
proteins. Membrane cofactor protein and C receptor-1 (CR1) are cell surface cofactors, and factor H is a soluble cofactor. CR1 also serves as a
cofactor for cleavage of iC3b to C3dg. Deposited C4b composes part of the classic pathway C3-convertase and generates C3b unless the
convertase decays or C4b is inactivated (cleaved) by factor I. Membrane cofactor protein and CR1 are cell surface cofactors for the cleavage of
C4b, and C4 binding protein (C4bp) is a soluble cofactor for this process.
1860 Clinical Journal of the American Society of Nephrology
of the role of C in the glomerular diseases. GN in a strain of
Norwegian Yorkshire pigs was caused by congenital de-
ficiency of factor H (33). Mouse models of C deficiency
have defined a role for C in both IC-mediated glomerular
diseases (34) and in glomerular injury in the absence of Ig
(35). More recently, animal models led to the discovery
that C activation contributes to diseases such as ANCA-
associated vasculitis (36) and FSGS (37), diseases not pre-
viously considered to be C-mediated. Animal models have
also been instrumental in demonstrating the efficacy of C
therapeutics before clinical trials (38,39).
There are several differences between the mouse and
human C systems that limit the applicability of mouse
models to human disease. Although the general organiza-
tion of the cascade is the same, structural differences
between mouse and human proteins prevent some human
therapeutics from working in mice. Eculizumab, for exam-
ple, does not inhibit mouse C5 (40), and compstatin (a
small molecule inhibitor of human C3) does not inhibit
mouse C3 (41). Mouse C also has lower lytic activity
than that of other species, possibly because murine C4
does not generate an effective CP C5-convertase (42). The
role of C5b-9 may therefore be underrepresented in
murine models of IC-mediated diseases. The study of
IC-mediated glomerular disease is also complicated by
differences between rodents and humans in the mecha-
nisms of IC clearance. In humans, C receptor-1 (CR1) on
erythrocytes binds to C3b containing ICs and transports
them to the liver. In rodents, on the other hand, ICs are
transported to the liver by platelets, and adherence of the
ICs is mediated by factor H on the platelet surface instead
of CR1 (43).
Molecular Studies
A large number of different molecular abnormalities are
associated with C dysregulation within the glomerulus
(44–46). Rare variants in the genes for factor H, C3, factor
B, factor I, membrane cofactor protein (MCP, or CD46),
and thrombomodulin have been identified in patients
with aHUS (46,47). Studies have also revealed that rare
variants and hybrid forms of the CFHR genes are associ-
ated with aHUS (18,48–52), and deletion of CFHR1–3 is
associated with the development of autoantibodies to fac-
tor H, an abnormality that is found in approximately 10%
of aHUS patients (53).
C3 nephritic factor (an autoantibody against the AP C3-
convertase) is the most common C abnormality found in
patients with C3G (54). A number of genetic impairments
in AP regulation have also been identified in patients with
this disease, including variants in the genes for factor H,
factor B, C3, and the CFHRs (27,44,45,55). Experimental
analyses of the disease-associated CFHR variants suggest
that they impair the ability of factor H to control AP acti-
vation on tissue surfaces (18,56).
All of these molecular defects are associated with un-
controlled activation of the AP, and in some cases a causative
relationship between the genetic abnormality and functional
C dysregulation has been confirmed experimentally (57).
From a diagnostic perspective, however, the large number
of possible genetic variants and autoantibodies makes the
analysis of individual patients complicated. Nevertheless,
testing for genetic variants and autoantibodies can help
establish the diagnosis, and identifying autoimmune
causes of C dysregulation can guide immunosuppressive
treatment (58).
Mechanisms of C Activation in Glomerular Diseases
Pathologic C activation within host tissues involves: (1)
molecular events that promote C activation (e.g., IC depo-
sition), and/or (2) local impairments in the regulation of C
activation. These mechanisms are not mutually exclusive,
as ICs cause CP activation but can also create a micro-
environment from which C regulators are excluded (59).
All of the resident renal cells express C regulatory proteins
(16). Yet, the frequent involvement of the C system in renal
disease demonstrates that the regulatory capacity of these
proteins can be overwhelmed or subverted.
Vasculature and Glomerular Endothelial Cells
Subendothelial deposition of ICs is common in lupus
nephritis and membranoproliferative GN (Figure 3). IgG
and IgM containing ICs activate the CP, causing direct
injury and inflammation of nearby tissues. Animal models
also demonstrate that injury of the glomerulus in IC-me-
diated diseases involves amplification through the AP
(34,60). In aHUS, the AP may be activated directly on
glomerular endothelial cells due to impaired regulation.
Even in patients with a genetic predisposition to aHUS,
however, the majority of flares occur after a systemic ill-
ness or stressor (61). A recent study reported that C1q and
C4d can be seen in the vasculature of most patients with
aHUS (62). It is possible that illness or endothelial damage
triggers C activation through the CP, but that uncon-
trolled AP activation perpetuates microvascular injury in
susceptible patients. The AP is also critical for the devel-
opment of ANCA vasculitis (36), although the exact mech-
anism and location of AP activation are not yet known.
GBM
In contrast to cells, basement membranes do not in-
trinsically express regulatory proteins and are dependent
on circulating factor H to control AP activation (2). Genetic
defects (61), autoantibodies (53), or other proteins can in-
terfere with the function of factor H (22). Factor H defi-
ciency is associated with C activation in the fluid phase
and directly on the GBM (63), mechanisms that are be-
lieved to cause C3G (Figure 4). Dysregulation of the AP
results in C3 deposits in the relative absence of Ig, and this
is the diagnostic basis of C3G (27). Dense deposit disease
is a subtype of C3G characterized by detection of electron
dense deposits in the GBM by electron microscopy (27).
The composition of these deposits is not known, but sim-
ilar deposits are seen in factor H deficient mice (35). Anti-
bodies to the noncollagenous-1 domain of type 4 collagen
directly activate C on the GBM (2). Activation is initiated
through the CP in that setting, but detection of AP pro-
teins suggests that this pathway is also involved (2).
Podocytes
ICs are often seen in the subepithelial space of pa-
tients with membranous disease. IgG binds to the M-type
Clin J Am Soc Nephrol 11: 1856–1866, October, 2016 Complement and Glomerulonephritis, Thurman et al. 1861

Figure 3. | Conditions within the kidney that are conducive to C activation. The C cascade is activated by distinct mechanisms at various
ultrastructural locations within the kidney. Immune-complexes can deposit in the mesangium and at different locations within the glomerular
capillary wall. In some diseases, autoantibodies bind to specific renal antigens. Other conditions in the kidney that favor C activation are
increased concentrations of C proteins in the efferent vessels, low pH, increased local concentrations of C proteins due to production by tubular
epithelial cells, and high concentrations of ammonia which can activate the alternative pathway. The glomerular basement membrane does not
express C regulatory proteins, although factor H controls alternative pathway activation on the glomerular basement membrane. The apical
surface of tubular epithelial cells also does not express C regulatory proteins, and alternative pathway proteins may be activated at this location
in proteinuric conditions. EC, endothelial cell; PO, podocyte; fB, factor B; fD, factor D.

phospholipase A2 receptor on podocytes in some patients
(64), and other podocyte antigens have also been identified
(65). Podocytes express CR1, which can regulate the CP and
AP, but CR1 is cleaved from the surface of the cells in
patients with lupus nephritis (66). The loss of CR1 may
permit C activation at this location, or it may be a con-
sequence of C5b-9 formation (66).
Mesangium
ICs deposit in the mesangium in several different types
of GN, including lupus nephritis, causing C activation. Pa-
tients with C3G can also present with C3 deposits in the
mesangium (55), indicating that factor H is functionally
important for controlling AP activation at this location
even though mesangial cells express cell surface C regula-
tors (16). In IgA nephropathy ICs containing IgA1 deposit
in the mesangium, similar to other IC-mediated glomeru-
lar diseases (67). Not surprisingly, there is extensive clin-
ical evidence of glomerular C activation in patients with
this disease (68). Unbiased genome wide association stud-
ies have also identified variants in CFH and the CFHRs
that strongly associate with the risk of developing IgA
nephropathy (69,70). Thus, the disease may be caused by
the formation of IgA1 containing ICs, but injury of the glo-
merulus may also be determined by an individual’s ability
to regulate amplification through the AP.
Tubulointerstitium
There is minimal expression of the C regulatory proteins
on the apical surface of tubular epithelial cells (16). Ordinarily
this surface does not come in contact with C proteins,
but the AP may cause tubulointerstitial injury in pa-
tients with proteinuric kidney diseases due to free pas-
sage of C proteins into the tubules (71). Tubular
epithelial cells also synthesize C3, and locally produced
C3 may be an important cause of acute and chronic
tubulointerstitial injury (20,72). Other conditions in
the tubulointerstitium also favor AP activation. Ammo-
nia can form an amide linkage with C3 and activate the
AP. In settings of reduced nephron mass, the amount
of ammonia produced by each nephron increases to
maintain acid-base balance, and this adaptation may
drive progressive tubulointerstitial inflammation and
damage (73).
The Unique Susceptibility of the Glomerulus to
C-Mediated Injury
In spite of intensive study, it still is not known why the
glomerulus is so uniquely vulnerable to C-mediated injury.
Factor H circulates in plasma and should control AP activa-
tion throughout the body. Similarly, MCP is expressed on
endothelial cells and other cells throughout the body. Why,
then, do genetic defects in these proteins primarily cause
inflammation within the glomerulus? Other attributes of the
microenvironment within the kidney (concentrated plasma
proteins, local production of C proteins, and pH) likely
contribute to C activation (Figure 3). Nevertheless, further
study is needed in order to fully understand all of the mech-
anisms that cause pathologic C activation in the kidney.
1862 Clinical Journal of the American Society of Nephrology

Figure 4. | Molecular defects in C regulation associated with C3 glomerulopathy and atypical hemolytic uremic syndrome. In health, factor H
controls C activation in the fluid phase and on the glomerular basement membrane. Factor H and cell surface C regulatory proteins (MCP,
membrane cofactor protein; DAF, decay accelerating factor; THBD, thrombomodulin) control C activation on glomerular endothelial
cells. In patients with C3 glomerulopathy, congenital or acquired defects probably cause dysregulated C activation in the fluid phase and/
or on the glomerular basement membrane. In atypical hemolytic uremic syndrome, congenital or acquired defects probably cause
dysregulated C activation on glomerular endothelial cells. Defects in C regulation in the different conditions are indicated with red boxes
or red font.

Why Do Some Defects in AP Regulation Cause C3G
and Some Cause aHUS?
Impaired AP regulation by factor H is strongly associ-
ated with both aHUS (61,74) and C3G (27,45,55), yet these
diseases are clinically and pathologically distinct. The ma-
jority of the genetic variants in factor H associated with
aHUS affect the carboxy terminus of the protein (61,74). As
the carboxy terminus facilitates binding to cell surfaces,
dysfunction in this region may limit the ability of factor
H to protect glomerular endothelial cells from the AP
(Figure 4). Autoantibodies to factor H also predominantly
affect this region of the protein (75). The defects in MCP,
factor I, C3, factor B, and thrombodmodulin that are asso-
ciated with aHUS are also believed to impair regulation of
the AP on the endothelial cell surface (61,74).
The autoimmune and genetic defects associated with
C3G, on the other hand, tend to affect C regulation by the
protein (Figure 4). The most common C defect in C3G is
the presence of C3 nephritic factor, an autoantibody that
protects the AP C3-convertase from inactivation by factor
H (45,54). Genetic variants in C3 and factor B that confer
resistance to inactivation of the C3-convertase by factor
H (and hence, overactivity of the convertase) have
also been found in patients with C3G (57). A variety of
different histologic patterns and ultrastructural changes
are observed in patients with C3G (45,55), but it remains
unclear whether these are related to the associated C
abnormalities.
The factor H defects that cause aHUS and C3G have been
recapitulated in mice. Homozygous factor H deficiency
caused C3G-like disease (35), whereas a partial deficiency
in the carboxy-terminus of factor H was associated with
aHUS-like disease (76). This paradigm does not apply to
all patients, however, and some of the genetic variants
associated with aHUS have also been identified in patients
with C3G (45). Thus, more work is needed to identify
the additional environmental, genetic, and epigenetic fac-
tors that influence the development and course of these
diseases.
C As a Therapeutic Target
In aHUS and C3G, C activation is the primary insult that
causes glomerular injury. Consequently, agents that pre-
vent C activation will block the underlying process that
causes these diseases. For antibody-mediated diseases, C
inhibition may reduce inflammatory effects of ICs depos-
ited within the glomerulus. In addition, C blockade may
reduce T cell activation at the antigen presenting cell–T cell
interface as well as the B cell response to antigens, thereby
reducing the magnitude of the adaptive response to anti-
gens (2).
Eculizumab is a monoclonal antibody that blocks the
cleavage of C5, preventing formation of C5a and C5b-9
(40). In phase 2 clinical trials, treatment with eculizumab
led to a rapid increase in the platelet count and steady
Clin J Am Soc Nephrol 11: 1856–1866, October, 2016
improvement in renal function (77,78), and it has been
approved for treatment of aHUS. These studies have dem-
onstrated the safety and efficacy of C inhibition in patients
with glomerular disease, and that inhibition can be main-
tained chronically.
Data suggest that eculizumab is superior to plasma
exchange/infusion for the treatment of aHUS, although it is
not effective in all patients (77,78). The response to treat-
ment does not seem to depend upon identification of a ge-
netic defect in a C-related gene (77,78), although a small
subset of patients are resistant to the drug due to a genetic
variant in the C5 gene (79). Earlier treatment with eculizumab
is associated with better renal outcomes (80), and pa-
tients with worse renal function at presentation are less
likely to achieve complete remission of thrombotic mi-
croangiopathy-related symptoms (77). This may be due
to the presence of irreversible renal damage at the time
of treatment. It is also possible that C3a and C3b/iC3b/
C3d contribute to the pathogenesis of renal injury
(9,81,82), and drugs that target the C system at the level
of C3 or higher may be advantageous in some patients.
Hemolytic uremic syndrome can also be caused by a va-
riety of different systemic stressors, including drugs, au-
toimmune disease, hypertension, infections, cancer, and
pregnancy (83). It is not yet clear whether eculizumab is
beneficial in these settings, although there is evidence that
pregnancy-associated hemolytic uremic syndrome is usu-
ally C-related (84).
Eculizumab has also been used off label for several other
renal diseases, including C3G (85), catastrophic antiphos-
pholipid antibody syndrome (86), lupus nephritis (87),
and IgA nephropathy (88). Eculizumab only appears to
be beneficial in a subset of patients with C3G. Earlier
treatment is associated with a better response, so some
of the patients may have already had irreversible renal
injury by the time they were treated (85). Different under-
lying C defects may lead to C3 activation in the fluid
phase or directly on the GBM (Figure 4), and these differ-
ences could affect how important C3 fragments are in the
disease. Patients with elevated levels of C5b-9 (i.e., evi-
dence of active terminal C activation) may be those
most likely to benefit from eculizumab (85). It is not clear
at this time whether the level of C blockade is the key to
successful treatment, or whether earlier intervention
would suffice.
Many other C inhibitors are currently in development
(89). Monoclonal antibodies that target other C proteins
have been tested, including antibodies to C1s, factor D,
factor B, properdin, C3b, and the mannose associated ser-
ine proteases. Small molecules have been developed to
block signaling of C3a and C5a at their receptors and
can be administered subcutaneously or orally. C5a
blockade was protective in a murine model of ANCA
vasculitis (90), and the C5a receptor antagonist used in
that study is currently being tested in a clinical trial of
patients with ANCA vasculitis (ClinicalTrials.gov iden-
tifier: NCT02222155). Engineered proteins that specifi-
cally block C activation at sites of tissue injury and
small interfering RNA agents that knock-down the pro-
duction of C proteins are also in development. Each of
the different therapeutic strategies has advantages as
Complement and Glomerulonephritis, Thurman et al. 1863
well as limitations, and the utility of these agents relative
to eculizumab are discussed in a recent review (91).
Because the C system is an important part of the immune
system, the major risk of all therapeutic C inhibitors is
likely to be that of infection. Deficiency or blockade of the
terminal C proteins is primarily associated with meningo-
coccal infections (92). Patients treated with eculizumab
should be immunized against Neisseria meningitides and/
or prophylactically treated with antibiotics. In spite of im-
munization, approximately 1% of treated patients per year
develop Neisserial infections (93). It has been suggested
that antibodies to the organism are less effective in the
setting of C inhibition. Drugs that block the C system
higher in the cascade might also increase the risk of infection
with encapsulated bacteria (92).
Conclusions and Future Directions
It has been known for .50 years that the C system plays
an important role in IC-mediated glomerular injury, yet
the field of C biology continues to rapidly change as new
discoveries are made. Although aHUS and C3G are rare
diseases, they are extreme examples of AP dysregulation
that provide crucial insight into the biology of the AP.
Careful examination of patients with these diseases has
resulted in major advances in our understanding of C
activation and C regulation within the glomerulus. These
advances were made possible by multicenter clinical trials
as well as multinational disease registries. The knowledge
gained by these studies has already affected the care of
these two diseases, and it has also informed our under-
standing of more common glomerular diseases. The con-
nection between CFHR1–3 deletion and IgA nephropathy
was discovered by a genome wide association study (69),
for example, but our understanding of the function of the
CFHRs is due to careful study of patients with aHUS
and C3G.
There is still a great deal to be learned regarding the
mechanisms by which the C system is activated within the
glomerulus, the roles of the different C activation frag-
ments in glomerular injury, and the optimal use of C
inhibitory drugs in patients with kidney disease. New
molecular causes of aHUS and C3G will undoubtedly be
discovered that will improve our understanding of these
diseases. Genetic studies of patients with other glomerular
diseases will also reveal disease-specific as well as gener-
alized mechanisms that increase or decrease the risk of
glomerular disease. Given the complexity of the C system
and the large number of molecules involved in C activation
and regulation, this field may particularly benefit from
large scale genomic and proteomic studies of patients with
GN. Perhaps most importantly, as additional patients with
glomerular diseases are treated with C inhibitory drugs,
efforts must be made to gain further insights into the risks
and benefits of targeting the C cascade in this group of
diseases.
Acknowledgment
J.M.T. is supported by the National Institutes of Health grant R01
DK076690. C.M.N. is supported by the Stead Family Department of
Pediatrics, University of Iowa.
1864 Clinical Journal of the American Society of Nephrology
Disclosures
J.M.T. receives royalties from Alexion Pharmaceuticals, Inc.,
Cheshire, CT.
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cjasn.org.
 Glomerular Diseases

Defining Glomerular Disease in Mechanistic Terms:

Implementing an Integrative Biology Approach in
Nephrology
Laura H. Mariani,* William F. Pendergraft III,† and Matthias Kretzler*

Abstract
*Division of
Advances in biomedical research allow for the capture of an unprecedented level of genetic, molecular, and Nephrology,
clinical information from large patient cohorts, where the quest for precision medicine can be pursued. An University of
overarching goal of precision medicine is to integrate the large–scale genetic and molecular data with deep Michigan Medical
phenotypic information to identify a new mechanistic disease classification. This classification can ideally be used Center, Ann Arbor,
Michigan; and
to meet the clinical goal of the right medication for the right patient at the right time. Glomerular disease †
Division of
presents a formidable challenge for precision medicine. Patients present with similar signs and symptoms, which Nephrology and
cross the current disease categories. The diseases are grouped by shared histopathologic features, but individual Hypertension,
patients have dramatic variability in presentation, progression, and response to therapy, reflecting the underlying Department of
biologic heterogeneity within each glomerular disease category. Despite the clinical challenge, glomerular dis- Medicine, University
of North Carolina
ease has several unique advantages to building multilayered datasets connecting genetic, molecular, and struc- Kidney Center, Chapel
tural information needed to address the goals of precision medicine in this population. Kidney biopsy tissue, Hill, North Carolina
obtained during routine clinical care, provides a direct window into the molecular mechanisms active in the
affected organ. In addition, urine is a biofluid ideally suited for repeated measurement from the diseased organ as Correspondence:
a liquid biopsy with potential to reflect the dynamic state of renal tissue. In our review, current approaches for Dr. Matthias Kretzler,
large–scale data generation and integration along the genotype-phenotype continuum in glomerular disease will Medicine/Nephrology
and Computational
be summarized. Several successful examples of this integrative biology approach within glomerular disease will be Medicine and
highlighted along with an outlook on how achieving a mechanistic disease classification could help to shape Bioinformatics,
glomerular disease research and care in the future. University of
Clin J Am Soc Nephrol 11: 2054–2060, 2016. doi: 10.2215/CJN.13651215 Michigan, 1560 MSRB
II, 1150 West Medical
Center Drive,
SPC5676, Ann Arbor,
Introduction the health providers caring for them. Patients present MI 48109-5676.
The last decade has seen rapid advances in biomedical with multiple signs and symptoms (e.g., edema, pro- Email: kretzler@
umich.edu
research, now allowing the capture of genetic, molec- teinuria, hematuria, and reduced renal function),
ular, and clinical information from large patient which cross the current disease categories. At the
cohorts. These advances motivated the strategy pro- same time, patients grouped into a common diagnosis
posed in the 2011 Institute of Medicine (IOM) report by histopathologic features often have dramatic vari-
Toward Precision Medicine: Building a Knowledge Network ability in presentation, progression, and response to
for Biomedical Research and a New Taxonomy of Disease therapy. The mainstay of therapy includes immuno-
(1). This strategy aims to use prospective cohorts of suppressive drugs, which have an unpredictable re-
patients under routine clinical care to map genetic sponse at the individual patient level and frequent
and molecular profiles with clinical disease course. toxicity (3–5). These clinical observations are a direct
The overarching goal is to use large–scale data integra- consequence of the underlying biologic heterogeneity
tion paired with deep phenotypic clinical data to within each glomerular disease currently lumped to-
establish a disease classification (i.e., a new taxonomy) gether by our descriptive classifications. The applica-
rooted in molecular causes as well as clinical presenta- tion of precision medicine to glomerular disease
tion. The approach of precision medicine, endorsed provides an opportunity to identify molecular predictors
by a major initiative from the National Institutes of of underlying disease mechanisms, response to therapy,
Health (NIH) (2), strives to achieve the goal of targeted and progression of disease. Combined with currently
treatment assignment. Precision medicine in this con- available clinical and pathologic features as well as
text takes into account individual disease presentation validating the findings in model systems, this approach
and variability in mechanistic terms to realize the con- ultimately strives to inform treatment decisions and
cept of the right medication for the right patient at the improve patient outcomes.
right time. The field of oncology is commonly looked to as a
This concept of precision nephrology certainly reso- model of success in leveraging this approach to not
nates with patients affected by glomerular disease and only better understand disease heterogeneity but also,

2054 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 November, 2016
Clin J Am Soc Nephrol 11: 2054–2060, November, 2016 Integrative Biology Approach to Glomerular Disease, Mariani et al. 2055

translate such insights into novel therapies (6). The success-
ful use of whole-exome sequencing to identify the genetic
basis for response to cytotoxic T-lymphocyte antigen 4
blockade in melanoma is one such example (7). In this land-
mark study, a discovery cohort of only 25 patients (11 who
responded to therapy and 14 who did not) was analyzed
through a bioinformatic pipeline, which included sequenc-
ing for mutational load in the tumor tissue, translating
mutations into altered peptides, and simulating MHC class
1 binding, leading to the identification of a neoepitope sig-
nature that correlated with clinical response. Furthermore,
the Cancer Genome Atlas (TCGA) aims to establish a core
resource to facilitate this approach in other cancer diagno-
ses. TCGA is funded by the National Cancer Institute and
the National Human Genome Research Institute and has
collected tumor and normal tissue from 11,000 patients
with 33 types of cancer to generate multiple large–scale
databases of DNA, RNA, and proteomics. Among other
advances, this database was used to identify biologically
based subtypes of glioblastoma, setting up improved trial
design, and enabling novel therapeutic developments (8,9).
This article will highlight definitions, important limita-
tions, and approaches to large–scale dataset generation in
glomerular disease (excluding genetics, which will be dis-
cussed separately in this series). Examples of the successful
application of an integrative approach in glomerular dis-
ease will be provided, with the anticipation that more suc-
cess stories are expected in the future. The power of
analyzing the human disease as a unified whole has inde-
pendent value, but combining with parallel work in model
systems, cell cultures, and observational and interven-
tional clinical studies allows each approach to inform the
other and expedite discovery and clinical translation.
Generation of Large-Scale Data in Glomerular
Disease
Generation of multilayered large–scale datasets for glo-
merular disease begins to address the goals of precision
medicine for nephrology (Figure 1). Not unlike oncology,
there are unique advantages of applying this approach to
kidney disease, where the biospecimens needed to gener-
ate the datasets highlighted in Figure 1 are frequently ob-
tained during routine clinical care. For example, biopsy
tissue (morphology) not only provides valuable structural
information currently in clinical use, but also offers a win-
dow into the molecular mechanisms active in the tissue of
the affected organ (transcriptome). Another advantage is
the easy access to urine, which can be tested repeatedly
and serves as a potential liquid biopsy to capture changes

Figure 1. | Large–scale dataset integration across the genotype-phenotype continuum. Integrative biology approaches can be initiated with
any dataset across the genotype-phenotype continuum and then, evaluated against the other domains to help identify novel risk factors,
pathogenic pathways, or biomarkers of progression and therapeutic response. As a result, novel mechanisms can be further investigated in
model systems to confirm findings and test therapies. Mechanistic–based patient groups can be identified and targeted for enrollment in proof of
concept clinical trials.
2056 Clinical Journal of the American Society of Nephrology
in the renal tissue with high precision (proteome and
metabolome).
Epigenetics
Epigenetics generally refers to changes in nucleic acids
of a given cell or cell type and its descendants that do not
involve alteration in the underlying DNA sequence. Epi-
genetic modifications include DNA methylation, histone
modification, and noncoding RNA (e.g., microRNAs),
which can activate or silence genes. These modifications
help to explain why a given transcription factor may have
different effects in different cell types (10). These changes
may be induced by aging and environmental exposures
and have been linked to many chronic diseases (10,11).
There are multiple methods to generate epigenetic datasets
that capture the variety of modifications, but in general,
they can be assessed in a genome-wide fashion using se-
quencing (e.g., bisulfite-seq) or microarrays. As with other
large–scale datasets, the generation method has advantages
and disadvantages, including coverage of the genome, quan-
titative information availability, and resolution (11). Of note,
epigenetic changes in the kidney vary by cell type and may
change over time, and should be accounted for in the anal-
ysis of this type of data.
Transcriptomics
Transcriptomics refers to the set of mRNA produced by
the genome in a cell or tissue. Also referred to as gene ex-
pression, it is the integrated response of a cellular system
to its environment and can vary widely by cell type, by
tissue type, by disease state, and in response to treatment.
As a result, it is far more dynamic than the epigenome.
These data can be obtained from prospectively procured
or archival tissue samples and analyzed by quantitative
PCR for transcripts of interest, microarrays that can detect
thousands of transcripts and transcript-wide sequencing
(e.g., RNA-seq). Expression profiles can be analyzed at the
specific transcript level, or prior knowledge can be used to
aggregate transcripts known to interact in functional
groups for association with disease groups or clinical dis-
ease progression (12). Of note, the mRNA levels may not
necessarily correlate with actual protein levels given the
additional regulation of protein production, modification,
and degradation. Also, mRNA analysis at the tissue level
will be affected by the cell composition. Newer techniques,
such as Drop-seq, can generate single–cell transcription
profiles (13).
Proteomics
Proteomics, including phospho- and glycoproteomics,
aims to capture the complexity of the human protein
machinery, which further exceeds that of the genome by
several orders of magnitude. Proteomics refers to the com-
plete set of proteins expressed within a cell, tissue, or
organism. Detection approaches have diversified substan-
tially ranging from antibody–based, targeted strategies
(identification of a previously known protein) to unbiased
mass spectrometry profiling (screening proteins that may
or may not have previously been identified). Microarrays
and suspension-bead assays can detect multiple proteins
in a single analysis. Detection depth is increasing steadily
to capture several thousand molecules per analysis run but
has not reached the same comprehensive level as for nu-
cleic acids. Proteomic analysis of serum, plasma, urine,
and kidney tissue is readily possible and may ultimately
prove fruitful in numerous forms of glomerular disease
with regard to unbiased biomarker discovery (14). How-
ever, each approach has its set of limitations, including
that more abundant proteins are more easily identified,
that mapping of peptides to proteins remains imperfect,
and that results may be influenced by various methods of
protein extraction and purification before analysis. That
said, proteomic analyses were critical to identifying phos-
pholipase A2 receptor (PLA2R) as the key antigen in id-
iopathic membranous nephropathy (MN) (15), and a
comparison of the proteome of urinary microvesicles
from patients with idiopathic MN, patients with FSGS,
and healthy controls revealed a potential association of
increased lysosome membrane protein-2 as a biomarker
in idiopathic MN (16).
Metabolomics
Metabolites (i.e., amino acids, bile acids, organic acids,
and sugars) are the downstream products of enzymatic
activity and considered the “currency of the cell,” reflect-
ing the metabolic state of an organism. Most currently
used biochemical markers of renal function fall into this
category (e.g., creatinine, urea, uric acid, and cystatin C).
They represent not only the active biologic processes, but
they are also thought to have possible functional roles in
health and disease (17). Metabolomics datasets can be gen-
erated using high–field nuclear magnetic resonance spec-
troscopy or mass spectrometry to separate and detect
metabolites followed by data processing and bioinformat-
ics analyses for identification (18,19). Targeted approaches
can be used to identify a smaller number of metabolites
with high accuracy. Finally, separate approaches, using
heavy isotope–labeled substrates, allow for analysis of
the amount of a metabolite derived from a particular sub-
stance or cellular pathway (20). Of note, metabolites are
very diverse biochemical entities, and no single platform is
able to capture the full spectrum given their chemical di-
versity, huge range of observed concentrations, and vari-
ations by cell and tissue type. Additionally, metabolites
can be alternated by environmental exposures (e.g., food,
medication, or microbes), which vary by person (20).
Microbiomics
Microbiomics captures the commensal flora present on
and in the human body, most often by identification of
known microbe DNA or RNA. There has been limited
application of microbiomics to glomerular disease with re-
gard to analysis of flora from different areas of the body,
including but not limited to saliva and stool (21). However,
with an increased understanding of the tight interaction of
the resident human flora with a multitude of physiologic
functions ranging from immune response to metabolism,
discoveries could be made in glomerular diseases that
have strong pathogenetic associations with intestinal flora
and the immune system. This connection is starting to be
made with regard to IgA nephropathy, and a recent study
provides the first evidence in support of an association of
Clin J Am Soc Nephrol 11: 2054–2060, November, 2016
stool microbiota in patients with and without progressive
IgA nephropathy (22).
Large–Scale Data Capture for Structural, Clinical, and
Environmental Measures
Structural information from tissue biopsies has been the
prime source of disease classification of glomerular dis-
eases. The rich visual information can now be captured by
digital whole–slide imaging and made accessible to data
mining tools used for the genetic and molecular informa-
tion described above (23). These images can be accessed
remotely for analysis by pathologists for systematic scoring,
morphometric measurements, and potentially, computer–
assisted image analysis.
With the mandated implementation of electronic health
records in routine care, data sources for clinical informa-
tion are starting to match the scale and complexity of the
genetic and molecular datasets described above. A detailed
discussion of research using electronic health records, its
opportunities, and its challenges is beyond the scope of this
review. However, it is noted that simplifying the ability to
easily extract, annotate, and understand unstructured clin-
ical data from electronic health records through natural
language processing has been developed and is starting to
be deployed for renal diseases (24).
Comprehensive capture of glomerular disease etiologies
should also include the definition of potential environ-
mental determinants. Approaches that link environmental
exposures to defined neighborhoods on a national scale,
referred to as “geomapping,” can be used to effectively eval-
uate the interaction of the environment with genetic and
molecular disease determinants (25).
Team Science and Data Integration
One of the main opportunities and challenges of an in-
tegrative biology approach is the wide range of research
approaches deployed and data types generated as noted
above. This mandates investigative teams with the ability
to integrate diverse research strategies and expertise. This
team science approach maximizes the potential of any indi-
vidual multilayered dataset by analyses conducted across
the different data domains, facilitating discovery of novel
associations and disease mechanisms (26).
Making the large-scale data accessible to the research
teams and in particular, researchers collaborating outside
of their domain expertise is an essential step of the pre-
cision medicine approach, but it requires unique tools
to facilitate the engagement of the scientific community.
Indeed, the 2015 IOM report on team science highlighted
diversity of expertise in team membership and deep knowl-
edge integration as two of the key challenges for team science
in precision medicine (27).
Several approaches have been developed for exploration
of large-scale datasets from renal disease and are currently
used by the community. One example is Nephroseq, a web-
based tool designed to make gene expression datasets
readily searchable by researchers with a wide range of ex-
pertise. Renal gene expression datasets are obtained from
the public domain, such as with Gene Expression Omnibus
(National Center for Biotechnology Information; www.
ncbi.nlm.nih.gov/geo), or directly from investigators,
Integrative Biology Approach to Glomerular Disease, Mariani et al. 2057
annotated against a standardized ontology, and loaded
into Nephroseq. The datasets are linked and dynamically
analyzed with a wide variety of systems biology tools. Users
can search the datasets by a single gene, a list of genes, or a
predefined gene list to conduct a variety of analyses with
visualization, including differential expression between
groups, coexpression, and outlier sample identification.
Another example is data sharing and analytic platforms
designed to allow a group of investigators with diverse
methodologic expertise to collaborate around a cohort of
patients with several large–scale datasets. These platforms
for joint data analysis and data mining by research con-
sortia, for example, are a critical prerequisite for success-
ful collaboration. One of the several currently available
platforms is tranSMART, which was initially developed
by Johnson and Johnson and subsequently released as
open source software in 2012. It is now supported by the
tranSMART Foundation (transmartfoundation.org) and its
open user community. A research consortium can load
their independently governed tranSMART instance with a
wide variety of data types, including clinical data and ge-
nomic, proteomics, metabolomics, and expression datasets.
Loaded data are then available for a wide range of analyses
(e.g., descriptive statistics, correlations, survival analysis,
clustering, and heat maps). Furthermore, using the same
data–sharing platform across diseases and consortia allows
for more efficient collaboration by scientists with different
expertise and tools inside research teams, and most excit-
ingly, across different research efforts in a globally distrib-
uted manner, while maintaining scientific independence
and control by each participating network.
Examples of Successful Integrative Biology
Approaches in Nephrology
Identification of Disease Etiology: M-Type PLA2R
In the pivotal work to identify M-type PLA2R as an au-
toantigen in idiopathic MN, proteomic work played a crit-
ical role (15). After serum from patients with MN was used
to identify a previously unseen band in extracts of normal
human glomeruli, mass spectrometry proteomics allowed
for identification of candidate peptide sequences contained
in the human protein band extract without prior knowl-
edge. These peptides were then compared with existing
databases of human proteins to narrow to a list of 18 can-
didate proteins. Candidate proteins, in turn, could then be
evaluated against available antibodies and recombinant
proteins, which led to the identification of PLA2R. The
ability to map peptide sequences from this unknown
Western blot band against known proteins is an example
of the value of large-scale data available to inform and
enhance mechanistic laboratory approaches. However,
the MN story of integrating additional genome–scale data-
sets goes even farther. Independent of the immunology
efforts, a genome–wide association study performed on
European patients with MN showed two significant asso-
ciations. One was located, as expected for an autoimmune
disease, in the HLA region, but the second signals tagged
PLA2R as a genetic risk factor for MN, linking genetic risk
with immunopathology in this disease and implicating
PLA2R into the pathophysiology (28). Efforts are under-
way to combine genetics, transcriptomics, proteomic, and
2058 Clinical Journal of the American Society of Nephrology
immunology to define the exact mechanism linking the
genetic polymorphism with the immunopathology (29).
Identification of Progression Risk Factors: Urinary EGF
A data–driven, unbiased approach implemented across
several large–scale data domains recently identified a uri-
nary marker that predicts progression of kidney disease in
three independent cohorts, including two glomerular dis-
ease cohorts (30). The pipeline began with identifying re-
nal biopsy mRNA transcripts that correlated with eGFR
and also were differentially regulated compared with
live kidney donor tissue. Next, the gene list was narrowed
by including those transcripts that underwent validation
in a separate cohort, had kidney-specific expression, and
had compelling biology for a mechanistic role in CKD.
EGF was the top gene transcript meeting these criteria
and is a protein that modulates the response to tubuloin-
terstitial damage. EGF was then evaluated as a potential
noninvasive urine marker in three independent glomerular
disease cohorts. Urine EGF protein level not only corre-
lated with tissue gene expression level but also added
predictive value in predicting progression of CKD above
baseline eGFR, urine albumin, and demographics. It is
proposed that EGF may capture the functional reserve of
the tubulointerstitial compartment not currently captured
by eGFR and urine protein. These results were highlighted
in the NIH Director’s blog as an example of a precision
medicine approach to identifying novel prognostic mark-
ers as well as identifying biologic mechanisms, which can
then be further studied in a more targeted fashion (31).
Identification of Novel Therapeutic Targets: Baricitinib for
Diabetic Nephropathy
A systems-level analysis was to undertaken to better un-
derstand the molecular commonalities and differences in
underlying disease mechanisms between human diabetic
nephropathy and diabetic mouse models, which do not
completely recapitulate the human disease. In two studies,
analysis of kidney tissue mRNA expression in human
diabetic kidney biopsies compared with normal human
samples and diabetic mouse models revealed an associa-
tion of the JAK-STAT pathway expression with human
disease progression (32,33). Baricitinib is a small molecule
inhibitor of JAK-1 and -2, and it was previously approved
for the treatment of rheumatoid arthritis. On the basis of
the human systems–level analysis and prior tissue and an-
imal studies, a phase 2 clinical trial, sponsored by Eli Lilly
(Indianapolis, IN), was conducted in 129 patients. Lower
urinary albumin-to-creatinine ratio was seen at 3 and 6
months in the treatment groups compared with placebo
groups, supporting additional study of baricitinib as a
new therapy for diabetic nephropathy (34). Using ap-
proaches such as these to better understand disease driv-
ers in both human disease and animal models holds
promise for novel treatment design and drug repurposing
in glomerular disease.
Identification of Novel Diagnostic Markers: Anti-Myeloperoxidase
Autoantibodies in Patients with ANCA-Negative Vasculitis
Although many technologies described here are unbiased
in their approach, there are new immunologic technologies
emerging that allow for clarification of unanswered ques-
tions in a targeted manner. One such example is a technology
termed autoantigen excision (35). There is a small subset
of patients with pauci–immune necrotizing and crescen-
tic GN who have signs and symptoms consistent with
ANCA-associated GN but whose ANCA serology is negative.
For years, this was a perplexing clinical and serologic discrep-
ancy that resulted in diagnostic and therapeutic delays until
the advent of autoantigen excision. Briefly, this methodology
involves incubation of autoantigen with autoantibody bound
to a protein column, which then is exposed to trypsin, thereby
leaving only the complementarity-determining region of the
autoantigen bound to the antibody followed by mass spec-
trometry for protein identification. The application of autoan-
tigen excision to serum from patients with ANCA-negative
GN resulted in the identification of anti-myeloperoxidase
autoantibodies. Additional studies determined that cerulo-
plasmin, the endogenous inhibitor of myeloperoxidase, was
removed during purification of IgG, which explained why the
standard clinical serum–based ANCA test was negative (35).
Such a methodology and test will not only expedite diagnosis
and treatment of patients with ANCA-negative GN but also,
allow for unbiased identification of autoantigens associated
with other purported humoral autoimmune glomerular
diseases, such as minimal change glomerulopathy and
FSGS, which have autoantigens that remain unknown.
The Road Ahead
Glomerular disease research has made significant prog-
ress in understanding underlying disease mechanisms. In
many patients with inherited glomerular diseases, single-
gene defects with pathologic molecules and pathways have
been defined (36). These specific molecular signals are
now integrated into the larger functional context using com-
prehensive datasets linking genotype to molecular path-
ways, structural lesions, and clinical outcomes. For example,
the interaction of genetic risk loci with steady–state gene
expression profiles and clinical outcomes can be defined
using expression quantitative trait loci, where genetic variants
can be tested for their effect on gene expression variation. This
has been successfully applied for APOL1–associated glomer-
ular disease, lupus nephritis, and CKD (37–40). Linking
genome–wide association study, gene expression, and clini-
cal outcomes allows inferences beyond pure associations to-
ward identification of potential causal disease mechanisms
as therapeutic targets. An intriguing strategy in this context
is the Mendelian randomization approach (i.e., stratifying a
disease population on the basis of a genetic marker closely
linked with a specific molecular function). The subgroups
exhibiting the genetically determined molecular difference
are then evaluated for differences in clinical outcomes us-
ing the genetic variability as the intervention in an in silico
clinical trial.
The approaches above still constrain the analyses to-
ward a predefined set of molecules. A series of computa-
tional strategies has been developed in the field of artificial
intelligence to identify patterns and interdependencies in
multidimensional datasets referred to as machine-learning
approaches. In a variety of biomedical fields, these approaches
are being tested for their utility on large–scale clinical and
genomic datasets. For example, the NIH-International
Clin J Am Soc Nephrol 11: 2054–2060, November, 2016
Business Machines (IBM)–funded Dialogue for Reverse Engi-
neering Assessments and Methods Challenges provide infor-
mation from a study with genome-scale datasets and outcome
data in an open competition for investigators to develop out-
come or treatment predictor algorithms for the given dataset
(www.dreamchallenges.org). The algorithms from the par-
ticipating scientists compete on a test dataset, and the best
performing algorithms are published and in some instances,
directly used in clinical trials for patient selection (41).
In summary, we are seeing glomerular research tran-
sition to an information-rich science, offering intriguing
opportunities and new challenges. Extracting disease–
relevant, actionable knowledge from the novel big data
sources will be a critical task ahead. Efforts are ongoing
to generate and share high-quality samples and datasets
in globally distributed research networks to define key
drivers of glomerular disease. With access to biopsy tissue
and noninvasive biofluids for molecular profiling strate-
gies, nephrology offers unique opportunities to advance
our molecular understanding of not only glomerular dis-
eases but also chronic diseases in general. With these
advantages in our field, we have to attract the best and
brightest trainees to move precision medicine from labo-
ratory benches and computer hard drives to our nephrology
clinics.
Acknowledgments
L.H.M. is supported by University of Michigan Institute for Clinical
and Health Research Career Development grant KL2-TR000434. W.F.P
is supported by National Institute of Diabetes and Digestive and
Kidney Diseases grants P01DK058335-15 and 1UM1DK100845-01 and
receives translational research funding from The Broad Institute
(Cambridge, MA). M.K. is supported by National Institutes of Health
grants U54DK083912 Nephrotic Syndrome Rare Disease Clinical
Research Network II, UM1DK100845 CureGN, and P30DK081943
George M. O’Brien Kidney Research Core Center at the University of
Michigan.
Disclosures
L.H.M. and W.F.P. have no financial conflicts of interest in
relationship to the data presented. M.K. leads a precompetitive
consortium partially supported by a grant from Eli Lilly (Indian-
apolis, IN) and has provided consultations to Eli Lilly as a Univer-
sity of Michigan employee. M.K. also has a patent pending covering
the use of urinary EGF as a prognostic biomarker in CKD.
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 Glomerular Diseases

Glomerular Diseases: Registries and Clinical Trials

Marva M. Moxey-Mims, Michael F. Flessner, Lawrence Holzman, Frederick Kaskel, John R. Sedor, William E. Smoyer,
Aliza M. Thompson, and Lynne Yao

Abstract
Nephrology has conducted few high–quality clinical trials, and the trials that have been conducted have not
resulted in the approval of new treatments for primary or inflammatory glomerular diseases. There are over-
arching process issues that affect the conduct of all clinical trials, but there are also some specialty–specific issues.
Due to the number of
Within nephrology, primary glomerular diseases are rare, making adequate recruitment for meaningful trials contributing authors,
difficult. Nephrologists need better ways, beyond histopathology, to phenotype patients with glomerular diseases the affiliations are
and stratify the risk for progression to ESRD. Rigorous trial design is needed for the testing of new therapies, where provided in the
most patients with glomerular diseases are offered the opportunity to enroll in a clinical trial if standard therapies Supplemental
Material.
have failed or are lacking. Training programs to develop a core group of kidney specialists with expertise in the
design and implementation of clinical trials are also needed. Registries of patients with glomerular disease and Correspondence:
observational studies can aid in the ability to determine realistic estimates of disease prevalence and inform trial Dr. Marva M. Moxey-
design through a better understanding of the natural history of disease. Some proposed changes to the Common Mims, Division of
Kidney, Urology and
Rule, the federal regulations governing the ethical conduct of research involving humans, and the emerging use of Hematology, National
electronic health records may facilitate the efficiency of initiating multicenter clinical trials. Collaborations Institute of Diabetes
among academia, government scientific and regulatory agencies, industry, foundations, and patient advocacy and Digestive and
groups can accelerate therapeutic development for these complex diseases. Kidney Diseases,
National Institutes of
Clin J Am Soc Nephrol 11: 2234–2243, 2016. doi: 10.2215/CJN.00540116 Health, 6707
Democracy
Boulevard, Bethesda,
Introduction process issues are certainly not unique to nephrology— MD 20892. Email:
mm726k@nih.gov
It has been a little over a decade since Strippoli et al. slow institutional review board (IRB) approval, slow
(1) pointed out that nephrology was at the bottom of contract/subcontract ratification, and recruitment
the list of medical subspecialties with regard to the shortfalls often caused by an overestimation of avail-
conduct of clinical trials in both quantity and quality. able participants (6) as well the need for more training
The authors of the accompanying editorial felt that in clinical trial design and implementation. However,
perhaps the problem was overstated but concurred some issues are more specific to nephrology. One issue
that there was a need for improvement (2). More could simply be labeled culture—nephrologists’ uncer-
recently, a review of ClinicalTrials.gov seemed to show tainty that there is truly equipoise between different
some improvement, although the overall percentage of treatment options, resulting in an unwillingness to re-
nephrology interventional studies remained low at linquish control of their patients to a randomized
2.6% of the trials reviewed, about one half that of car- study, even for a short time (1,6). Another is the need
diology (3). This paucity of high-quality data, primarily for accurate disease phenotyping and risk classification.
randomized, controlled trials (RCTs), to evaluate new The clinical classification of many glomerular diseases
therapies in kidney diseases remains a concern (4,5), (noninflammatory and inflammatory) is inadequate, re-
and among the various subcategories of nephrology lying primarily on histopathology rather than an un-
research, primary glomerular disease represents a derstanding of the molecular underpinnings of these
comparatively small percentage of the group (1,2). diseases. Histopathology alone does not adequately
Additionally, it is particularly striking to note that, predict the heterogeneous natural history or response
since the 1962 Drug Efficacy Amendments, which re- to therapy for individuals within a given glomerular
quired that new drugs be shown to be effective as disease category. There are difficulties in identifying
well as safe to be approved in the United States, the appropriate druggable targets and clinically useful
US Food and Drug Administration (FDA) has ap- biomarkers that could serve as indicators of disease
proved no drug for the treatment of a primary or in- activity or surrogate end points in primary glomerular
flammatory glomerular disease. Recently, belimumab disease (7–9). One promising target for the treatment
and rituximab were approved by the FDA for the treat- of membranous nephropathy (MN) is the phospholi-
ment of SLE, granulomatosis with polyangiitis and pase A2 receptor, and circulating levels may also be a
microscopic polyangiitis, respectively, but were not marker of disease activity (10). Hopefully, we will be
specifically approved for the associated GN. So what able to identify similar potential targets for other forms
issues underlie the difficulties of conducting, and suc- of primary glomerular disease. The inflammatory glo-
cessfully completing clinical trials in nephrology? Some merulonephritides have a relatively longstanding history

2234 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 December, 2016
Clin J Am Soc Nephrol 11: 2234–2243, December, 2016
of defined biomarkers associated with disease diagnosis
and activity—anti-double stranded DNA, anti-C1q, and
complement levels in lupus nephritis, and ANCAs for
pauci-immune/ANCA-associated vasculitis—which has
contributed to strong trial design. More recently, serum
thiols and anti-C3b IgG have been proposed for lupus
nephritis (11,12), and urinary soluble CD163 has been pro-
posed for ANCA-associated vasculitis (13).
There are now registries of patients with glomerular disease
in place that may alleviate some recruitment challenges.
The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) has invested in several observational
studies that should help to inform clinical trial design. The
FDA and the American Society of Nephrology have part-
nered to establish the Kidney Health Initiative (KHI). The
KHI objectives include fostering the development of ther-
apies for diseases that affect the kidney by facilitating col-
laborations among patient groups, nephrologists and other
health professionals, industry, and government (https://
www.asn-online.org/khi/). The Critical Path Institute, an in-
dependent, nonprofit organization, was created to increase
collaboration among scientists within the FDA, academia,
and industry to improve the drug development and regula-
tory process for medical products. Some ways in which these
organizations, basic scientists, and clinical trialists can all en-
gage to move the field forward will be discussed in this paper.
National Institutes of Health Investments,
Requirements, and Limitations
The NIDDK at the National Institutes of Health (NIH)
funds much of the glomerular disease research in the United
States. Although 60%–70% of the funding is for basic re-
search, there have been significant investments in glo-
merular disease clinical consortia. In 2008, a multicenter,
prospective, open label, RCT in FSGS (the FSGS-Clinical
Trial) was completed in children and young adults to de-
termine if treatment with mycophenolate mofetil (MMF) in
conjunction with oral pulse corticosteroids is superior to
treatment with cyclosporin A in inducing remission of pro-
teinuria over 12 months. The findings have been published,
but the conduct of the trial reflected many of the challenges
referenced above, including slow IRB approval, slow sub-
contract ratification, and recruitment shortfalls (14,15).
Currently, there are two longitudinal, observational
glomerular disease cohorts that are recruiting patients:
the Nephrotic Syndrome Study Network (NEPTUNE)
and Cure Glomerulonephropathy (CureGN) studies. NEPTUNE
is in its sixth year and focuses on three glomerular
diseases associated with the nephrotic syndrome: mini-
mal change disease (MCD), FSGS, and MN. Participants
are enrolled before their first clinically indicated biopsy,
and when the biopsy is performed, a research core is
obtained for genomic analysis. Using systems biology,
NEPTUNE is analyzing tissue, serum, urine, and pheno-
typic and genomic data in approximately 500 children and
adults. CureGN, however, is projected to recruit 2400
patients, 600 in each of four disease categories: MCD, FSGS,
MN, and IgA nephropathy. The plan is to recruit equal
numbers of prevalent (defined as having a renal biopsy
obtained within 5 years of disease) and incident (defined as
having a biopsy ,6 months before enrollment) patients.
Registries and Clinical Trials, Moxey-Mims et al. 2235
There are other large NIH–funded consortia that include
significant numbers of participants with glomerular dis-
ease, although glomerular disease is not their specific fo-
cus. These include the Chronic Renal Insufficiency Cohort,
the Chronic Kidney Disease in Children Study, and the
Human Heredity and Health in Africa Kidney Disease Re-
search Network (16).
Although these clinical research investments are signif-
icant, there are requirements and limitations inherent in
the NIDDK funding of large consortia. The entire process
from initial concept to funding of a consortium can take
2–2.5 years and is very dependent on available or pro-
jected funds. The first step in the creation of a consortium
is the drafting, refining, and thorough discussion by the
NIDDK staff of an initiative concept, which must sub-
sequently be approved by the NIDDK External Advisory
Council to go forward. An open meeting with invited
speakers is usually planned to discuss the initiative and
get a sense of the state of the science to appropriately de-
velop the basis for a request for applications. An example
of such a meeting occurred before the initiation of CureGN
(http://www.niddk.nih.gov/news/events-calendar/
Pages/glomerular-disease-pathophysiology-biomarkers-
and-registries-for-facilitating-translational-research.
aspx#tab-event-details). If funding is approved for the
project, a request for applications is issued. Proposals
are received, evaluated, and ultimately approved by the
Advisory Council for funding. In contrast, investigator-
initiated projects (R01s) can move forward more quickly
but are often limited in size and scope because of budget
restrictions. In some instances, to facilitate feasibility and
help with budgetary constraints, the NIH partners with
industry or advocacy groups for provision of pharmaceu-
ticals and/or financial support.
Partnering with Industry
Given the expense and complexity in design and execu-
tion of RCTs, more nimble approaches are needed to
identify molecular targets with promise, especially those
that could be amenable to intervention with drugs repur-
posed from other uses. Partnering with industry early in
the translation of bench discoveries into the clinic would
facilitate proof of concept human studies and the conduct
of adaptive clinical trials (17). In adaptive trials, prespeci-
fied changes in design or analyses are guided by exami-
nation of the accumulated data at an interim point in the
trial. Such designs can improve trial efficiency, make trials
more informative, and increase the likelihood of detecting
a treatment effect (if such an effect exists) (18). Ultimately,
cooperation with industry partners should accelerate trial
implementation and improve the care of patients. How-
ever, barriers to establishing industry partnerships must
be addressed. Change is needed by both our community
and industry colleagues to improve our record in clinical
trials completion.
Recently, the pharmaceutical industry has recognized
opportunities for drug development for glomerular dis-
ease. However, budgets often fail to adequately recognize
the effort needed to identify patients with glomerular disease
who meet eligibility criteria for trials. These participants
have rare diseases, and eligibility criteria often require
2236 Clinical Journal of the American Society of Nephrology
time-consuming interactions outside of the home institu-
tion. Although clinical trials are most often driven by
industry, trial designs are often improved with early input
from basic and clinical scientists, clinicians, and patients.
An alternate model, in which an academic investigator
serves as the sponsor of a study that is funded by industry,
may also be an important means to advance drug devel-
opment in this area. Industry should also codify and post
mechanisms for investigators to propose novel targets and
clinical trials; currently, identification of the correct in-
dustry contact can be difficult. Early interactions with the
FDA can also significantly improve trial design and the
likelihood that the trials will be sufficiently rigorous in design
and execution to meet FDA requirements for drug registra-
tion. Unfortunately, interactions between academic inves-
tigators, their universities, and industry partners often bog
down over intellectual property ownership. These protracted
negotiations need reform, particularly at early stages when the
goal is to establish data suggesting efficacy of a drug in patients.
There are recent developments that promote interactions
between academic centers, practice groups, patients, in-
dustry, and the government. The goal of the KHI is to foster
new therapies for kidney diseases by creating a collabora-
tive, precompetitive space for interactions between indus-
try, government, patients, scientists, and the kidney care
community. NephCure Kidney International created the
NephCure Accelerating Cures Institute to reduce obstacles
to successful implementation of glomerular disease trials
by creating a national network of clinical trial sites in research
hospitals and community clinics with established infra-
structure, facilitating interactions with industry partners
with novel glomerular disease treatments, and engaging the
patient community to reduce the drug development timeline
from 15 to 5 years (http://nephcure.org/research/naci/).
Regulatory Considerations
End Points
In early phases of drug development, pharmacodynamic
or response biomarkers are used to show that a biologic
response has occurred in an individual who has received
an intervention or exposure. Treatment effects on such bio-
markers are used to support proof of concept and guide
dose selection for later clinical trials. Given their impor-
tant role in drug development, more attention should be
given to identifying pharmacodynamic biomarkers, beyond
proteinuria, that can be used in clinical trials in primary
glomerular disease. Phospholipase A2 receptor is a good
example for MN. In later phases of drug development, the
goal is to establish that a drug is safe and effective for its
intended use. ESRD is an important clinical outcome, but
it is a late event in many glomerular diseases, making it
potentially difficult to show an effect on ESRD over the
course of a feasible clinical trial. Accordingly, there has been
significant interest in the use of surrogate end points in
clinical trials of glomerular diseases.
A surrogate end point is a biomarker used in therapeutic
trials as a substitute for a clinically meaningful end point.
Surrogate end points offer important advantages, because they
can enable faster and cheaper drug development. They may be
viewed as the only viable option in some settings, particularly
when a therapy is being developed to treat early stages of a
slowly progressive disease. However, disease processes are
often complex, and drugs can have unintended effects, making
identification of biomarkers that can reliably predict a treat-
ment’s effect on clinical outcomes very challenging.
In trials of CKD, a doubling of serum creatinine and
lesser declines in renal function have been accepted as
surrogate end points of treatment effects on progression
to ESRD. Although there has been significant interest
in proteinuria reduction as a surrogate end point, the
FDA has not broadly accepted this as a basis for approval
of therapies being developed to treat kidney diseases but
has focused on data supporting the use of proteinuria
reduction as a surrogate end point within the context of
specific glomerular diseases. One recently completed col-
laborative effort evaluated the data supporting complete
and partial remission of proteinuria as surrogate end points
for a treatment effect on progression to ESRD in patients
with primary MN at high risk of progression. A new project,
sponsored by the KHI, plans to evaluate the data sup-
porting proteinuria reduction and other biomarkers as
surrogate end points for registration trials in IgA nephrop-
athy. Another KHI project in collaboration with the Lupus
Nephritis Trial Network will examine the strengths and
weaknesses of existing surrogate end points and make data-
driven recommendations about biomarker outcome mea-
sures and surrogate end points for lupus nephritis trials.
Although surrogate end points provide an important
means to establish the efficacy of therapies, it is important
not to lose sight of other end points that can be used to
support medical product approval. In recent years, there
has been increasing recognition of the importance of the
patient voice in drug development, particularly the use of
patient–reported outcome (PRO) measures as end points.
Available data indicate that patients with primary glo-
merular disease have significant impairments that can be
detected with generic PRO measures; however, disease-
specific instruments may be needed to adequately capture
the distinctive features of glomerular disease and how
these affect the patient experience. PRO issues are dis-
cussed more extensively in another paper in this series.
Pediatric Issues
Historically, the majority of drugs used in pediatric
practice were used off label, because most drug develop-
ment programs did not include children. Medications were
often administered to children empirically, assuming that
they were “little adults.” This resulted in pediatric dosing
recommendations derived solely as fractions of adult dos-
ing. Safety and efficacy were assumed to be the same in
children and adults, not taking into account known or po-
tential safety and efficacy differences in a growing and de-
veloping pediatric patient. Before the passage of important
pediatric legislation, many pharmaceutical manufacturers
were reluctant to study drugs in children because of ethi-
cal, financial, or trial design challenges (19). Under the Best
Pharmaceuticals for Children Act (BPCA), first passed by
Congress in 2002, the FDA may grant 6 months of market-
ing exclusivity to sponsors who complete the voluntary
pediatric studies that the FDA determines are of public
health benefit (20). The Pediatric Research Equity Act
(PREA), first enacted in 2003, gives the FDA authority to re-
quire pediatric assessments of new drugs for all new active
Clin J Am Soc Nephrol 11: 2234–2243, December, 2016
ingredients, indications, dosage forms, dosing regimens, and
routes of administration. The pediatric assessment must in-
clude data adequate to assess the dosing, safety, and effective-
ness of the product for the claimed indications in all relevant
pediatric subpopulations (21).
Importantly, the BPCA and the PREA do not provide
for a different evidentiary standard for the demonstration
of effectiveness and safety for products intended for use
in children. However, the feasibility of adequate and well
controlled clinical efficacy trials may be hindered because
of limited availability of pediatric patients. Moreover, there
are additional safeguards that must be considered when
conducting research in pediatric patients (22). In 1994, the
FDA finalized a set of rules for the extrapolation of efficacy
to the pediatric population from adequate, well controlled
studies with adults. Such extrapolation depends on a se-
ries of evidence-based assumptions—the disease progres-
sion and responses to intervention are similar in the adult
and pediatric populations, and the two populations have
similar exposure-response relationships (23). The FDA ex-
amines several factors before making assumptions of sim-
ilarity, including disease pathogenesis, criteria for disease
definition, clinical classification, measures of disease pro-
gression, and pathophysiologic, histopathologic, and path-
obiologic characteristics. Support for these assumptions
may be derived from sponsor data, published literature
findings, expert panel, workshop or consensus documents,
or previous experience with other products in the same
class. Importantly, safety profiles may differ between adult
and pediatric populations; therefore, safety information
cannot be extrapolated from trials in adults (24). In the
case of glomerular diseases that affect both adults and chil-
dren, development of evidence that could support the use
of pediatric extrapolation may increase the efficiency and
feasibility of product development. In addition, under cer-
tain circumstances (e.g., for rare, life–threatening diseases
or for studies in which sufficient safety data in children
already exist), clinical investigations may include both
children and adults in the same trial. For example, a con-
trolled trial evaluating sparsentan in the treatment of both
pediatric and adult FSGS (the Randomized, Double-Blind,
Safety and Efficacy Study of RE-021 [Sparsentan] in FSGS
[DUET]) was initiated in 2012.
The Case for Registries
Registries can take different formats depending on the
intended use of the registry data. Investigators around the
world have initiated a variety of observational studies of
patients with glomerular disease during the past decade.
These studies have used a spectrum of methodologic ap-
proaches from simple cross–sectional contact registries of
self-reported diagnosis to single–center longitudinal obser-
vation registries of clinical phenotype to national observa-
tional studies using linked electronic health records
(EHRs) to international multicenter consortia of basic,
translational, and clinical scientists conducting detailed
long–term longitudinal observational studies (Table 1).
The emerging use of EHRs both nationally and interna-
tionally offers unique opportunities to facilitate harmo-
nized clinical research endeavors. The exchange of
standardized health information, customized for clinical
Registries and Clinical Trials, Moxey-Mims et al. 2237
studies while assuring confidentiality, will enable investiga-
tors to expand cohorts for collaboration and sharing of in-
formation regarding trials, registries, and biorepositories (25).
There can be a significant cost to setting up a patient registry,
and the Health Insurance Portability and Accountability Act
Privacy Rule mandates the way in which protected health
information is used or shared. Therefore, each individual
may be assigned a unique reference code with all personally
identifiable information removed, or patients may consent to
participate in studies that include personally identifiable in-
formation. These registries should have appropriate methods to
protect privacy and data security as well as appropriate ethics
board approval. There are multiple ways to capture data,
which can also affect cost—paper forms and electronic
application–based forms as well as web-based forms.
There are many ways in which registries can be valuable
tools for enhancing potential trial success, not the least of
which is assessing the size of the potential study population
to allow for more realistic estimates of target recruitment
numbers (Table 2). However, with multiple registries for glo-
merular diseases, there is concern about redundancy, com-
peting interests, and dividing patients and resources as well
as participant confusion and fatigue because of participation
in multiple registries. One consideration may be the estab-
lishment of global registries for glomerular diseases. There
are a few global registries fairly early in development that
may serve as examples for such an effort for glomerular dis-
eases. One is the National Center for Advancing Transla-
tional Sciences Global Rare Diseases Patient Registry Data
Repository Program, which integrates coded data from nu-
merous national and international patient registries for rare
diseases. Investigators representing glomerular disease regis-
try programs in several countries are working to harmonize
protocols and approaches in an informal International Ne-
phrotic Syndrome Network. This loose network includes
.9500 patients from 12 national networks in the United
States, the United Kingdom, Europe, sub-Saharan Africa,
and China. Of course, these global efforts require consensus
on many levels—identification of topics for joint/compara-
tive studies, consensus on end point definitions, common
data elements and terminology, support for compatibility
and interoperability, and a global unique identifier as-
signed to each patient for tracking.
Are We Ready to Conduct High-Quality Trials?
Given our inadequate understanding of the biology and
our archaic classification system for glomerular disorders,
it is not surprising that our therapeutic approach to these
diseases is imperfect; current therapies lack a clear biologic
basis, are often ineffective, and are complicated by signif-
icant toxicity. Therefore, there is significant interest in
clinical interventional trials for glomerular disease (Table
3). The size of a clinical trial is driven primarily by the
expected effect size and event frequency. Heterogeneous
cohorts defined by histopathology alone are workable only
if the therapeutic target is integral to a biologically mean-
ingful common pathway. The good news is that research
has progressed to the point where some specific disease
cohorts, like that for MN, might have specific biomarker
targets as mentioned above. However, we are not so for-
tunate for many other types of glomerular disease. Even
 2238

Table 1. Current glomerular disease clinical consortia and registries

Consortium Namea Type of Study Biosampling Funding Sources Still Enrolling Clinical Phenotypes

United States
CureGN Observational Yes NIDDK Yes Biopsy-proven MCD, FSGS,
MN, IgAN
NEPTUNE Observational Yes NIDDK and NCATS Yes NS with biopsy-proven MCD,
FSGS, MN
UNC Glomerular Disease Registry Yes NIDDK P01 and Philanthropy Yes All glomerular diseases
Collaborative Network
NephCure Accelerating Cures Registry No NephCure Kidney International Yes All forms of NS
Institute
Chronic Kidney Disease in Observational Yes NIDDK No All causes of CKD in children
Children Study
Chronic Renal Insufficiency Cohort Observational Yes NIDDK No All causes of CKD in adults
North American Pediatric Renal Registry No Industry Yes All causes of CKD in children
Trials and Collaborative Studies
Clinical Journal of the American Society of Nephrology

Group
International
Toronto Glomerulonephritis Registry No Divisional Fund University Yes All biopsy–proven forms of GN
Registry Health Network
British Columbia Registry No BC Provincial Renal Agency Yes Biopsy-proven GN
Glomerulonephritis Network
and Registry
PodoNet (Europe only) Observational Yes EU via EURenOMICS Project Yes Steroid-resistant NS
NephroS—part of the United Observational Yes National Institute for Health Yes Idiopathic NS in children and adults
Kingdom Renal Rare Disease Research; Kidney Research
Registry UK; Kids Kidney Research;
industry partnerships
EURenOMICS Observational Yes European community— Yes SRNS, MN, tubulopathies,
International Rare Disease complement disorders, congenital
Research Consortium kidney malformations
China-DiKip Observational Yes National funding Yes Glomerular disease
Human Heredity and Health in Observational Yes NIH (common fund, NHGRI, Yes All causes of CKD in adults and
Africa Kidney Disease Research NIDDK) children
Network

CureGN, Cure Glomerulonephropathy; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; MCD, minimal change disease; MN, membranous nephropathy; IgAN, IgA
nephropathy; NEPTUNE, Nephrotic Syndrome Study Network; NCATS, National Center for Advancing Translational Sciences; NS, nephrotic syndrome; UNC, University of North Carolina;
BC, British Columbia; EU, European Union; SRNS, steroid responsive nephrotic syndrome; NIH, National Institutes of Health; NHGRI, National Human Genome Research Institute.
a
Consortia websites have information on entry criteria and available data.
Clin J Am Soc Nephrol 11: 2234–2243, December, 2016 Registries and Clinical Trials, Moxey-Mims et al. 2239

Table 2. Potential value of disease registries and cohorts

(1) Defining the disease to be studied

Determining disease prevalence: size of the potential study population and how this cohort changes as one alters
enrolment criteria
Natural/clinical history: disease characteristics, including how biomarkers perform over time
(2) Defining meaningful therapeutic end points and/or surrogate end points for a particular disease cohort
(3) Identifying and evaluating human therapeutic targets
(4) Defining biomarkers that may be relevant to the full disease cohort or a disease subgroup
(5) Improving access for patient recruitment and enhancing patient retention
(6) Comparisons of global treatment modalities and patient survival rates
(7) Achieving critical patient mass to reach sufficient power for multiple comparisons (efficacy/safety)
(8) Valid adjustments in multivariate analyses (age and ethnicity)

diseases like Alport syndrome, where the genetic defect
has been identified, pose difficulties for studying treat-
ment because of slow progression and our poor knowl-
edge of its natural history.
The possibility of conducting pragmatic trials rather than
the classic RCTs to test marketed drugs in patients with
glomerular diseases has been raised. Pragmatic trials com-
pare medical interventions under usual conditions of care
in a broad population of patients with the disease of in-
terest (26,27). Pragmatic trials and comparative effective-
ness research may be useful in some contexts of study in
primary glomerular disease, such as testing the effect of
differing durations of common therapies or comparing
two commonly prescribed second–line therapies. How-
ever, given the rarity and heterogeneity of primary glo-
merular diseases as well as the significant toxicities of
current therapies, efforts should also focus on improving
the phenotyping of patients with these diseases and de-
veloping more personalized medical interventions.
Some proposed changes to the regulation of clinical trials
may contribute to more efficient execution. The intent of the
proposed changes to the Common Rule is to reduce unnec-
essary burden and calibrate the oversight to the risk level,
while enhancing the safeguards for research participants.
Of particular relevance to glomerular disease trials, which
require a large number of participating sites, because these
are rare diseases, is the proposed use of a single IRB to
facilitate multisite involvement (28). Examples of attempts
to streamline IRB approval already exist. Recently, the
concept of reliant review has been implemented by some
consortia of institutions and community partners (29) and
the NephCure Accelerating Cures Institute. Reliant review
allows one IRB, designated as the IRB of record, to be re-
sponsible for reviewing, approving, and monitoring a study
across its lifecycle. The process requires a single IRB submis-
sion to the IRB of record by the lead investigator. Collabo-
rating IRBs agree to rely on the analyses of the IRB of record
but assure compliance with institution-specific policies. Elec-
tronic IRB platforms can be used, which securely connect
participating sites to a hub with all study documents and
reviews from the IRB of record. Reliant review facilitates
collaboration between investigators at multiple institutions,
increases the population available for recruitment, and re-
moves regulatory barriers by eliminating the need for inde-
pendent human subjection protection review at multiple
study sites. Other models include the use of a central IRB,
independent of the participating sites (e.g., Western IRB or
Chesapeake Research Review, Inc.). If the Common Rule
proposal goes into effect, the use of a single IRB will be
required rather than a piecemeal voluntary occurrence.
There is the need to engage all stakeholders in clinical
trial development—regulatory agencies, academics, indus-
try, and patient advocacy organizations—as well as the
opportunity to develop and obtain information from
EHRs and informatics platforms (30).
Conclusions
Although many RCTs have led to advances in the un-
derstanding and treatment of inflammatory glomerulone-
phritides, such as lupus nephritis and ANCA-associated
nephritis (31,32), this has not been duplicated in the pri-
mary glomerular diseases. As a community, nephrologists
have to address the practices that might impair successful
implementation of clinical trials. If possible, all or most
patients with glomerular diseases should be offered the
opportunity to enroll in a clinical trial if standard therapies
have failed or are lacking. The ad hoc approaches that re-
sult from thinking “I know how to treat this disease best” fail
to create the culture and the knowledge base needed to im-
prove the management of this patient population. Training
programs to develop a core group of kidney specialists with
expertise in design and implementation of clinical trials are
needed. Where practical, fostering relationships with ne-
phrologists outside of large academic centers along with im-
proved infrastructure would likely facilitate patient accrual
into studies. Additional consideration needs to be given to
the use of EHRs to streamline the collection of data on the
natural history of a disease and use it to inform trial design.
Industry partners need to see that the nephrology commu-
nity is engaged in these strategies to improve participant
enrollment into trials to ensure success.
Lessons learned in a multinational, multicenter, RCT
designed to identify a marketed therapy protective against
cardiovascular events in patients on hemodialysis are also
applicable to glomerular disease trials (33). The commentary
emphasized the need for stratification for key prognostic
factors, avoidance of treatment crossover during the trial,
enhanced engagement of site investigators and study partic-
ipants in a long-term trial, and the need to educate the ne-
phrology community to avoid prescribing therapeutic
agents without evidence-based efficacy. Development of
new glomerular disease therapies has been hindered by
poor understanding of their molecular mechanisms and
 2240

Table 3. United States glomerular disease trials ongoing or completed within the last 5 years

Ongoing/
Trial Name Disease(s) Intervention Sponsor Recruitment Target
Completed

RAMP Study
Rituximab 1 Cyclosporine
in Idiopathic Membranous
Nephropathy
Mycophenolate Mofetil
(MMF) in Patients with
IgA Nephropathy
A Study of Fresolimumab
in Patients with Steroid-
Resistant Primary
Children with frequent Rituximab versus Nationwide Children’s 64 Ongoing
relapsing or steroid- mycophenolate mofetil Hospital/Genentech
dependent NS (South San Francisco,
CA)
Idiopathic membranous Rituximab and cyclosporin NIDDK NIH Clinical 30 Ongoing
nephropathy Center
IgA nephropathy Mycophenolate mofetil St. Joseph’s Hospital and 184 (52 randomized) Completed; results
versus placebo Medical Center, Phoenix published
FSGS Fresolimumab versus Genzyme 36 Completed; results
placebo not yet published
Clinical Journal of the American Society of Nephrology

Focal Segmental
Glomerulosclerosis
(FSGS)
MENTOR Membranous Cyclosporin A versus Mayo Clinic 126 Ongoing; in follow-
nephropathy rituximab up phase
DUET FSGS Sparsentan versus placebo Retrophin 100 Ongoing
Safety and Efficacy of FSGS and MCD Abatacept Bristol-Meyers Squibb 90 Ongoing
Abatacept in Adults and (Princeton, NJ)
Children with FSGS or
MCD
ACCESS Lupus nephritis CTLA4Ig (abatacept) plus NIAID 137 Completed; results
cyclophosphamide published
versus
cyclophosphamide alone
Laquinimod Study in Lupus nephritis Laquinimod combined Teva Pharmaceutical 47 Completed; results
Systemic Lupus with mycophenolate Industries not yet published
Erythematosus (SLE) mofetil and steroids
Patients with Active
Lupus Nephritis
Efficacy and Safety Study Lupus nephritis BMS-188667 (abatacept) or Bristol-Myers Squibb 400 Ongoing
of Abatacept to Treat placebo with
Lupus Nephritis mycophenolate mofetil
and corticosteroids
AURA-LV Lupus nephritis Voclosporin (23.7 or 39.5 Aurinia Pharmaceuticals 258 Ongoing
mg twice a day) versus Inc.
placebo
Rituximab and Belimumab Lupus nephritis Rituximab plus NIAID 40 Ongoing
for Lupus Nephritis cyclophosphamide
followed by belimumab
Table 3. (Continued)

Ongoing/
Trial Name Disease(s) Intervention Sponsor Recruitment Target
Completed

BLISS-LN Lupus nephritis Belimumab plus standard Human Genome Sciences 464 Ongoing
of care versus placebo Inc. (GlaxoSmithKline,
plus standard of care Brentford, United
Kingdom)
TULIP-LN1 Lupus nephritis Two doses of anifrolumab AstraZeneca 150 Ongoing
versus placebo Pharmaceuticals
(Wilmington, DE)
A Study to Evaluate the Lupus nephritis Obinutuzumab Hoffmann-La Roche 120 Ongoing
Safety and Efficacy of
Obinutuzumab, an
Antibody Targeting
Certain Types of Immune
Clin J Am Soc Nephrol 11: 2234–2243, December, 2016

Cells, in Participants with

Lupus Nephritis (LN)
Efficacy and Safety Study of Lupus nephritis Abatacept versus placebo Bristol-Myers Squibb 423 Completed; results
Abatacept to Treat Lupus on a background of published
Nephritis mycophenolate mofetil
and glucocorticosteroids
Clinical Trial to Evaluate ANCA-associated Two-dose regimens of the ChemoCentryx 42 Ongoing
Safety and Efficacy of vasculitis complement C5a
CCX168 in ANCA- receptor CCX168
Associated Vasculitis
Safety and Efficacy Study of IgA nephropathy Fostamatinib Rigel Pharmaceuticals 75 Ongoing
Fostamatinib to Treat
Immunoglobin A (IgA)
Nephropathy

Search of ClinicalTrials.gov was limited to the United States, phase 2 or 3, and recruitment of $30 participants. RAMP, Randomized Trial Comparing Rituximab Against Mycophenolate Mofetil
in Children Wtih Refractory Nephrotic Syndrome; NS, nephrotic syndrome; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIH, National Institutes of Health;
MENTOR, MEmbranous Nephropathy Trial Of Rituximab; DUET, Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in FSGS; MCD, minimal change disease;
ACCESS, Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis; CTLA4Ig, abatacept; NIAID, National Institute of Allergy and Infectious Diseases; AURA-LV, Aurinia
Urinary Protein Reduction Active—Lupus with Voclosporin; BLISS-LN, Efficacy and Safety of Belimumab in Patients with Active Lupus Nephritis; TULIP-LN1, Safety and Efficacy of Two
Doses of Aifrnolumab Compared with Placebo in Adult Subjects with Active Proliferative Lupus Nephritis.
Registries and Clinical Trials, Moxey-Mims et al.
2241
2242 Clinical Journal of the American Society of Nephrology

Figure 1. | Industry and academia are two different origins, but their roads must merge to get to the destination. Nephrology-specific barriers
(culture, lack of druggable targets, and lack of phenotypes) are shown as speed bumps with accompanying slow signs. Multiple registries (ABC
and XYZ) need to merge into a global registry along with information from the observational studies. Surrogate end points are a potential
shortcut, but this road is still under construction. Pragmatic trials are a toll bridge, because they are not appropriate for novel target agents but
may be useful for comparing marketed therapies.

reliance on histopathology as key entry criteria into clinical
trials. Recent identification of familial (Mendelian) FSGS and
genes associated with treatment-resistant MCD, the target
podocyte antigen characterizing MN, and the association of
apoL1 variants with disease risk in black participants with
glomerular disease provides indisputable evidence that mul-
tiple specific disease processes can present with indistinguish-
able glomerular histopathology. The ability to phenotype
patients with glomerular diseases on a molecular level will
allow these novel targets to be used for therapeutic testing.
This along with the progress being made in establishing
high–quality glomerular disease registries and consortia (Fig-
ure 1) offer significant hope for our ability to conduct higher–
quality and more efficient future clinical trials that will lead
to more effective therapies for this patient population.
Acknowledgments
The authors thank Ms. Jenna Norton for drafting the figure concept.
There was no financial support provided for this function. Ms. Norton
works in the Division of Kidney, Urology and Hematology with
Dr. Moxey-Mims.
This article reflects the views of the authors and should not be
construed to represent the views or policies of the Food and Drug
Administration.
Disclosures
M.M.M.-M. and M.F.F. have National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK; Bethesda, MD) oversight
for the Cure Glomerulonephropathy (CureGN) and the Nephrotic
Syndrome Study Network (NEPTUNE) studies. L.H. is funded by
the NIDDK as a principal investigator for CureGN, a site principal
investigator for NEPTUNE, and a consultant for GlaxoSmithKline
(Brentford, United Kingdom), Pfizer (New York, NY), and Bristol-
Meyers Squibb (Princeton, NJ). F.K. is a site principal investigator for
CureGN and NEPTUNE studies. J.R.S. is funded by the NIDDK and
serves as a site principal investigator for NEPTUNE and CureGN and a
consultant for Bristol-Meyers Squibb, GlaxoSmithKline, Sanofi-
Genzyme (Framingham, MA), and Third Rock Ventures (Boston, MA).
Clin J Am Soc Nephrol 11: 2234–2243, December, 2016
J.R.S. is on the Scientific Advisory Board for the Phase II Treat-
ment Resistant Nephrotic Syndrome Trial with Abatacept by
Bristol-Myers Squibb. W.E.S. is funded by the NIDDK as a principal
investigator for CureGN, has received funding from Genentech (South
San Francisco, CA) as a principal investigator on the Randomized Trial
Comparing Rituximab Against Mycophenolate Mofetil in Children
With Refractory Nephrotic Syndrome Trial, and is coprincipal investi-
gator of the Ohio State University Clinical and Translational Science
Awards. A.M.T. and L.Y. have no disclosures.
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Published online ahead of print. Publication date available at
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DCSupplemental.
 Glomerular Diseases

Patient-Reported Outcomes in Glomerular Disease

David T. Selewski,* Aliza Thompson,† Sarrit Kovacs,‡ Elektra J. Papadopoulos,‡ Noelle E. Carlozzi,§
Howard Trachtman,| Jonathan P. Troost,* Peter A. Merkel,¶ and Debbie S. Gipson*

Abstract
Incorporation of the patient perspective into research and clinical practice will enrich our understanding of the
status and management of patients with glomerular disease and may result in therapies that better address patient
needs. In recent years, the importance of the patient experience of glomerular disease has become clear, and
*Division of
significant efforts have been undertaken to systematically capture and describe the patient’s disease experience. Nephrology,
Patient–reported outcome instruments provide a means to assess the patient’s experience in a quantitative Department of
manner, thus enabling for comparisons within and between patients. Patient–reported outcome assessments are Pediatrics and
solely on the basis of a patient report about the status of their health without amendment or interpretation by a Communicable
Diseases, C.S. Mott
clinician or others. Patient–reported outcome assessments provide an opportunity to incorporate the patient
Children’s Hospital
perspective into clinical care, research, and clinical trials. Our paper provides an overview of terminology and and §Department of
development methods for patient-reported outcomes and reviews (1) currently available patient–reported out- Physical Medicine and
come instruments appropriate for use in glomerular disease, (2) existing patient–reported outcome data in glo- Rehabilitation,
merular disease, and (3) opportunities for incorporating patient–reported outcome instruments into clinical care University of
Michigan, Ann Arbor,
and research. Michigan; †Division of
Clin J Am Soc Nephrol 12: 140–148, 2017. doi: 10.2215/CJN.13231215 Cardiovascular and
Renal Products and
‡
Immediate Office,
Office of New Drugs,
Introduction Glossary Center for Drug
Although the health of a patient and consequences Health–related quality of life (HRQOL) is a multi- Evaluation and
of a disease can be assessed in a number of ways, the domain concept representing the patient’s general Research, Food and
perceptions of a patient’s health and disease are perception of the effect of illness and treatment on Drug Administration,
Silver Spring,
primarily ones of an individual—the patient (Fig- physical, psychologic, and social aspects of life. Maryland;
ure 1) (1,2). Subsequently, the outcome of a disease Clinical outcome assessment (COA) is an assess- |
Department of
experience may be defined in patient-centered ways ment of a clinical outcome that can be made through Pediatrics, Division of
considering, for example, physical, mental, and so- report by a clinician, patient, or nonclinician observer Nephrology, New
York University
cial functioning, perception of wellbeing, and clini- or with a performance-based assessment. There are
Langone Medical
cal outcomes, such as organ function and patient four types of COAs: PRO, observer-reported outcome Center, New York,
survival. In clinical practice, the patient voice is of- (ObsRO), clinician-reported outcome (ClinRO), and New York; and
¶
ten sought and documented in qualitative ways that performance outcome. Division of
PRO is a measurement on the basis of a patient Rheumatology and
are difficult to track within groups of patients
Department of
with a similar condition or longitudinally in the report that comes directly from the patient (i.e., study Biostatistics and
management of a single patient. Use of patient– subject) about the status of his/her health condition Epidemiology,
reported outcome (PRO) instruments in clinical and without amendment or interpretation by a clinician University of
research settings allows the clinician and researcher or anyone else. Pennsylvania,
Philadelphia,
to capture the patient perspectives of health and ObsRO is a measurement on the basis of a report of Pennsylvania
disease in a quantitative way that can be readily observable signs, events, or behaviors related to a
incorporated into patient management and clinical patient’s health condition by someone other than the Correspondence:
research. patient or a health professional. Dr. Debbie S. Gipson,
The value of high–quality PRO instruments has ClinRO is a measurement on the basis of a report University of Michigan
that comes from a trained health care professional Pediatrics Nephrology,
been recognized by clinicians, payers, and regu-
C.S. Mott Children’s
lators in a variety of therapeutic areas. This after observation of a patient’s health condition. Hospital, 15004 East
manuscript contains a general discussion of PRO Most ClinRO measures involve a clinical judgment Hospital Drive, Ann
instruments and provides an overview of the use or interpretation of the observable signs, behav- Arbor, MI. 48109
of PRO assessments in clinical trials, observational iors, or other manifestations related to a disease Email: dgipson@med.
umich.edu
studies, and clinical care of patients with glomeru- or condition. ClinRO measures cannot directly
lar disease. assess symptoms that are known only to the
The key point is that PRO instruments provide a patient.
means to incorporate a quantitative assessment Content validity is the extent to which the assess-
of the patient voice into clinical practice and ment measures what it purports to measure in a
research. specific context of use (1,3).

140 Copyright ©2016 by the American Society of Nephrology www.cjasn.org Vol 12 January, 2017
Clin J Am Soc Nephrol 12: 140–148, January, 2017
Figure 1. | A comprehensive view of the health of a patient with
glomerular disease may include clinical markers, physician de-
termination of clinical disease severity, patient-reported outcomes,
and hard end points. UPC, urine protein-to-creatinine ratio.
Terminology
In 2016, the US Food and Drug Administration (FDA)
–National Institutes of Health (NIH) Biomarker Working
Group published the Biomarkers, Endpoints, and Other
Tools (BEST) Resource (3). The resource includes defini-
tions of terms used in translational science and medical
product development, including terminology related to
PRO instruments. Although this paper discusses the use
of PRO instruments in the clinical practice setting as well
as the research setting, for the purpose of this paper, we
provide definitions compiled from the BEST and PRO
guidance for industry (1,3).
PROs are a type of COA; hence, to appreciate the
meaning of a PRO, one needs to understand a COA. A
COA is an assessment of a clinical outcome made through
report by a clinician, patient, or nonclinician observer or
with a performance-based assessment (3). It is important
to distinguish among the types of COAs, particularly
PROs, ObsROs, and ClinROs. A PRO is defined as a mea-
surement on the basis of a patient report that comes di-
rectly from the patient about the status of his/her health
condition without amendment or interpretation by a cli-
nician or anyone else (1). A PRO instrument can be used
to assess concepts that may be narrow (e.g., pain inten-
sity) or broad (e.g., HRQOL). In contrast, an ObsRO is a
measurement on the basis of a report of observable signs,
events, or behaviors related to a patient’s health condi-
tion by someone other than the patient or a health pro-
fessional (3). ObsRO can be used in settings where a
patient is too young or otherwise unable to complete a
self-reported instrument. Finally, a ClinRO is a measure-
ment on the basis of a report that comes from a trained
health care professional after observation of a patient’s
health condition (3). Neither the observer nor the clini-
cian can validly report information known only to the
patient, such as an inability to perform a task because of
pain interference.
Patient-Reported Outcomes in Glomerular Disease, Selewski et al. 141
Some PRO instruments may have an associated proxy
version that allows a parent or other family member to
complete questions about the physical, mental, or social
health of the patient. These tools may include questions
that require inference by the proxy reporter about how a
patient feels and hence, should not be considered a PRO or
an ObsRO. Parent report of a child’s HRQOL is an example
of a proxy instrument that does not meet the definitions
of a PRO or an ObsRO. This distinction has important
implications when evaluating COAs in clinical trials, par-
ticularly those that are intended to support medical prod-
uct approval as discussed.
The key point is that a PRO is defined as a measurement
on the basis of a patient report about the status of his/her
own health condition without amendment or interpretation
by anyone else.
PRO Instruments
PRO instruments have been developed for generic and
disease-specific use. Generic instruments, such as the
Pediatric Quality of Life Inventory (PedsQL) (4), the
Short–Form Health Survey (SF-36) (5), and the Patient–
Reported Outcome Measurement Information System
(PROMIS) (6), assess concepts that may be relevant across
diseases or patient populations (Table 1). PRO measures
differ in the quantitative approaches used in development,
which include classic test theory and item response theory
(including Rasch analysis or graded response model) (7,8).
Detailed descriptions of each methodology and the asso-
ciated statistical methods are beyond the scope of this re-
view and can be found in the associated references (8–12).
In practical terms, PRO instruments aim to balance re-
sponse burden and precision by using high-quality items
(questions), which measure a single concept across a range
of responses. Administration of several items within a do-
main may improve the precision of the score. Figure 2
provides an example of item selection using item response
theory and items with good versus poor discrimination
properties.
There are important differences between how PRO
instruments that are developed using classic test theory
and those that are developed using item response theory
are used or administered. PRO instruments developed
using classic test theory (e.g., SF-36 and PedsQL) require
administration of the entire test with a prespecified set of
domains. Conversely, PRO instruments developed using
item response theory, such as the PROMIS, allow the
selection of a single item or a subset of domains or items
deemed to be of greatest relevance to the patient popula-
tion under study or care. Indeed, the effective use of the
PROMIS requires the selection of relevant domains from
the library of 23 adult and 21 pediatric domains (www.
nihpromis.org) (Figure 3). One approach to domain selec-
tion includes (1) concept elicitation from patients across a
spectrum of disease severity, (2) selection of existing items
that match the patient defined concepts, and (3) develop-
ment and validation of items to capture high-priority con-
cepts missing from available PRO resources. The goal of
disease-specific tailoring of the PRO instrument is to re-
duce the burden of administering the PRO and the noise
from domains that are irrelevant to the patient disease
142 Clinical Journal of the American Society of Nephrology

Table 1. Patient–reported outcome measures used in research in glomerular disease

Intended
Measure Domains Examples of Populations
Population

Generic outcome
tools
SF-36 General: adult Eight scored sections: vitality, CKD (40,41), lupus nephritis (42),
physical functioning, bodily autosomal dominant
pain, general health polycystic kidney disease (43),
perceptions, physical role transplant (44), hypertension
functioning, emotional role (45), nephrotic syndrome (25),
functioning, social role vasculitis (23,24)
functioning, and mental health
PedsQL 4.0 General: child Physical, emotional, social, school CKD (46–48), nephrotic
functioning syndrome (25)
PROMIS Adult General: adult Figure 3A
PROMIS General: child Figure 3B CKD (49), nephrotic syndrome
Pediatric (26,27)
Disease–specific
outcome tools
FSGS PRO Adults with FSGS Not yet published FSGS, adults
AAV PRO Adults with AAV Not yet published AAV, adults

The measure development methodology is labeled as classic test theory or item response theory. Measures developed with classic test
theory have been developed to be administered as a single set. Components of measures developed with item response theory may be
individually selected for administration while preserving the validity of the results. SF-36, 36-Item Short–Form Health Survey; PedsQL
4.0, Pediatric Quality of Life Inventory 4.0; PROMIS, Patient–Reported Outcome Measurement Information System; PRO, patient-
reported outcome; AAV, ANCA-associated vasculitis.

experience while preserving the signal from relevant do-
mains (see the Outcome Measures in Rheumatology
[OMERACT] example below).
Regardless of how they are developed, a common limita-
tion of generic PRO instruments is that they lack domains
that capture unique disease experiences particular to spe-
cific conditions, such as glomerular disease. As a result of
these limitations, researchers may choose to use disease-
specific instruments alone or in combination with generic
instruments.
The key point is that there are adult and pediatric PRO
instruments currently available. However, generic instru-
ments may lack the specificity needed to precisely capture
the patient glomerular disease experience.
Incorporating PRO Instruments in Clinical Trials
In recent years, there has been increasing interest in
incorporating the patient voice into drug development.
PROs provide an important means to incorporate the
patient perspective into clinical trials end points. Ac-
cording to the US Code of Federal Regulation (CFR),
particularly 21 CFR 314.126, methods of assessing a
patient’s response to a treatment should be “well de-
fined and reliable” (13). In 2009, the FDA finalized a
PRO Guidance for Industry to communicate how the
FDA reviews PRO instruments to determine whether
they meet this regulatory standard to support claims
in medical product labeling (1). However, regulatory
flexibility and judgment are necessary to meet the prac-
tical demands of drug development, and other ap-
proaches may also be acceptable.
From a regulatory perspective, a key aspect of a PRO
instrument is its content validity (i.e., the extent to which
the instrument measures what it purports to measure in a
specific context of use). Establishing the content validity of
an instrument is important for describing the benefit and
effect of a treatment (i.e., how the drug affects how pa-
tients feel or function) in drug labeling. The process of
establishing content validity includes generating evidence
from qualitative studies that the items of an instrument are
appropriate and comprehensive relative to what the in-
strument claims to measure in the targeted patient popu-
lation and context of use. Quantitative evaluation of an
instrument’s other measurement properties (e.g., reliability
and ability to detect change) is important to establish but
cannot replace evidence of content validity. In general,
when developing or selecting a PRO instrument, it is im-
portant to include patient input and use qualitative re-
search methodology to identify the most important and
relevant aspects of the patient experience (1,14).
Another important aspect of capturing the patient voice
in clinical trials is deciding what to measure. PROs and
other COAs that aim to measure a broad range of concepts
reported in a summary score are generally not optimal for
showing the efficacy of a therapy in a clinical trial. Included
in these instruments are often questions that are indirectly
related to the potential therapeutic action of a drug,
whereas others may not describe a treatment benefit at
all (e.g., presence of family support) or may capture infor-
mation on aspects of life that can be affected by many
factors other than the underlying disease and treatment.
Although such instruments can be important in clinical
care from a drug development standpoint, it is important
Clin J Am Soc Nephrol 12: 140–148, January, 2017 Patient-Reported Outcomes in Glomerular Disease, Selewski et al. 143

Figure 2. | Examples of item response theory item characteristics curves. These three-item information plots provide descriptive information
for Likert scale items with five different response options (never, rarely, sometimes, often, always). Higher values for probability (y axis, left) and
information (y axis, right), non-overlapping peaks, and a plot that is centered at u=0 (x axis; u values should be normally distributed) indicate
better item characteristics. The dotted lines indicate overall item information. High and wide is better. Plot (A) provides an example of an
excellent item. Plots (B) and (C) provide examples of poor items ([B] 5 poor discrimination; [C] 5 poor difficulty).

to use specific PRO instruments that focus on core,
disease–related symptoms or functional effects of a dis-
ease, which may be affected by the experimental
intervention. In general, the inclusion of attributes of
wellbeing that are indirectly related to the potential
therapeutic action of a drug (e.g., worry and hope) at-
tenuates the overall ability of the instrument to detect a
product’s efficacy and makes interpretation of any ob-
served changes challenging. That is not to say that such
multidomain PRO instruments are never useful in the
clinical trial context, but careful thought and planning
are important when selecting a PRO instrument to en-
sure that the effects of the treatment can be clearly de-
scribed in product labeling.
Although many of the concepts related to PRO instru-
ments apply to both adult and pediatric populations, one
issue that arises when conducting pediatric trials is how to
capture the response in children who are unable to respond
for themselves. In such a setting, it may be reasonable to
use ObsROs. Observer reports should only be used to
capture events or behaviors that can be observed. In
relation to glomerular diseases and the manifestations of
nephrotic syndrome, certainly parents and caregivers can
observe the presence of edema in a child. However, a key
issue is whether the observed changes in edema are
meaningful to the child (i.e., affect how the child feels or
functions). Because edema can interfere with activities de-
pendent on physical functioning, observer report of
edema could be complemented by an observation-based
instrument assessing the effect of the edema on daily life
functioning or mobility. Furthermore, a pattern of im-
provement on both outcomes in a clinical trial could
provide evidence of clinical benefit.
The key point is that PRO assessments may be used as
end points in clinical trials to establish the effectiveness of
medical products and support claims in medical product
labeling. Guidance is available from the FDA on the
development and use of PRO instruments in medical
product development.
Existing PRO Studies in Glomerular Disease and
Lessons Learned from Vasculitis
Lessons Learned from Vasculitis
Vasculitis provides an excellent example of the evolution
of PRO instruments in a therapeutic area that overlaps with
other glomerular diseases. Similar to many other glomer-
ular diseases, the vasculitides are systemic in nature and
affect multiple organ systems. Moreover, kidney dysfunc-
tion is also a critical component of many vasculitides and
contributes significantly to patient morbidity. Thus, the
strategies adopted and lessons learned from the develop-
ment of PRO instruments for vasculitis serve as a useful
model.
The OMERACT group is an international group of
clinical investigators, patients, methodologists, and repre-
sentatives from the biopharmaceutical industry and regu-
latory agencies focused on data-driven approaches to
validating outcome instruments for use in clinical trials.
The OMERACT Vasculitis Working Group implemented a
multiyear research agenda, which led to the evaluation,
validation, and endorsement of a “Core Set” of outcome
measurements for use in clinical trials of ANCA-associated
vasculitis (15). The Core Set includes the following do-
mains: disease activity, disease damage, PRO instruments,
and mortality. Before endorsement of the Core Set, each
domain had to have at least one associated validated out-
come assessment.
Early efforts to identify a PRO instrument to use as an
outcome assessment examined the SF-36, and differences
were detected in a manner comparable with the experience
with other chronic diseases with modest correlation to
physician-based instruments (16,17). Similarly, a simple
Patient Global Assessment was useful in assessing disease
144 Clinical Journal of the American Society of Nephrology

Figure 3. | The Patient–Reported Outcome Measurement Information System (PROMIS) was developed with item response theory methods.
Selection and use of an individual or a subset of items or domains that are specifically relevant to a specified patient population can improve
patient–reported outcome measurement precision and reduce question burden for irrelevant domains. (A) Adult domains for ages 18 years old
and older. (B) Pediatric domains. Children can complete the PROMIS reliably at age 8 years old and older. Reprinted from the PROMIS Health
Organization and the PROMIS Cooperative Group (http://www.nihpromis.org/measures/full_framework.aspx), with permission.

activity in ANCA-associated vasculitis (18). Although
these instruments had some use in vasculitis, it became
clear that generic instruments lacked the ability to capture
the full spectrum of outcomes important to these patients
(19–22).
In response to the unmet need to develop PRO instru-
ments, the OMERACT Vasculitis Working Group spear-
headed parallel projects to advance the development and
validation of PROs in vasculitis. Three initial projects
focusing on PROs in ANCA-associated vasculitis were
Clin J Am Soc Nephrol 12: 140–148, January, 2017
undertaken: (1) exploration of the utility and validity of
different PROMIS domains and instruments in ANCA-
associated vasculitis, (2) development of a disease–specific
PRO instrument for ANCA-associated vasculitis (ANCA-
associated vasculitis PRO), and (3) examination of out-
come instruments in vasculitis according to the World
Health Organization’s International Classification of Func-
tion (22). Through individual interviews with patients in
three countries using standard qualitative methods,
themes of importance to patients were extracted; these
data guide all three projects. This collaborative effort,
which represents a work in progress, provides a useful
model for clinicians and researchers working in the arena
of glomerular diseases.
To date, several large randomized trials in ANCA-
associated vasculitis have included PRO instruments as
secondary outcomes using the SF-36. These include the
trials of etanercept as adjuvant to standard therapy and
rituximab for induction of remission (23,24). In each of
these studies, treatment was associated with an improve-
ment in the PRO score. To date, trials using a disease-
specific instrument as a protocol–defined outcome assessment
have not been conducted in patients with vasculitis.
The medical literature in vasculitis has taught us several
valuable lessons. First, generic PRO instruments in clinical
trials provide insight into the patient experience and show
that the ANCA-associated vasculitides significantly affect
patients. Second and more importantly, the work of the
OMERACT group has shown that generic instruments do
not fully capture the relevant disease experience in these
patients. Third, this group has created a path forward,
which may be modeled by other study groups, that has
resulted in the creation of a disease-specific instrument
that, when validated, may serve to better characterize PRO
measurement in these patients.
Generic PRO Instruments in Nephrotic Syndrome
Some studies have evaluated PRO instruments in adults
and children with nephrotic syndrome. In the NIH–
sponsored FSGS Clinical Trial, 138 patients with steroid-
resistant FSGS were randomized to one of two treatment
arms. PROs were assessed using the PedsQL in the 94
pediatric participants and the SF-36 in the 45 adult partic-
ipants. At enrollment, trial participants had a worse PRO
than healthy controls. Children with FSGS reported lower
domain scores in physical, emotional, and school function-
ing and lower total score. Similarly, the adults reported
lower domain scores than healthy controls in the SF-36
Mental Health and Physical Health composites and the
domains of mental health, vitality, general health, role
physical, and social functioning (25). This trial did not
show a difference in proteinuria end points or PRO out-
comes between the study arms. In a cross-sectional study
of 151 children with nephrotic syndrome designed to val-
idate the PROMIS instruments, children with active dis-
ease (edema) had worse scores on the anxiety, fatigue,
pain interference, and mobility domains (26). In a prospec-
tive study of 127 children with active nephrotic syndrome,
the PROMIS scores were worse in prevalent versus inci-
dent patients in the domains of peer relationship and pain
interference. Within this same study, the PedsQL scores
Patient-Reported Outcomes in Glomerular Disease, Selewski et al. 145
were also worse among prevalent patients in comparable
domains of social functioning and school functioning (27).
Finally, in a cross-sectional study of 99 patients with ne-
phrotic syndrome, the SF-36 PRO scores were associated
with proteinuria clinical outcomes (28).
In total, PRO studies have shown that adults and
children with nephrotic syndrome have significant impair-
ments detectable with generic PRO instruments compared
with healthy controls and active nephrotic syndrome
compared with inactive disease. However, similar to
studies in vasculitis, generic instruments alone may lack
the ability to capture the patient disease experience in
nephrotic syndrome in a precise, sensitive, and patient-
relevant manner. Specifically, generic instruments do not
describe all of the disease characteristics, such as individual
symptoms (e.g., edema), overall symptom burden, and the
relapsing nature of the disease, that are relevant to this
patient population. A single disease–specific PRO for
adults with FSGS has been generated and is now under-
going testing within an ongoing clinical trial (29). No other
disease–specific PRO instruments for adults or children
with nephrotic syndrome or its associated conditions
have been published.
PRO Instruments in Observational Studies
PRO instruments are important outcome assessments in
observational studies of patients with glomerular disease
for many of the same reasons that they are important for
clinical trials. PROs can be informative for short-, intermediate-,
and long-term studies. The importance of PRO assessments
in cohort studies has been recognized by the NIH, and PRO
instruments have been increasingly incorporated into lon-
gitudinal glomerular disease cohort studies, such as the
Nephrotic Syndrome Study Network and CureGN projects
as well as the those of the Vasculitis Clinical Research
Consortium (30,31). Information obtained from these pro-
spective observational studies may be used to help estab-
lish the validity and reliability of these PRO instruments
and support the use of these assessments as end points in
future drug development trials.
The key point is that PRO instruments have consistently
shown that patients with a variety of glomerular diseases
have impairments but that generic instruments do not fully
capture the patient disease experience. Disease-specific
instruments are needed, and they are being developed for
glomerular diseases.
Implementing PROs in Clinical Trials and Clinical
Care
PRO Instruments in Clinical Trials
Across the medical fields, PRO use has been increasing in
clinical trials; currently, 27% of all clinical trials registered
on Clinicaltrials.gov incorporate PRO instruments (32).
Several drugs have been approved with FDA labeling de-
scribing the effect of the drug on a PRO instrument. An
example of one such drug is ruxolitinib, an mAb kinase
inhibitor that is used to treat severe myelofibrosis. Specif-
ically, the product labeling notes a “a greater likelihood
of a 50% or greater reduction in Total Symptom Score
from baseline to Week 24 as measured by the modified
Myelofibrosis Symptom Assessment Form.” As of the
146 Clinical Journal of the American Society of Nephrology
publication of this manuscript, there have not yet been any
clinical trials in glomerular disease where PRO assess-
ments have served as the primary outcome or where
PROs have served an important role in drug approval or
labeling.
Transitioning from Research to Clinical Care
Although PRO instruments have been administered in
patients with glomerular disease in a number of research
settings, incorporation of PRO assessments into clinical
practice requires an implementation strategy and PRO results
that are readily available, interpretable, and relevant to
treatment decision making. In nephrology practice, PRO
assessments have been added to the care of patients on
dialysis in the United States on the basis of a mandate by the
Center for Medicare and Medicaid Services (33). An equiv-
alent mandate does not exist in glomerular disease, but PRO
instruments are available within many nondialysis care en-
vironments and electronic health record systems.
Typically, PRO responses are transformed into continu-
ous scores, often ranging from zero to 100. From a clinical
standpoint, a clinician might ask “what does a mobility
score of 55 indicate?” When the score is reported on a T
scale normed to 50 with an SD of 10, we know that a value
of 55 is five points or one half of an SD above the calibra-
ted mean (34). Nephrologists already routinely interpret
clinically meaningful strata and changes of other markers
of glomerular disease, such as eGFR, serum albumin, and
proteinuria. The interpretation of PRO scores may simi-
larly use the concept of strata of scores and meaningful
changes in scores. PRO score strata may be defined rela-
tive to a healthy population or relative to the range of
scores observed from within the same disease population.
In longitudinal single–patient follow-up, the determina-
tion of a score change of sufficient magnitude to
consider a change in management may be informed by
prior publications documenting the minimally important
difference in score within the same population (35) statis-
tically by, for example, a change of $0.5 SD or anchor-
based methods. A minimally important difference of three
points in the PROMIS instruments has been defined for
children with nephrotic syndrome and other chronic
health conditions through research including patients, par-
ent caregivers, and physicians (35). The determination of
the meaning of PRO scores assessed cross-sectionally and
changes in scores assessed longitudinally will advance the
clinical utility of these outcomes.
PRO instruments can include multiple or single domains.
When patients are invited to identify the domains of
relevance, physical, mental, and social health concepts
may emerge as important. Incorporating a meaningful set
of PRO domains in a single instrument as part of a clinical
visit may help pinpoint which domains are problematic for
an individual patient. Targeted intervention may then be
prescribed to improve the physical, mental, or social health.
For example, patients with active glomerular disease often
report poor mobility and pain (26). Recognition of these
PROs and targeted treatment may improve patient out-
comes and satisfaction with care (36–38).
Administration of PROs in clinical settings may be
delivered through electronic medical record patient portals,
in paper format, or administered verbally. When incor-
porating PRO assessments into clinical care, a variety of
options for administration of PRO instruments may be
needed to assure assessment of all patients, regardless of
access to computers, literacy, or functional differences in
vision, hearing, and dexterity (39).
The key point is that PRO instruments are increasingly
being incorporated into clinical trials. PROs can be used in
medical product development to support claims in medical
product labeling. The electronic medical record provides an
opportunity for the incorporation of PRO instruments into
clinical care.
Conclusions
Incorporation of the patient perspective into research
and clinical practice will enrich our understanding of the
status and management of patients with glomerular
disease beyond the traditional clinical and laboratory-
based assessments. Current methodologies for the de-
velopment, validation, and selection of PRO instruments
can be readily adopted by the research, clinical, and
patient communities to accelerate the use of PRO instru-
ments. The experience in the field of vasculitis provides a
paradigm that can be applied in nephrology and in
particular, to patients with other forms of glomerular
disease. Incorporation of PRO assessments into clinical
trials can provide end points that are meaningful and
measureable, even in short-term studies. The importance
of the patient experience has been recognized by the FDA
with acceptance of PRO assessments as end points for
clinical trials. The FDA provides guidance so that PRO
instruments are developed in a way that supports their
use in the generation of evidence to support medical
product testing. Several generic PRO instruments exist
for use by clinicians and researchers, but they may not
adequately capture the patient experience with glomer-
ular diseases. Disease-specific instruments are emerging
that may, alone or with generic measures, augment our
ability to capture the patient experience with greater
precision.
Acknowledgments
D.T.S., J.P.T., D.S.G., and the work described for pediatric
nephrotic syndrome received support from National Insti-
tutes of Health, National Center for Research Resources (grant
5U01AR052181-05), National Institute of Arthritis and Musculo-
skeletal and Skin Diseases (grant 2U01AR05218106), and the
NephCure Kidney International Foundation. The Nephrotic Syn-
drome Patient–Reported Outcomes Workshop was supported by
the NephCure Kidney International Foundation. P.A.M. and the
work described for vasculitis was supported by the Vasculitis
Clinical Research Consortium, which has received support from
National Institute of Arthritis and Musculoskeletal and Skin Dis-
eases (grants U54 AR057319, U01 AR5187404, and R01 AR064153);
the National Center for Advancing Translational Science; and the
Office of Rare Diseases Research. Additional support for the work
of the Outcome Measures in Rheumatology Vasculitis Working
Group was received through a Patient–Centered Outcomes Re-
search Institute Pilot Project grant. D.S.G. served as a coinvestigator
in the development of the FSGS patient–reported outcome spon-
sored by GlaxoSmithKline (Brentford, United Kingdom).
Clin J Am Soc Nephrol 12: 140–148, January, 2017
This article reflects the views of the authors and should not be
construed to represent the views or policies of the US Food and Drug
Administration.
Disclosures
D.T.S., A.T., S.K., E.J.P., N.E.C., and J.P.T. have no conflicts of interest
to report. H.T. serves as a consultant to Otsuka and Kaneka. P.A.M.
receives research support from Actelion, Bristol-Myers Squibb
(Princeton, NJ), Celgene, ChemoCentryx, Genentech (South San
Francisco, CA)/Roche (Basel, Switzerland), and GlaxoSmithKline
(Brentford, United Kingdom) and provides consulting for Actelion,
Alexion, Bristol-Myers Squibb, ChemoCentryx, Genentech/Roche,
MedImmune/AstraZeneca Pharmaceuticals (Wilmington, DE),
Prothena, and Sanofi US (Bridgewater, NJ). D.S.G. serves as a
consultant for GlaxoSmithKline, Retrophin, Janssen Biotech (Hor-
sham, PA), and Bristol-Myers Squibb (through University of
Michigan) and receives research support from Retrophin,
GlaxoSmithKline, and Bristol-Myers Squibb.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Minimal Change Disease
Marina Vivarelli,* Laura Massella,* Barbara Ruggiero,† and Francesco Emma*

Abstract
Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense
proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15%
of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%–90% in children >1
year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient *Division of
responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS Nephrology and
can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by Dialysis, Bambino
light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is Gesù Children’s
Hospital, IRCCS,
likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and
Rome, Italy; and
modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement †
Clinical Research
membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive Center for Rare
forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immu- Diseases “Aldo e Cele
nosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic Daccò”, IRCCS –
Istituto di Ricerche
renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. Farmacologiche Mario
However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, Negri, Ranica,
with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 Bergamo, Italy
antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.
Clin J Am Soc Nephrol 12: 332–345, 2017. doi: 10.2215/CJN.05000516 Correspondence:
Dr. Marina Vivarelli,
Division of
Nephrology and
Introduction Therefore, the terms steroid-sensitive NS on the basis Dialysis, Ospedale
In adults, minimal change disease (MCD) represents Pediatrico Bambino
of clinical features and MCD on the basis of histo-
Gesù–IRCCS, Piazza
approximately 10%–15% of patients with idiopathic logic picture are not entirely equal. In clinical practice, S. Onofrio 4, 00165
nephrotic syndrome (Figure 1) (1,2). In children .1 year however, especially in children who do not systemat- Rome, Italy. Email:
of age, MCD is the most common cause of nephrotic ically undergo a renal biopsy, these terms are often marina.vivarelli@
syndrome, accounting for 70%–90% of patients; used as synonyms. In this review, the term MCD will opbg.net
around puberty, this proportion decreases signifi- include all children with classic clinical features of
cantly as other glomerular diseases, such as membra- steroid-sensitive NS in which a renal biopsy was not
nous nephropathy, become more frequent (Figure 1) performed, and all adults with the histologic pattern of
(3,4). The histologic picture of MCD is identical in MCD regardless of response to therapy.
adults and children. Because most children respond
to steroid treatment, the disease is termed “steroid-
sensitive nephrotic syndrome” (steroid-sensitive NS) Definitions and Epidemiology
on the basis of clinical features, and renal biopsy is The reported incidence of MCD in children varies
not performed unless steroid resistance is observed. If between two and seven new cases per 100,000 chil-
performed, it usually shows the absence of significant dren (3,7). The exact prevalence is not known, but on
changes by light microscopy (LM), a finding that has the basis of disease evolution and average age of
puzzled physicians for decades. When ultrastructural onset, it can be estimated at approximately 10–50 cases
analyses were first performed in the 1950s, extensive per 100,000 children. The disease is slightly more com-
fusion of podocyte foot processes was observed (5). mon in Asia and has a male predominance (approxi-
Soon after, the term “lipoid nephrosis,” introduced mately 2:1) in young children that disappears in
in the early 1900s to describe the presence of micro- adolescents and adults (3,8). MCD is much less fre-
scopic lipid droplets in urine and tubular cells, was quent in adults, but the exact incidence in this popula-
replaced by MCD, to highlight the existence of mini- tion is less well documented.
mal alterations of the glomerulus by LM. However, a Defining steroid sensitivity represents a first critical
minority of patients that have FSGS lesions on their aspect for prognosis, as forms that respond do not evolve
renal biopsy do respond to steroids and, conversely, toward chronic renal failure. In MCD, unlike other
patients with steroid-resistant nephrotic syndrome glomerular diseases, steroid response when present
(steroid-resistant NS) may have MCD at disease onset, is often complete, with total disappearance of protein-
before developing FSGS lesions later in the course of uria. However, time to remission is very different in
their disease (6). children compared with adults. As shown in Figure 2,

332 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 February, 2017
Clin J Am Soc Nephrol 12: 332–345, February, 2017 Minimal Change Disease, Vivarelli et al. 333

Figure 1. | Etiology of nephrotic syndrome according to age from 1 year onwards. (A) Minimal change disease. (B) Focal segmental glo-
merulosclerosis. (C) Membranous nephropathy. Data are approximated from Nachman et al. (1) and Cameron (2).
334 Clinical Journal of the American Society of Nephrology
Figure 2. | Time-to-response to prednisone is much shorter in children than in adults with minimal change disease. Data are extrapolated from
references Waldman et al. (12) and Vivarelli et al. (82) for children (A and B), from references (83) and Chen et al. (84) for adults (C and D).
after a first episode, approximately 50% of children achieve re-
mission within 8 days of steroid treatment and most patients
who are going to respond to steroids do so within 4 weeks.
In contrast, in adults the median time to remission exceeds
2 months. In both populations, MCD has a high tendency to
relapse, and relapses tend to be more rapid in children.
In Table 1, a further classification of MCD in clinical
subgroups on the basis of response to therapy, separating
children and adults, is reviewed. This classification for
children was initially proposed by the International Study
of Kidney Disease in Children (ISKDC) (9) and has been
adapted over the years (10).
Pathology
MCD accounts for the vast majority of idiopathic NS in
children, particularly for the steroid-sensitive forms (3,11).
In adults the picture is much more varied, with MCD be-
ing the third cause of idiopathic NS, after FSGS and mem-
branous nephropathy (1,2,4). Thus, whereas in adults early
kidney biopsy is crucial in driving the therapeutic ap-
proach (12), the indications for renal biopsy in children
are limited to features that may suggest alternative diag-
noses: at onset, age ,1 or .12 years, gross hematuria, low
serum C3, marked hypertension, renal failure without
severe hypovolemia, and positive history for secondary
cause; subsequently, steroid resistance or therapy with cal-
cineurin inhibitors. By LM, no glomerular lesions or only
mild focal mesangial prominence not exceeding three or
four cells per segment are seen. The presence of more than
four mesangial cells per mesangial region affecting at least
80% of the glomeruli defines the diffuse mesangial hyper-
cellularity variant of MCD. These patients can present
with hematuria and hypertension, unlike children with
classic MCD (13). Immunofluorescence is usually negative.
However, low-intensity mesangial IgM (sometimes accom-
panied by C3 or C1q) staining can be found (14) and MCD
is occasionally accompanied by glomerular IgA deposits, a
histologic picture that has been defined as IgA nephro-
pathy with MCD (15). Focal segmental distribution of IgM
and C3 staining should strongly suggest FSGS even when
no sclerotic lesions are captured by LM, whereas more
than trace amounts of IgG and IgA suggest alternative di-
agnoses. By electron microscopy, foot process effacement
is the only morphologic feature of MCD. Other pathologic
features automatically exclude the diagnosis of MCD,
which is therefore a diagnosis of exclusion.
Clinical Features
Rarely, nephrotic-range proteinuria is discovered on a
routine urinalysis, but most frequently the presenting
symptom of MCD is nephrotic syndrome, characterized by
edema, periorbital (often misinterpreted as allergic), of the
scrotum or labia, and of the lower extremities (11). Anasarca
may develop with ascites and pleural and pericardial effu-
sion, leading to abdominal pain because of hypoperfusion
and/or thrombosis, dyspnea (rarely), and cold extremities
with low BP (11). Especially in children, severe infections
such as sepsis, pneumonia, and peritonitis may be present at
disease onset or during disease course because of Ig de-
pletion and altered T cell function (16). Moreover, onset is
frequently preceded by upper respiratory tract infection.
Intravascular volume depletion and oliguria are also pres-
ent, and concomitant factors (sepsis, diarrhea, diuretics) can
lead to AKI, which is more frequently seen in adults (12),
although it occurs in about half of children hospitalized for
nephrotic syndrome (17). Rarely, AKI with gross hematuria
followed by anuria can also be secondary to bilateral renal
vein thrombosis. Gross hematuria is rare, occurring in 3% of
patients (11).
Laboratory analyses begin with urinalysis, with urinary
dipstick showing 31/41 proteinuria (corresponding to
$300 mg/dl on urinalysis) and, in about 20% of pa-
tients, microhematuria, which may resolve during remission
of proteinuria. Urine collection shows nephrotic-range
Clin J Am Soc Nephrol 12: 332–345, February, 2017 Minimal Change Disease, Vivarelli et al. 335

Table 1. Definitions on the basis of references (9,10,64) and on the authors’ clinical experience

Nephrotic Syndrome
Edema
Massive proteinuria (.40 mg/m2 per h in children, .3.5 g/d in adults)
Hypoalbuminemia (,2.5 g/dl)
Remission
Resolution of edema
Normalization of serum albumin ($3.5 g/dl)
Marked reduction in proteinuria
Complete remission (,4 mg/m2 per h or negative dipstick in children, ,0.3 g/d in adults)
Partial remission (,2 g/1.73 m2 per d, decreased by 50% and serum albumin $2.5 g/dl in children, ,3.5 g/d and
decreased by 50% in adults)
Relapse
Recurrence of massive proteinuria (.40 mg/m2 per h in children, .3.5 g/d in adults)
Positive urine dipstick ($31 for 3 d or positive for 7 d, usually applicable to children)
6Edema
Steroid-Sensitive Nephrotic Syndrome
Response to PDN 60 mg/m2 per d within 4–6 wk 6MPD boluses in children
Response to PDN 1 mg/kg per d or 2 mg/kg every other d, within 16 wk in adults
Nonrelapsing Nephrotic Syndrome
No relapses for .2 yr after the end of therapy for the first episode of nephrotic syndrome (applicable to children, not
yet defined in adults)
Infrequently Relapsing Nephrotic Syndrome
,2 relapses per 6 mo (or ,4 relapses per 12 mo)
Frequently Relapsing Nephrotic Syndrome
$2 relapses per 6 mo (or $4 relapses per 12 mo)
Steroid-Dependent Nephrotic Syndrome
Relapse during steroid therapy or within 15 d of discontinuation
Steroid-Resistant Nephrotic Syndrome
No response to PDN 60 mg/m2 per d within 4 wk 6MPD boluses in children
No response to PDN 1 mg/kg per d or 2 mg/kg every other d, within 16 wk in adults
Multidrug-Resistant Nephrotic Syndrome
Poorly defined as absence of partial remission after 6 mo OR absence of complete remission after 2 yr
Treatment often consists of MPD boluses 1 oral prednisone for 6 mo 1 CsA and, in some cases, rituximab. Other
protocols are also used

PDN, prednisone; MPD, methylprednisolone; CsA, cyclosporine A.

proteinuria (urine proteins .40 mg/h per m2 or urine
protein-to-creatinine ratio .200 mg/mmol in children (11)
and urine proteins .3.5 g/d in adults [12]). Blood chem-
istry shows a reduction in serum total protein and serum
albumin, frequently ,2 g/dl, with an increased a2-globulin
and a reduced g-globulin fraction. The reduction in serum
protein leads to a reduced total serum calcium, with ion-
ized calcium usually within the normal range. IgG is mark-
edly decreased, IgA is slightly reduced, IgM is increased,
and IgE is normal or increased. Hyperlipidemia is pres-
ent, and is a consequence of (1) an increased hepatic syn-
thesis of cholesterol, triglycerides, and lipoproteins; (2)
a decreased catabolism of lipoproteins because of a de-
creased activity of lipoprotein lipase which transforms
VLDL to LDL; and (3) a decreased LDL receptor activity
and an increased urinary loss of HDL and proteins with
anticoagulant properties, such as antithrombin III. Regard-
ing hematologic parameters, hemoconcentration leads to
increased hemoglobin and hematocrit levels, and thrombo-
cytosis is frequently observed (11). This array of alter-
ations (hypovolemia, hyperdyslipidemia, urinary loss of
anticoagulants, and thrombocytosis) is worsened by
an increase in circulating fibrinogen, factors V and VIII,
and protein C, leading to a state of hypercoagulability and
therefore to an increased risk of thrombosis, usually (97% of
patients) venous thrombosis (18). Added risk factors for
thromboembolic disease are infection, the presence of a
central venous line, immobilization, and underlying genetic
thrombophilia (11).
Pathogenesis
It is as yet debated whether MCD and FSGS represent
a disease continuum with a common pathogenesis or two
separate disease entities. Excluding secondary forms of
MCD (Table 2), the vast majority of cases arise in other-
wise healthy individuals. Because the main histologic
feature is foot process effacement, visible by electron mi-
croscopy, studies have concentrated on finding what
disrupts the integrity of the glomerular filtration barrier.
Figure 3 shows a sketch of this disruption and of some of
the mechanisms that may contribute to determining it. The
existence of one or more circulating factors capable of in-
creasing its permeability, thus resulting in proteinuria,
was first hypothesized on the basis of observations of
the capability of plasma taken from nephrotic subjects to
336 Clinical Journal of the American Society of Nephrology

shown an imbalance in T cell subpopulations during active

Table 2. Secondary causes of minimal change disease (1,11) phase of disease, with a prevalence of circulating CD81
T suppressor cells that aggravate renal damage in mouse
Allergy models of nephrotic syndrome (24) and a prevalence of a
Pollen type 2 T helper cell (Th2; IL4, IL5, IL9, IL10, and IL13)
Dust
cytokine profile in patients (25), which is mirrored by the
Fungi
Bee sting spontaneous model of idiopathic nephrotic syndrome in
Cat fur the Buffalo/Mna rat (26). These observations fit with the
Food allergens (cow’s milk, egg) clinical observation of an association between MCD and
Malignancies atopy, as allergies are driven by Th2 responses. Of all Th2
Hodgkin disease cytokines, IL13 overexpression has been shown to induce
Non-Hodgkin lymphoma foot process effacement and proteinuria in rats (27). Certainly,
Leukemia no single cytokine can be considered pathogenic per se in
Multiple myeloma MCD, but rather may play a role in the context of a complex
Thymoma network with multiple cellular and circulating players (28).
Bronchogenic cancer
Moreover, different lines of evidence suggest a reduced
Colon cancer
Eosinophilic lymphoid granuloma (Kimura disease) function of regulatory T cells in MCD in adult patients
Drugs (29). Confirming this, MCD has been observed in immune
Nonsteroidal anti-inflammatory drugs dysregulation, polyendocrinopathy, enteropathy, X-linked
Salazopyrin syndrome, a congenital immunodeficiency with severe T
D-penicillamine regulatory cell hypofunction (30).
Mercury In the last few years, clinical evidence of the effectiveness
Gold of B cell depletion via rituximab, an anti-CD20 monoclonal
Tiopronin antibody, in different forms of nephrotic syndrome has
Lithium suggested a role for B cells as drivers of disease. Looking
Tyrosine-kinase inhibitors
back, multiple lines of evidence implicate B cells in the
Infections
Viral pathogenesis of nephrotic syndrome (reviewed in Elie
Parasitic et al. [20]): (1) total IgG and IgG subclasses display pro-
Mycoplasma pneumoniae tracted alterations in nephrotic patients during remission;
Autoimmune disorders (2) MCD has been observed in diseases associated with
SLE monoclonal light chains, implicating altered Igs in disease
Diabetes mellitus pathogenesis; (3) plasma soluble CD23, a classic parameter
Myasthenia gravis of B cell activation, is increased during relapse; (4) measles
Autoimmune pancreatitis virus also has an inhibitory effect on Ig synthesis; and (5)
Celiac disease the immunosuppressors employed in the treatment of
Allogeneic stem cell transplantation
Immunizations MCD have an antiproliferative effect on B cells, as well
as on T cells. However, there are also lines of evidence
against a direct role of B cells in MCD pathogenesis. First
of all, by definition in MCD there is little or no Ig deposi-
induce proteinuria in previously non-nephrotic subjects, tion on renal biopsy. In vitro, rituximab has been proven to
and a vast body of literature in both human and mouse bind directly to podocyte SMPDL3b and it has been sug-
models has been accrued regarding FSGS (19). In MCD gested that its antiproteinuric effect may be independent
there is less clinical evidence of this, but the existence of B cell depletion (31). Moreover, after rituximab infusion,
of a circulating mediator produced by abnormal T cells some patients maintain prolonged remission despite re-
was postulated as far back as 1974 by Shalhoub, on the constitution of B cells (32). Regarding this aspect, we
basis of the following observations: (1) remission may fol- have recently shown that after rituximab-induced B cell
low measles infection, which causes cell-mediated immu- depletion in children with frequently relapsing nephrotic
nosuppression; (2) MCD may occur in Hodgkin disease, syndrome or steroid-dependent nephrotic syndrome, the
a lymphoid neoplasia; (3) MCD responds to drugs that reconstitution of memory B cells predicts relapse (33). Tar-
suppress cell-mediated immunity; and (4) unlike other geting B cells may affect costimulatory pathways involved
glomerular disorders, there is an absence of humoral (Ig in T cell activation, and this may well be one of the mech-
and complement) deposition in glomeruli (16,20). This hy- anisms involved in the effectiveness of CD20-depleting
pothesis was strengthened by studies showing that super- agents, such as rituximab and the newer humanized
natants of T cell hybridoma lines produced from patients anti-CD20 monoclonal antibody, ofatumumab (34).
with MCD were able to induce foot process effacement In the last decade, studies have focused on the role of
and proteinuria in rats (21). Subsequently, a vast body of podocytes in determining proteinuria in MCD. A variety of
evidence has emerged implicating different aspects of interesting studies have investigated this aspect of MCD
T cell regulation and function in driving podocyte injury pathogenesis. One potential target of T cells on the podocyte
in MCD (20). These are reinforced by the therapeutic ef- is CD80 (also known as B7–1), a T cell costimulatory mole-
fectiveness of immunosuppression, both with prednisone cule expressed on antigen-presenting cells and B cells, which
and second-line steroid-sparing agents, as will be dis- has been found in the urine of patients with MCD during
cussed below. In summary, these results (22,23) have disease relapse (35). Recently, however, the presence of
Clin J Am Soc Nephrol 12: 332–345, February, 2017 Minimal Change Disease, Vivarelli et al. 337

Figure 3. | Pathogenesis of minimal change disease: hypotheses. In the presence of a normal glomerular basement membrane (shown at the
center), with healthy podocyte foot processes (light blue), serum proteins, mainly albumin, remain within the glomerular capillary lumen.
Mechanisms, that are as yet not fully elucidated but are partly intrinsic to the podocyte and partly due to the presence of soluble mediators
released by a disregulated immune system (see top of the figure and text), modify this integrity. Therefore (red arrow), the actin cytoskeleton of
the podocyte and the glomerular basement membrane are disrupted, and albumin and other serum proteins filter out of the bloodstream and
into the urinary space. This leads to the intense proteinuria seen in nephrotic syndrome.

CD80 on human podocytes during renal disease, including
MCD and FSGS, as well as in experimental models of the
diseases, has been excluded and the efficacy of recombinant
CTLA4-Ig (abatacept and belatacept, which downregulate
CD80) in reducing proteinuria was not confirmed (36). These
results suggest caution and the need for thorough valida-
tion of preclinical results before passing from bench to bed-
side. Another mediator that has been implicated in the
pathogenesis of MCD is hemopexin, a plasma protein that
binds sialoglycoproteins in podocytes, leading to proteinuria
and foot process effacement in rats and cytoskeletal re-
arrangement in human cultured podocytes (37). A key pro-
tein found to be upregulated in both MCD and FSGS is c-mip
(reviewed in Ollero and Sahali [38]). Transgenic mice
overexpressing c-mip in podocytes develop heavy proteinuria
without any inflammatory lesions or cell infiltration. c-mip
 338

Table 3. Therapy procedures for children, modified by KDIGO 2012 (43), Prof. Arvind Bagga, and authors’ clinical experience

Italy 2016 (SINePe

Therapy United States 2009 India 2008 France 2008 KDIGO 2012 Recommendations in
Preparation)

PDN at onset 2 mg/kg per d, 6 wk 2 mg/kg per d, 6 wk 60 mg/m2 per d, 4 wk 60 mg/m2 per d (or 2 mg/kg 60 mg/m2 per d, 6 wk
1.5 mg/kg every other d 1.5 mg/kg every 60 mg/m2 every other d per d), 4–6 wk 40 mg/m2 every other d,
6 wk, no taper other d 8 wk, taper 40 mg/m2 every other d (or 6 wk
Duration 12 wk 6 wk, no taper Duration 18 wk 1.5 mg/kg every other d), No taper
Duration 12 wk 2–5 mo, taper Duration 12 wk
Minimum duration 12 wk
PDN in relapse 2 mg/kg per d until 2 mg/kg per d until 60 mg/m2 per d until 60 mg/m2 per d (or 2 mg/kg 60 mg/m2 per d until
(first relapses, 3 d after remission; 3 d after remission 6 d after remission per d) until 3 d after 5 d after remission
NRNS) 1.5mg/kgeveryotherd 1.5 mg/kg every 60 mg/m2 every other remission 40 mg/m2 every other d,
4 wk, no taper other d, 4 wk, no d, 4 wk, taper 40 mg/m2 every other d (or 4 wk
Clinical Journal of the American Society of Nephrology

taper 1.5 mg/kg every other d), No taper

4 wk
No taper
Long-term 2 mg/kg per d until 2 mg/kg per d until 60 mg/m2 per d until 60 mg/m2 per d (or 2 mg/kg Not yet available
PDN (FRNS 3 d after remission 3 d after remission 6 d after remission per d) until 3 d after
or SDNS) 1.2 mg/kg every other 1.2 mg/kg every 60 mg/m2 every other remission
d, 4 wk other d, 4 wk d, 4 wk 40 mg/m2 every other d (or
Taper by 0.5 mg/kg Taper by 0.5–0.7 mg/ Taper by 15 mg/m2 1.5 mg/kg every other d)
every other d over kg every other d every other d, Taper over $3 mo
2 mo Continue for 9–18 mo every 2 wk up to Lowest every other d or
15 mg/m2 every daily dose to maintain
other d, continue for remission
12–18 mo
Steroid-sparing FRNS: CPA 12 wk Lev 1–2 yr Lev CPA 8–12 wk Not yet available
agents (FRNS MMF 1–2 yr CPA 12 wk CPA Chlorambucil 8 wk
or SDNS) CsA/TAC 2–5 yr CsA/TAC 1–2 yr CsA Lev.1 yr
SDNS: CsA/TAC MMF 1–2 yr MMF CsA/TAC.1 yr
MMF MMF.1 yr
CPA Rituximab

KDIGO, Kidney Disease Improving Global Outcomes; SINePe, Società Italiana Nefrologia Pediatrica; PDN, prednisone; NRNS, nonrelapsing nephrotic syndrome; FRNS, frequently relapsing
nephrotic syndrome; SDNS, steroid-dependent nephrotic syndrome; CPA, cyclophosphamide; Lev, levamisole; MMF, mofetil mycophenolate; CsA, cyclosporine A; TAC, tacrolimus.
Clin J Am Soc Nephrol 12: 332–345, February, 2017 Minimal Change Disease, Vivarelli et al. 339

Table 4. Therapy procedures for adults (64,66,75)

First Episode of Nephrotic Syndromea

PDN 1 mg/kg per d or 2 mg/kg every other d (maximum 80 mg/d or 120 mg every other d) for 4–16 wk (evidence
level 2C)
Taper slowly over a total period of up to 6 mo after achieving remissionb (evidence level 2D)
Infrequent relapses
PDN 1 mg/kg per d or 2 mg/kg every other d (maximum 80 mg/d or 120 mg every other d) for 4–16 wk (evidence
level 2C)
Taper slowly over a total period of up to 6 mo after achieving remissionb (evidence level 2D)
Frequent relapses and steroid dependencyc
CPA 2–2.5 mg/kg per d for 8 wk (single course) (evidence level 2C)
If relapse occurs despite CPA or to preserve fertility:
CsA 3–5 mg/kg per d in two divided doses for 1–2 yr (evidence level 2C)
Or TAC 0.05–0.1 mg/kg per d in two divided doses until 3 mo after remission, then tapered to the minimum efficient dose for 1–
2 yr (evidence level 2C)
If intolerant to PDN, CPA, and CsA or TAC:
MMF 500–1000 mg twice daily for 1–2 yr (evidence level 2D)

PDN, prednisone; CPA, cyclophosphamide; CsA, cyclosporine A; TAC, tacrolimus; MMF, mofetil mycophenolate.
a
During first episode, statins for hypercholesterolemia and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers
for proteinuria in normotensive subjects are not indicated.
b
Taper by 5–10 mg/wk (it is preferable not to exceed a total maximum steroid exposure of 24 mo).
c
In patients with frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome who develop steroid-related side
effects (evidence level 1B).

interferes with podocyte signaling, potentially leading to cy-
toskeletal disorganization and foot processes effacement. Re-
cent studies have found that changes in the podocyte
expression of angiopoietin-like 4 are able to induce protein-
uria, foot process effacement, and dyslipidemia, another key
clinical feature of MCD (39).
Treatment
Pathologic features of MCD may be found even in renal
biopsies of patients with primary steroid resistance. In the
vast majority of these cases, however, it can be safely as-
sumed that the pathology will shift over time to FSGS (6).
Therefore, for the purpose of this review we will consider
MCD equivalent to steroid-sensitive NS. Treatment of
steroid-resistant forms is therefore excluded from this review.
In acute management, salt and fluid intake restriction is
mandatory to improve clinical manifestations (edema) (40).
Steroid treatment with prednisone or prednisolone, its active
metabolite, are the primary drugs used at disease onset. There
is no definitive consensus on the optimal dose and duration
of therapy, which combines maximum remission duration
with minimal side effects including stunted growth in children,
obesity, osteopenia, cataracts, glucose intolerance, hyperten-
sion, and behavioral disorders (41). Therefore, in Tables 3
and 4 we have summarized different attempts to an evidence-
based standardized approach in children and adults.
Children
In 1979, the ISKDC led to indications for optimal treatment
regimen at onset of pediatric nephrotic syndrome (predni-
sone 60 mg/m2 per day for 4 weeks and 40 mg/m2 3 days a
week for another 4 weeks [42]). Subsequent studies com-
pared different therapeutic regimens of longer duration,
most with an increase in total dose of steroids but some
used a matching cumulative dose spread over two periods
of different length. In the regimens where the total dose of
steroid was increased, the probability of relapse after 12 or
24 months was lower, but not all of these studies were
randomized and were often retrospective. On the basis of
these results, the 2012 Kidney Disease Improving Global
Outcomes (KDIGO) guidelines were issued (Table 2) (43).
Over the past 3 years, however, the results of three pro-
spective controlled studies have, to some extent, modi-
fied our point of view on the optimal therapeutic approach
at onset. In summary, as evidenced in the most recent
Cochrane review (44), extending the treatment regimen for
.12 weeks total or giving higher doses does not signifi-
cantly modify the onset of frequent relapses.
Even greater uncertainty exists in the treatment of relapses.
It is known that 80%–90% of children with steroid-sensitive
NS have at least one relapse in their history of the disease.
The most difficult patients to treat are those with frequently
relapsing NS or steroid-dependent NS. KDIGO recommen-
dations on the treatment of relapses are, in fact, made on the
basis of levels of evidence that are never more than grade C
or D (43). Despite the lack of controlled studies, the use of
low-dose steroids on alternate days is recommended for fre-
quent relapses (45). Interestingly, because of the extreme fre-
quency of minor infectious episodes triggering relapse, three
recent studies have been published confirming the clinical
experience that in the pediatric setting, a low dose of pred-
nisone switched from alternate days to daily at the onset of
low-grade proteinuria is frequently sufficient in preventing
a full-blown relapse (reviewed in Hahn et al. [44]).
Nonsteroidal Immunosuppressive Drugs
Children with MCD who develop frequently relapsing
NS or steroid-dependent NS need steroid-sparing agents
340 Clinical Journal of the American Society of Nephrology
to reduce the secondary side effects of prolonged pred-
nisone. Currently used agents are levamisole, alkylating
agents, calcineurin inhibitors, antiproliferatives, and rituximab.
Azathioprine, vincristine, mizobirine, and fusidic acid have
also been used, though they are not currently recommended.
The Cochrane review, updated in 2013 (46), provides a clear
overview of studies assessing the drugs in use over the
greatest number of years.
Levamisole, an immunostimulatory drug with an an-
thelmintic effect in animals, is reported to increase time to
relapse in frequently relapsing NS compared with predni-
sone alone, but in the absence of clear data from controlled
studies, it is rarely used. However, a randomized controlled
multicenter study (European Clinical Trials Database iden-
tifier 2005–005745–18) was recently completed, coordinated
by the Dutch, on its effect in both frequently relapsing NS
and steroid-dependent NS compared with placebo. These
findings, once published, should indicate the ideal patients
to treat with this drug. In our experience, levamisole can
be a safe and effective steroid-sparing option in relatively
mild forms of frequently relapsing NS. Alkylating agents
such as cyclophosphamide (47) or chlorambucil (48), as well
as levamisole, were some of the first steroid-sparing drugs to
be used in this disease. In current clinical practice, chloram-
bucil is infrequently or no longer used. Many studies show
that they reduce the number of relapses compared with
prednisone alone, and that cyclophosphamide induces
more prolonged remission in patients with frequently relaps-
ing NS compared with those with steroid-dependent NS.
In the 1990s, cyclosporin A (CsA) was introduced. It in-
hibits calcineurin (like tacrolimus; TAC) and thus blocks
the activation of T cells, modifying the immune re-
sponse. The first comparative studies published on this
drug involved alkylating agents, showing no superiority of
CsA versus chlorambucil (46) or versus cyclophosphamide
(46). The fact that CsA is easier to handle (no need for
frequent check of the blood count and no gonadal toxicity)
and that alkylating agents seemed to be more effective in
frequently relapsing NS than steroid-dependent NS, led
to a preference for CsA, especially in steroid-dependent
NS. Moreover, calcineurin inhibitors also act through a va-
soactive mechanism and by modifying podocyte perm-
selectivity, which also makes them effective in reducing
proteinuria in some steroid-resistant forms (49). CsA is
effective in controlling the disease over time, allow-
ing prednisone discontinuation in many patients with
steroid-dependent NS. Unfortunately, it has disadvantages,
as many patients relapse after interruption and prolonged
use leads to significant nephrotoxicity (50). TAC acts in a
similar way but there are no studies on whether it is better
than CsA (51). However, published and personal experi-
ence suggest that TAC can be a good alternative to CsA in
adolescents, especially girls, as it does not induce hyper-
trichosis or gingival hypertrophy, side effects to which
these patients are very sensitive, thus improving thera-
peutic compliance. An oral glucose tolerance test before
starting is prudential (52).
More recently, mycophenolate mofetil (MMF) has been
used in MCD. It has an antiproliferative effect on both B
and T cells. There are no superiority studies with regard
to CsA, however, a post hoc analysis by Gellermann et al.
showed that the disease control in patients with a higher
plasma level of MMF (area under the curve .50 mg) was
very similar to CsA (53). As for calcineurin inhibitors, the
probability of relapse is very high after withdrawal. Apart
from effects on the gastrointestinal system and bone mar-
row, which are very dose–dependent, the main advantage
of MMF compared with CsA is that it is not nephrotoxic.
This has made it the first choice in treating steroid-dependent
NS, where a long history of disease is expected.
The drug that has aroused the most interest over the last
decade is rituximab. Rituximab is a chimeric monoclonal
antibody that binds to the CD20 antigen expressed on B
cells, thus inducing B cell depletion. Although there have
been few randomized controlled studies, rituximab reduces
drug dependency, allowing interruption of all therapy,
though often only temporarily, as recently reviewed (54). In
2013, Boyer and Niaudet hypothesized that rituximab may
change the dependence of nephrotic syndrome on steroids
or CsA to dependence on rituximab itself, often requiring
multiple infusions (55). Though its overall safety profile is
reassuring (56), rituximab use in children is not without rare
serious side effects: fulminant myocarditis, pulmonary fibro-
sis, fatal Pneumocystis jirovecii infections, severe ulcerative
colitis, and severe allergic reactions (reviewed in Avner
et al. [11]). We have shown that, in children with frequently
relapsing NS or steroid-dependent NS, rituximab infusion
determines a prolonged depletion of memory B cells (33),
and have observed long-term hypogammaglobulinemia
in a few patients. Therefore, prospective long-term studies
are necessary to evaluate the effect of repeated infusions
on immune competence in the pediatric setting. A new fully
humanized anti-CD20 monoclonal antibody, ofatumumab,
is available, which appears effective in some patients with
multidrug resistance (34).
Of note, live vaccines are contraindicated in patients
receiving steroid-sparing agents and in patients receiving
high-dose steroids; inactivated vaccines should be admin-
istered, keeping in mind that suboptimal response re-
quiring a repeated dose may be an issue (40,57).
Steroid-Resistant Forms
In children, steroid resistance is defined as lack of re-
mission despite therapy with oral prednisone at adequate
dosage (see Table 3) for a number of weeks that is still
controversial. However, because of the finding that 95%
of children with steroid-sensitive NS respond to pred-
nisone within 4 weeks (9), most centers declare steroid re-
sistance after 4 weeks of treatment. At this point, in
addition to requesting genetic screening for genetic forms
of nephrotic syndrome and performing a renal biopsy,
three intravenous methylprednisolone boluses followed
by the introduction of a calcineurin inhibitor, most fre-
quently CsA, are recommended (10). Oral prednisone is
usually reduced to alternate days and gradually tapered
until discontinuation within 6 months (10). Response to
CsA, when present, is gradual, and has been observed
even many months after the introduction of CsA in about
80% of patients (58). In about 30% of children, the presence
of a genetic mutation determines the course of the disease
(59), and in this case the chances of response to treatment
are extremely low. Children that respond to CsA in sub-
sequent relapses become steroid-sensitive (secondary ste-
roid sensitivity). Some of these patients display prolonged
Clin J Am Soc Nephrol 12: 332–345, February, 2017
remission with calcineurin inhibitors and can therefore
be gradually shifted to therapy with MMF (60). In children
who do not respond to CsA in 6–12 months, the use of
TAC can be attempted in the absence of known genetic
causes (61). Other therapeutic approaches have been at-
tempted but response is uncertain. The use of rituximab
is still controversial, appearing successful in some reports
and one study (62), which was not confirmed in a subse-
quent open-label randomized trial (63). Other anecdotal
therapeutic successes with ofatumumab are yet to be con-
firmed (34). Plasmapheresis and immunoadsorption may
also be beneficial in some patients.
Adults
In adults, most indications for the treatment of MCD are
derived from clinical trials in children and from obser-
vational studies performed in patients of various ages.
Despite two small-sized placebo-controlled trials show-
ing no significant advantage with prednisone in inducing
complete or partial remission in adult MCD, even in the
long-term, KDIGO guidelines recommend oral prednisone
at onset (evidence level 1C), since patients treated with
steroids go more rapidly into remission than controls (64).
In these very old studies, steroids were given orally but
doses and schedules varied widely, ranging from an aver-
age of 25 mg daily dose in one study to 125 mg on alter-
nate days in the other. No subsequent, well designed, and
adequately sized controlled trials were conducted with
oral steroids in inducing remission of the nephrotic syn-
drome. Therefore, the currently accepted induction regimen
of 1 mg/kg per day (maximum 80 mg/d) or 2 mg/kg every
other day (maximum 120 mg/d) for 16 weeks (minimum
4 weeks if remission is promptly achieved; evidence level
2C) is extrapolated from pediatric randomized controlled
trials and observational studies in adults (12). Previous
studies failed to show a significant benefit of intravenous
methylprednisolone (20 mg/kg per day for 3 days) fol-
lowed by reduced-dose oral steroids (prednisone 0.5 mg/kg
per day) versus full-dose oral steroids alone (prednisone
1 mg/kg per day). In adults, there are no controlled studies
defining the best regimen for tapering the prednisone after
the initial response, and this remains one of the most con-
troversial issue for therapy since slow tapering may increase
cumulative steroid doses, but rapid tapering may expose
patients to the risk of relapses (reviewed in Hogan and
Radhakrishnan [65]). A reasonable compromise may be to
taper prednisone by 5–10 mg/wk after remission over
8 weeks for a total 24-week period of exposure to pred-
nisone (12).
Many questions on treatment efficacy and safety remain
unanswered regarding the optimal dose and duration of
steroids and steroid-sparing agents on subsequent relapses
in frequently relapsing NS and steroid-dependent NS
(64–66). The use of alkylating agents or calcineurin inhib-
itors in frequently relapsing NS or steroid-dependent NS is
determined on the basis of clinical studies in children or
small observational studies in adults. In adults, cyclophos-
phamide was shown to be better than CsA in steroid-
dependent NS, and even more in frequently relapsing
NS, in maintaining remission (67). In a randomized con-
trolled trial by Ponticelli et al. on 75 adults and children
Minimal Change Disease, Vivarelli et al. 341
with frequently relapsing NS and steroid-dependent NS
(31 were MCD), long-term outcome was better with cyclo-
phosphamide versus CsA, with 63% patients maintaining
remission after 2 years compared with 25% with CsA (68).
On the other hand, adding CsA to steroids was found to
induce remission more rapidly than steroids alone at first
relapse (69). The optimal CsA dose is not established, how-
ever, KDIGO guidelines suggest a 3–5 mg/kg per day range
on the basis of dosages used in these studies. Some patients
may relapse once CsA is discontinued. Only one study
has been conducted in frequently relapsing NS or steroid-
dependent NS, showing that TAC was equally effective to
intravenous cyclophosphamide in inducing and maintain-
ing remission at 2 years in 26 adults who had been previ-
ously treated with prednisone at onset (70). MMF use has
been reported only in small patient cohorts, showing efficacy
in about 60%–70% of patients (71,72). KDIGO guidelines (64)
suggest to use cyclophosphamide as a first-line therapy for
frequently relapsing NS or steroid-dependent NS, or alter-
natively CsA, to preserve fertility and MMF only in patients
intolerant to the other drugs (Table 3). Also, rituximab has
proven to be effective in adults (73), and data from another
frequent cause of nephrotic syndrome in adults, membra-
nous nephropathy, in which rituximab is used as single
agent, are encouraging even considering the long-term safety
(74). A current evidence-based approach to MCD therapy
in adults is shown in Table 3 and reviewed in Hogan and
Radhakrishnan (65) and Canetta and Radhakrishnan (75).
Steroid-Resistant Forms
About 10%–20% of cases of adult MCD are steroid-
resistant, defined as no response to 16 weeks of oral pred-
nisone daily or alternate days, and in these patients a second
renal biopsy may reveal FSGS. Treatment of steroid-resistant
MCD should follow KDIGO guidelines for steroid-resistant
FSGS (64). Genetic forms are much rarer than in chil-
dren, but should be investigated in young adults and in
the presence of positive family history, particularly re-
garding ACTN4 mutations (76). The mainstay of therapy
in these patients are calcineurin inhibitors, but cyclophos-
phamide, both oral and intravenous, has also been used
and proved effective in some patients (reviewed in Hogan
and Radhakrishnan [65]). An open-label trial compar-
ing TAC versus intravenous cyclophosphamide showed
an effective and more rapid induction of remission by
TAC (77). MMF, chlorambucil, azathioprine, ACTH, and
rituximab have been used only in the setting of small case
series with variable results.
Outcome
In children, after remission of the first episode of nephro-
sis, about 30% do not suffer relapses for 18–24 months, and
this usually indicates that the risk of future relapses is neg-
ligible. Approximately 20%–30% progress to infrequent relapses
and rarely experience more than three or four episodes in
total, managed by therapy with prednisone alone. The remain-
ing 40%–50%, more frequently children ,5 years of age, will
have a frequently relapsing or steroid-dependent course,
with relapses during steroid tapering or soon after discon-
tinuation, requiring second-line steroid-sparing therapy
342 Clinical Journal of the American Society of Nephrology
(3,12). Rarely, children with initially steroid-sensitive disease
will develop secondary steroid resistance. This clinical fea-
ture is highly predictive of post-transplant recurrence (78).
In adults, relapses are frequent, occurring in about 56%–76%
of patients (12,79). In all patients with MCD, the occurrence
of chronic renal failure is exceptional, providing the disease
maintains its response to steroids. Usually, no relapses for at
least 2 years from discontinuation of all therapy indicates
permanent remission. Occasionally, patients can relapse sev-
eral years after they have been declared cured. Long-term
outcome studies of large cohorts of childhood onset MCD
followed into adulthood show about 3% developing chronic
renal failure and 16%–42% recurring in adulthood. The main
risk factor for adult relapses is frequent relapses in child-
hood (41,80). The main morbidity of MCD at all ages there-
fore derives from the side effects of therapy discussed above,
primarily immunosuppression and, regarding prednisone,
inhibition of linear growth, worsened by urinary loss of thy-
roid hormones and IGF1–1 (11,41,81). Importantly, subjects
with childhood-onset MCD who maintain frequently relaps-
ing NS or steroid-dependent NS during adulthood are at
major risk for long-term toxicity, not exactly quantified be-
cause of the lack of long-term observational studies, including
sterility associated with cytotoxic agents, nephrotoxicity with
calcineurin inhibitors, diabetes, hypertension, obesity, osteo-
porosis, and cataracts related to steroids, and solid or blood
neoplasia because of prolonged immunosuppression (41,80).
Adults versus Children
MCD is a typical disease of childhood, accounting for the
vast majority of primary NS cases in children and for about
10%–15% in adults (1,3). Features common to all ages of on-
set are the renal pathology, the high prevalence of steroid-
responsiveness compared with most other nephropathies
and overall the favorable outcome. However, some rele-
vant differences exist between children and adults.
First, clinical features at onset: whereas in children and
young adults, edema is the main clinical symptom inducing
parents to seek health care, adults .60 years may frequently
present with impaired renal function and hypertension (12).
Patients with reversible acute renal failure, probably linked
with higher proteinuria levels, are more frequent in adults
than in children (12), although a recent paper shows that
AKI is frequently seen in children with nephrotic syndrome
seeking hospitalization (17). In addition, thrombotic com-
plications because of a combination of hypercoagulability,
increased blood lipids, and hemoconcentration occur in a
small percentage of children (2.7%) and in a much more
consistent proportion of adults (24.1%), most frequently at
disease onset (18). Second, a male preponderance has been
described in children (11), whereas a female preponderance
has been described in adults (12). Third, in children the
disease is usually idiopathic, excluding the trigger of infec-
tion, whereas secondary forms (Table 2) are more frequent
in adults (1,11). Fourth, focal areas of interstitial fibrosis or
tubular atrophy without the finding of sclerotic glomeruli
do not exclude MCD in adults and frequently associate
with chronic hypertension, particularly in the elderly,
whereas in children these lesions strongly suggest the pos-
sibility of a FSGS that was not correctly sampled at biopsy.
Fifth, the timing of treatment response is quite different in
terms of both time to remission and response rate between
children and adults. Children have a shorter time to remis-
sion, usually within days or weeks from treatment initia-
tion, whereas adults require months to achieve proteinuria
reduction (Figure 2) (12,82–84). Therefore, therapeutic pro-
tocols with steroids at onset differ in children versus adults,
as reported above, and consequently the definition of steroid-
resistant NS differs, as children are considered resistant
after 4 weeks of full-dose steroids (Table 1) whereas in
adults, 16 weeks of prednisone (1 mg/kg per day) are re-
quired to define patients as steroid-resistant NS. This oc-
curs in adults in approximately 10%–30% of cases, mostly
because of evolution to FSGS (12). Timing of relapses also
differs, with children relapsing more frequently and sooner
compared with adults.
Interestingly, some children demonstrate initial resistance
to oral prednisone but respond to additional therapies, such
as methylprednisolone boluses or CsA. After discontinua-
tion of therapy, these patients do not always relapse (9).
Conversely, patients with onset of MCD during early child-
hood who maintain active disease in adulthood continue to
present a relapsing nephrotic syndrome with the character-
istics of childhood onset MCD. These observations suggest
that MCD is not a homogeneous disease and that children
and adults present different forms of the disease. A subset
of children with a longer time to remission at disease onset
may represent a subgroup with childhood onset adult MCD.
Conclusions
MCD is a histologic picture than does not correspond to a
single disease entity. It can be found in very different clinical
settings, and at different ages in life. Therefore, recognition
of distinct subgroups of patients with common clinical and
laboratory features is essential in determining disease prog-
nosis and in tailoring optimal therapeutic strategies.
Acknowledgments
The authors wish to thank Dr. Andrea Pasini and Prof. Arvind
Bagga for their thoughtful contribution.
This work has been funded by the Associazione per la Cura del
Bambino Nefropatico, which supports M.V. and L.M.
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Focal Segmental Glomerulosclerosis
Avi Z. Rosenberg*† and Jeffrey B. Kopp*†

Abstract
Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of
primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney
transplant–important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload
due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain
*Department of
diseases.Additionaletiologies arenowrecognizedasdrivers ofFSGS:high-penetrance geneticFSGSdue tomutations inone Pathology, Johns
of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification Hopkins Medical
of a sixth category: APOL1 risk allele–associated FSGS in individuals with sub-Saharan ancestry. The classification of a Institutions,
particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, Baltimore, Maryland;
and †Kidney Disease
and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy Section, Kidney
(e.g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunoflu- Diseases Branch,
orescence (e.g., to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process National Institute of
effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal Diabetes and
Digestive and Kidney
histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS
Diseases, National
associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing Institutes of Health,
is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides Bethesda, Maryland
prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain,
including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation Correspondence: Dr.
of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS. Jeffrey B. Kopp, Kidney
Disease Section,
Clin J Am Soc Nephrol 12: 502–517, 2017. doi: 10.2215/CJN.05960616 National Institute of
Diabetes and
Digestive and Kidney
Diseases, 10 Center
Introduction difficult to ascertain given the large global variations Drive, Bethesda, MD
Focal segmental glomerulosclerosis (FSGS) is the in the indications, accessibility, and pathology sup- 20892-1268. Email:
leading glomerular cause of ESRD in the United port for kidney biopsy. McGrogan et al. (15) reviewed jbkopp@nih.gov
States. FSGS refers to a histologic pattern that is a published literature from around the world and
characteristic of perhaps six distinct underlying etiol- reported that annual incidence rates ranged from 0.2
ogies sharing a common theme of podocyte injury and to 1.8/100,000 population per year. Australia, with a
depletion. The diagnosis and evaluation of FSGS rely liberal biopsy policy, had among the highest inci-
on integration of the clinical history (family history, dence of FSGS (15,16). A population-based study in the
birth history, peak weight and body mass, and southwestern United States examined 2501 adult kidney
medication use), clinical laboratory findings (serum biopsies performed between the years 2000 and 2011
albumin, urine protein, and viral serologies), and renal (17). Over the 12 years studied, FSGS was the most
histopathology. Proteinuria may be in the nephrotic or common diagnosis (39% of biopsies), with an increasing
subnephrotic range. Critical is the elimination of other incidence rate (from 1.6 to 5.3 patients per million).
systemic diseases or primary renal diseases that may Although the average incidence rate was 2.7 patients per
result in a similar presentation. Many reviews cover million, there was a significant racial/ethnic predilec-
various aspects of FSGS and include comprehensive tion. FSGS incidence rates are generally higher in men,
reviews (1–4), disease mechanisms (5–8), pediatric dis- being approximately 1.5-fold higher than in women.
ease (9), immunologic aspects (10), treatment in children In 2004, Kitiyakara et al. (18) noted a two-decade-long
(11), and treatment in adults (12–14). We focus here on a trend of increasing ESRD attributed to FSGS in the
practical approach to FSGS assessment on clinical and United States. Incident rates, expressed as patients
histopathologic grounds in the context of our current per million, were 6.8 in blacks, 3.7 in Hispanics, and
understanding of disease mechanisms and genetics. 1.9 in whites. The rise in FSGS prevalence has been
observed in other populations as well. In Nigeria, the
leading cause of nephrotic syndrome has shifted from
Epidemiology and Global Burden quartan malaria (ca. 1960s) to membranoproliferative
The prevalence of FSGS, relative to other glomer- GN (ca. 1980s) to FSGS (present) (19). The factors re-
ular disease diagnoses, seems to be increasing world- sponsible for the increasing incidence and preva-
wide, and it is a major contributor to ESRD. However, lence of FSGS are largely unknown. Some of the
the absolute incidence and prevalence of FSGS are increase is likely attributable to improved recognition

502 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 March, 2017
Clin J Am Soc Nephrol 12: 502–517, March, 2017 FSGS, Rosenberg et al. 503

(particularly where indications for kidney biopsy are
broadening and the procedure is more available). There
may well be an absolute rise in incidence of adaptive FSGS
compounded by obesity and chronic inflammation, but
epidemiologic data are lacking.
Among the primary nephrotic diseases, FSGS is most
likely to progress to ESRD. Within FSGS categories, emerg-
ing data indicate that an association with APOL1 defines a
group most likely to progress to ESRD. Histologic variants
portend outcome with variable rates of progression (col-
lapsing variant greater than not otherwise specified [NOS]
greater than tip lesion).
Putting together the genetic susceptibility, pathophys-
iologic drivers, clinical history, and response to therapy
(summarized in Table 1), we believe that it is useful to cluster
FSGS into six clinical forms (Figure 1, Table 2). These
include two common forms (primary FSGS and adaptive
FSGS) and three less common forms (high-penetrance
genetic FSGS, viral-mediated FSGS, and medication-
associated FSGS) (24). Evidence is mounting to consider
another form—APOL1-associated FSGS (discussed below).
With regard to primary FSGS, some would prefer the term
idiopathic FSGS; both are defined as a disease that arises
spontaneously or is of unknown cause, and we would view
these terms as interchangeable.

Classification
Classification of FSGS is multifaceted and includes
pathophysiologic, histologic, and genetic considerations.
D’Agati et al. (20) initially proposed that FSGS be divided
into primary (idiopathic) and secondary forms. The latter
might be considered to include familial/genetic forms,
virus-associated forms, drug-induced forms, and forms
mediated by adaptive structural-functional responses
(i.e., in the setting of congenital or acquired reduction of
renal mass/nephron complement). Clinical response and
prognosis may relate to the histologic variant, most
notably the glucocorticioid responsiveness of the tip
lesion and the aggressive, unrelenting nature of the
collapsing variants (21,22). It is with this in mind that the
variants are included in standard pathology reports. More
recently, efforts to identify genetic drivers of FSGS in at-risk
populations have gained momentum, with the most recent
addition including the APOL1 genetic variant as a major
association with FSGS in individuals of sub-Saharan African
descent with FSGS (23).
Histopathology
Historically, degenerative glomerular lesions of FSGS were
those seen in the progression of minimal change disease (MCD;
formerly lipoid nephrosis), and it was subsequently noted that
these patients had an accelerated clinical course (25,26). In
contrast to MCD, FSGS glomeruli show segmental solidifica-
tion of the glomerular tuft. Tubulointerstitial scarring indica-
tive of glomerular disease may also be observed. It is not
uncommon that a biopsy with minimal glomerular changes
may have tubulointerstitial damage, suggesting that FSGS
might have been present on unsampled glomeruli.
The distinction between MCD and FSGS is critical,
because both present with proteinuria, podocyte injury,
and minimal immune deposits. For the biopsy to exclude
FSGS as a cause of nephrotic syndrome and assess the
degree of cortical involvement, adequate renal cortical sam-
pling is required. The involvement of glomeruli in focal
glomerular processes follows a binomial distribution, and
thus, for focal disease, more glomeruli are necessary to

Table 1. Data relevant in evaluating a patient with the histologic diagnosis of FSGS

Relevant Clinical History Laboratory Data Renal Biopsy Findings

Family history of kidney disease Serum albumin before therapy FSGS histologic variant
Birth weight, gestational age at Urine protein-to-creatinine ratio Glomerular size (glomerulomegaly)
birth, congenital cyanotic heart
disease
Sickle cell disease Change in urine protein-to- Electron microscopy: extent of foot
creatinine ratio after maximal process effacement; podocyte
renin-angiotensin-aldosterone mircrovillus transformation
therapy and dietary sodium
restriction
History consistent with reflux Change in urine protein-to- Electron microscopy:
nephropathy or reduced renal creatinine ratio after tubuloreticular inclusions in
mass immunosuppressive therapy glomerular endothelial cells (IFN
effect)
Peak and present body mass index:
obesity, extreme muscular
development
Viral infection: HIV, cytomegalovirus
Medication, past or present: IFN,
lithium, bisphosphonate,
androgen abuse, chronic use of
nephrotoxic drugs

Modified from Kopp (24), with permission.

504 Clinical Journal of the American Society of Nephrology

Figure 1. | Histopathology of minimal change disease and focal segmental glomerulosclerosis. Minimal change disease shows patent glomeruli
in the absence of tubulointersitial scarring (silver stain, 340). The tip lesion represents a focal adhesion of the glomerular tuft to Bowman’s capsule near
the proximal tubule takeoff (silver stain, 3400). The most common forms of FSGS seen in adaptive FSGS and across all etiologies of FSGS are the
perihilar variant (periodic acid–Schiff stain, 340) and not otherwise specified pattern (silver stain, 3400). The most distinctive variant is the collapsing
variant (collapsing glomerulopathy; silver stain, 340). A specific instance of collapsing variant can be appreciated in the setting of endothelial
tubuloreticular inclusions seen on ultrastructural analysis. These may be observed in high IFN states, including viral infection and exogenous IFN. The
red arrowhead indicates the relative response to therapy and propensity of progression of these various forms, with minimal change disease and tip
lesion being most responsive and least progressive and collapsing glomerulopathy being most therapy resistant and rapidly progressing.

observe an affected glomerulus (27,28). There is also zonal
proclivity for FSGS, such that juxtamedullary/inner cortex
glomeruli are the first affected progressing to involve the
outer cortex at a later stage of disease (24). Fogo et al. (29)
further show that the focality of sclerotic lesions is greater in
children than in adults, suggesting a need for more com-
prehensive sampling. Differential staining patterns for syn-
aptopodin (30) and dystroglycan (31) may distinguish
steroid-sensitive MCD versus steroid-resistant MCD (likely
unsampled FSGS) and FSGS.
A simulation study has highlighted two issues with
respect to diagnostic yield of renal biopsies in FSGS (28). (1)
If glomerular scars are uniformly distributed in a biopsy
with 10–30 glomeruli, the diagnostic accuracy for the
detection of at least one scarred glomerulus will be 80%
when at least 10% of juxtamedullary glomeruli or 20% of
other cortical glomeruli are scarred. (2) With an average of
20 glomeruli with 20%–60% glomerular sclerosis, the
predicted error rate is 650% for extent of glomerular
involvement. This suggests caution when making treatment
recommendations on the basis of the extent of involved
glomeruli (Supplemental Figure 1).
The Columbia classification of FSGS recognized five
morphologic patterns, all of which involve obliteration of
the capillary lumens and for the most part, have good
reproducibility across independent observers (20,32) (Fig-
ure 2). Two distinctive forms are the tip lesion and the
collapsing variant. Tip lesions affect the portion of the
glomerular tuft juxtaposed to the tubular pole. Abnormal-
ities include adhesion to Bowman’s capsule at the tip,
hypercellularity, presence of foam cells, and/or sclerosis.
By contrast, the collapsing variant shows segmental or
global mesangial consolidation and loss of endocapillary
patency in association with extracapillary epithelial hyper-
trophy and/or proliferation. Microcystic tubular dilation is
frequently present. The perihilar and NOS variants are
determined by whether the segmental sclerosis/segmental
obliteration of capillary loops with matrix increase (with or
Table 2. Characteristic clinical and pathology features of the six forms of FSGS

Infection/
Characteristic Medication-
Primary FSGS Adaptive FSGS APOL1 FSGS Genetic FSGS Inflammation
Features Associated FSGS
Associated

Mechanism of Circulating factor, Mismatch between APOL1 variant– High-penetrance Postulated role of Presumed direct
Podocyte Injury possibly a metabolic load and initiated genetic variants IFN and effect on
cytokine glomerular capacity inflammation (Mendelian or possible other podocytes
mitochondrial cytokines
inheritance)
History Acute onset of Reduced renal mass: Family history, Family history, HIV, CMV, Bisphosphonate,
edema low birth weight, may be may be possible: lithium
Clin J Am Soc Nephrol 12: 502–517, March, 2017

oligomeganephronia, unremarkable unremarkable parvovirus B19,

ureteral reflux, with recessive Still disease,
morbid obesity; inheritance natural killer
increased single- genes cell leukemia
nephron GFR:
cyanotic congenital
heart disease, sickle
cell anemia
Laboratory tests Many have high- Any level of proteinuria, Any level of Any level of Any level of Any level of
grade serum albumin may proteinuria proteinuria proteinuria proteinuria
proteinuria and be normal
nephrotic
syndrome
Renal Widespread foot Large glomeruli, May resemble Variable Variable Variable
pathology process perihilar sclerosis primary or
effacement variant most typical, adaptive forms
partial foot process
effacement
Treatment and May respond to Responds well to RAAS May respond to High-penetrance Treat the virus Stop the
response IST antagonism, often therapies used genetic medication
with .50% for primary and mutations:
proteinuria reduction adaptive forms usually does
not respond to
IST
Recurrence Possible Unlikely Possible Unlikely Possible if Unlikely
after renal infection/
transplant inflammation
persists

CMV, cytomegalovirus; IST, immunosuppressive therapy; RAAS, renin-angiotensin-aldosterone system; CG, collaspsing glomerulopathy. Modified from Kopp (24), with permission.
FSGS, Rosenberg et al.
505
506 Clinical Journal of the American Society of Nephrology

Figure 2. | The six forms of FSGS. These syndromes include three forms that are most common, including primary FSGS, adaptive FSGS, and
APOL1 FSGS. These forms are probably of approximately equal prevalence in the United States adult population. Three forms are less common,
including genetic FSGS (by which is meant high-penetrance genetic causes), medication-associated FSGS, and viral FSGS. The approximate
relative distribution of these variants in the United States population at present is shown by the size each cloud, although firm data on
prevalence are lacking. The absolute frequency of these FSGS forms is influenced by race/ethnicity (particularly in the frequency of APOL1 risk
variants), age (children are less likely to have adaptive FSGS), and the frequency of exposures to toxins (e.g., heroin) and medications and having
viruses (e.g., HIV).

without hyalinosis) involves the segment near the hilum or
the specific segment cannot be determined, respectively.
The cellular lesion is perhaps the most difficult lesion to
identify reproducibly and shows segmental endocapillary
hypercellularity occluding lumens with or without foam
cells and karyorrhexis (32). Some biopsies will show
multiple morphologic lesions (33,34), and the Columbia
classification suggests a hierarchy for diagnosis, such that the
presence of the higher-ranking lesion determines the clinical
course: collapsing variant, tip lesion, cellular variant, peri-
hilar variant, and lastly, NOS (reviewed in Stokes and
D’Agati [35]). Including the pattern of FSGS has standardized
the reporting of FSGS lesions and provides prognostic
information. Nonetheless, this classification system was
designed to rely solely on pathologic criteria and does not
integrate these findings with clinical and genetic information.
Complete renal pathologic evaluation includes immu-
nofluorescence analysis and electron microscopy, which
help to exclude focal and segmental glomerular scarring as
an injury pattern that can be seen as an element of any
chronic progressive renal diseases, including lupus nephri-
tis, IgA nephropathy, and diabetic nephropathy (36). As
such, to avoid confusion, it is probably best to avoid using
the term FSGS in this setting. Low or moderate amounts of
IgM are frequently present in the mesangium of patients
with FSGS. Thurman and colleagues (37) have proposed
that IgM may bind neoepitopes in the mesangium that are
exposed after nonimmune injury, resulting in complement
deposition and glomerular injury.
Ultrastructural examination adds to the assessment in
three ways. First, it can exclude the presence of immune
complexes and abnormal deposits, such as amyloid. Sec-
ond, it can exclude basement membrane abnormalities seen
in genetic disorders of collagen; the appearance of COL4
mutations among the list of genes associated with FSGS
suggests that the alterations in basement membrane at the
ultrastructural level may be subtle or undetectable. Third,
it can provide an estimate of the severity of podocyte
injury (fractional foot process effacement) and injury
pattern (microvillus transformation). Mean foot process
width is greater in primary FSGS compared with adap-
tive FSGS and may serve as a helpful, although subtle,
clue (38).
The use of all three renal pathology modalities (light
microscopy, electron microscopy, and staining for Ig and
complement) is critical in making the distinction between
MCD and FSGS. Extensive podocyte injury at the ultra-
structural level with adequate numbers of normal-appearing
glomeruli and nonscarred tubulointerstitium by light
microscopy suggests MCD. Nevertheless, individuals
with a diagnosis of MCD who are resistant to glucocor-
ticoid therapy or manifest deterioration in renal function
Clin J Am Soc Nephrol 12: 502–517, March, 2017
may have FSGS that was not sampled on the first biopsy
and is shown on a subsequent renal biopsy.
Mechanisms of Disease
FSGS is a diverse syndrome that arises after podocyte injury
from diverse causes: some known and others unknown (39).
The sources of podocyte injury are varied (circulating factors
[primary FSGS], genetic abnormalities, viral infection, and
medication), although the effect on podocytes is similar. For
the most part, the interplay among these drivers is unclear and
likely complex. For instance, adaptive FSGS involves both
podocyte stress (a mismatch between glomerular load and
glomerular capacity) and a genetic susceptibility. Wiggins and
colleagues (40) have elegantly shown this in a rat model that
combines genetic susceptibility, renal mass reduction (unin-
ephrectomy), and obesity (increased glomerular load).
Importantly, podocyte injury from any of the forms of
FSGS (or from other glomerular diseases) will initiate a
similar process, resulting in the pathologic features of
adaptive FSGS.
It is thought that there is progressive loss of injured
podocytes into the urinary space. Podocyte depletion arising
from an inability to replicate (although nuclear division may
occur, at least in animals) and results in podocyte catastro-
phe (41). To balance this deficit, podocytes compensate by
hypertrophy to cover more of the glomerular capillary
surface. In a recent insightful and provocative review, Kriz
and Lemley (42) proposed that shear stress forces on
podocytes are a critical factor driving podocyte injury. In
adaptive FSGS, glomerular hypertrophy occurs early in the
disease process; in other forms of FSGS and other glomer-
ular diseases, glomerular hypertrophy occurs with pro-
gressive nephron loss, leading to increased pressures and
flows in the remaining patent glomeruli.
The following sections address pathologic mechanisms,
therapy, and treatment for each of the FSGS syndromes.
The typical onset ages and approximate relative incidence
rates are shown schematically in Supplemental Figure 1.
Primary FSGS
Primary FSGS is a distinct entity, and paradoxically, it is best
defined, at this time, as what it is not (i.e., not one of the other
forms of FSGS). As a practical matter, this means assessing the
likelihood of other forms. This includes ruling out adaptive
FSGS (by medical history, peak or current body weight, renal
biopsy features, serum albumin, or proteinuria response to
renin-angiotensin-aldosterone system [RAAS] antagonism),
genetic FSGS (via genetic test panels on the basis of family
history and age of onset), viral FSGS (by appropriate virologic
testing), and medication-associated FSGS (by medication
history). Emerging data support that APOL1-associated
FSGS may make up yet another form of primary FSGS.
The mechanism of podocyte injury in at least some pa-
tients with primary FSGS likely involves a circulating factor,
possibly a cytokine that makes particular subjects susceptible.
The best evidence for a circulating factor comes from the
experience with recurrent FSGS immediately (on a scale of
hours to several weeks) after kidney transplant. The cyto-
kine or cytokines responsible for recurrent FSGS after
kidney transplant remain to be defined. In an unusual and
FSGS, Rosenberg et al. 507
striking case that supports the cytokine hypothesis, a kid-
ney was transplanted into a recipient with FSGS; proteinuria
developed, and the transplanted kidney showed podocyte
foot process effacement. Subsequently, the kidney was re-
moved and transplanted into a patient with ESRD due to
diabetes, and in the new host, the kidney functioned well
without proteinuria (43). Current candidates for the recurrent
FSGS factor, reviewed recently (44), include cardiotrophin-
like cytokine factor 1 (45), apoA1b (an isoform of ApoA1)
(46), anti-CD40 antibody (47), and serum urine–type plas-
minogen activator receptor (suPAR) (48). The role of suPAR
remains controversial (49). suPAR levels were reported in
FSGS and other primary glomerular diseases (50). In primary
and adaptive FSGS (51), elevated levels may (52) or may not
(53) predict glucocorticoid sensitivity, and a role for different
forms of suPAR has been suggested as reviewed recently
(54). Recurrent FSGS plasma affects the cytoskeleton of
cultured podocytes, including promoting cell mobility by
phosphorylating vasodilator-stimulated phosphoprotein (55)
and disassembling focal adhesion complexes (56). The lack of
suitable animal models has hindered progress in this area.
It is quite likely that other patients with what is now
diagnosed as primary FSGS will be reassigned to alterna-
tive etiologies, including new genes, environmental factors,
and/or microorganisms.
Primary FSGS has several prototypical characteristics. It
is probably the most common form in adolescents and
young adults, although it may occur at any age. It is com-
monly associated with nephrotic-range proteinuria (some-
times massive), reduced plasma albumin levels, and
hyperlipidemia. Histologically, it may manifest as the tip
variant, collapsing variant, or NOS variant.
Current therapy for primary FSGS is on the basis of im-
munosuppressive agents; it is now apparent that a number of
these, including glucocorticoids and calcineurin inhibitors,
directly modulate the podocyte phenotype (57). Recently, it
has been shown that the effects of glucocorticoids may be
mediated by Krüppel factor 15, a zinc finger transcription factor
(57,58). In a recent retrospective case series involving 476
subjects, the use of glucocorticoids and/or cyclosporin was
associated with improved outcomes compared to no immu-
nosuppression, with a hazard ratio of 0.49 (95% CI, 0.28 to 0.86)
for ESRD whereas the use of cyclosporine with or without
glucocorticoids was not associated with benefit HR 0.42 (95%
CI, 0.15 to 1.18) (59). Despite the limitations of a retrospective
study design, this provides new evidence to support therapy.
Recurrent FSGS remains a vexing clinical problem. The
histologic variant in the native kidney does not predict re-
currence, although it is notable that only one of 77 initial kidney
biopsies from subjects who subsequently had recurrent FSGS
showed the perihilar variant (60). Therapy with plasma ex-
change may induce a remission, typically temporary. Canaud
et al. (61) reported favorable results from a small series of adult
subjects (n510) with a regimen that included glucocorticoids
and cyclosporin initially administered intravenously.
Adaptive FSGS
Adaptive FSGS, which has also been called, perhaps
more accurately, postadaptive FSGS (62), arises after a
period of nephron-level glomerular hyperfiltration and
glomerular hypertension after pathophysiology as identified
508 Clinical Journal of the American Society of Nephrology
by Brenner and Mackenzie (63). Total GFR may be elevated,
normal, or decreased at the outset.
Conditions that are associated with an increase in total
kidney GFR include congenital cyanotic heart disease (64),
sickle cell anemia (65), obesity (66), androgen abuse (67),
sleep apnea (68), and high-protein diet. The duration of
single-nephron glomerular hyperfiltration is typically mea-
sured in decades before progressive glomerulosclerosis
eventually reduces total GFR. Conditions associated with
reduced renal mass include prematurity and/or small for
gestation age (69), renal anomalies, reflux nephropathy,
and AKI. Any chronic glomerular or tubular disease may
reduce the total nephron function and result in adaptive
FSGS that is superimposed on the primary disorder.
Adaptive FSGS arises from the processes described
above involving increased single-nephron GFR (often
with intraglomerular hypertension), leading to progressive
cycles of glomerular hypertrophy; podocyte hypertrophy,
stress, and depletion; and synechia formation and excess
extracellular matrix deposition within the glomerulus as
described so well by Kriz and Lemley (70).
Renal biopsy features that support the diagnosis of adaptive
FSGS include large glomeruli, a preponderance of perihilar
scars among glomeruli showing sclerotic changes, and only
partial foot process effacement. Clinical features include a
normal serum albumin, which is unusual in primary FSGS. A
complete response to RAAS antagonism, particularly when
combined with sodium restriction and a rise or normalization
of serum albumin, supports the diagnosis of adaptive FSGS,
although it does not exclude other forms of FSGS.
Genetic FSGS
Genetic FSGS takes two forms. First, some patients are
associated with variants in susceptibility genes (i.e., some
individuals with a particular variant will develop FSGS, and
other individuals will not). By far, the most common exam-
ple of this is the newly identified association with APOL1 as
discussed below. Other genetic risk loci include PDSS1 (71)
and numerous others (72,73). More are likely to be discovered
in the near future. Second, other patients are associated with
high-penetrance mutations that manifest either Mendelian
inheritance (for nuclear genes) or maternal inheritance (for
genes encoded by mitochondrial DNA). The number of genes
associated with FSGS rises every year, in large part because
of the dissemination of whole-exome sequencing. To date,
at least 38 genes have been identified as shown in Table 3 .
(For simplicity, genes such as CFH and C3, which represent
distinct syndromes that could be mistaken for FSGS when
ultrastructure examination is not performed, have not been
listed in Table 3. Other genes that have provisionally been
associated with FSGS but lack the robust data needed to
firmly establish causality are not shown [e.g., ACLS4, ALG1,
NEIL1, PMM2, PODLX, SYNPO, and ZEB1]).
Some genes are associated with a syndrome that includes
extrarenal manifestations, and this can provide a clinical
clue that a patient might have a mutation in a particular
gene. Some genes are associated with characteristic changes
in basement membrane morphology (e.g., LXMB1 and
COL4A3–5) or mitochondrial morphology (e.g., the genes
associated with mitochondrial encephalopathy, lactic acido-
sis, stroke-like episode syndrome) that may provide such
clues. Other genes are associated with therapeutic response.
(Table 5 does not include genes associated with steroid-
sensitive nephrotic syndrome, for which renal biopsies have
not been done. Some genetic variants shown in Table 5 are
associated with glucocorticoid sensitivity; e.g., PTPRO [74]).
Should patients with FSGS undergo genetic testing? The
answer to this question remains unclear. With regard to
pediatric patients, Hildebrandt and coworkers (75) have
suggested that every family with a child who has FSGS
deserves to be offered an opportunity to have a genetic
diagnosis (RE). Benefits of this approach may include a
guide to appropriate therapy (e.g., avoidance of glucocor-
ticoids except for in genetic forms that may be responsive
and coenzyme Q10 therapy for particular mitochondrial
mutations), prognosis (typical native kidney outcomes and
likelihood of transplant recurrence), and family issues (iden-
tification of disease in other family members and prenatal
testing). To be sure, caution is warranted, in that systematic
studies of the response of genetic forms of FSGS to various
therapies have not been carried out. High-penetrance genetic
causes are more likely to be identified in childhood nephrotic
syndrome (approximately 60%) than in that in older children
and adolescents (approximately 5%), with lower rates in
adults (75,76). Genetic testing in adults with FSGS is in-
dicated where there is a family history, because some genes
have mutations associated with autosomal dominant muta-
tions (IFN2 and ATCN4).
What is the most appropriate and cost-effective way to
carry out genetic testing? When a family has not had gene
testing previously that identified a specific gene, the most
effective approach is to use panels that focus on early-onset
FSGS (infant and early childhood) or adult-onset FSGS.
Genetic test resources around the world are available at the
Genetic Test Registry, National Center for Biotechnology
Information, National Institutes of Health (http://www.ncbi.
nlm.nih.gov/gtr).
A more comprehensive approach is a whole-exome scan,
which provides DNA sequence for the approximately 180,000
exons that make up the approximately 22,000 human genes;
this may, in the near future, replace the use of selected gene
panels. Genetic testing may identify known mutations that
prior experience has shown are associated with FSGS, but it
may also identify protein-altering mutations (e.g., missense
mutations that change an amino acid or introduce a stop
codon) of unknown significance. With comprehensive ge-
netic exploration, there is also the possibility of unexpected
identification of genetic variants that have significance for
the individual and family. An advisory group from the
American College of Human Genetics has provided a
recommended list of 56 genes for which variants that are
likely to be disease associated should be reported to the
individual or family; this list will likely expand over time
(77). Therapy for genetic FSGS is generally conservative and
on the basis of RAAS antagonism. Calcineurin inhibitors
may have an effect in a minority of patients (78). As noted
above, coenzyme Q10 may benefit individuals with muta-
tions in certain mitochondrial defects.
Virus-Associated FSGS
Among infections, viruses are predominantly implicated
in causing FSGS. HIV-1 is strongly associated with FSGS,
Table 3. Genetic FSGS: Genetic variants with syndromes with Mendelian and mitochondrial inheritance

Slit DNA Repair,

Cytoskeleton Mitochondria Cell
Cell Matrix Diaphragm Transcription, Lysosome Cilia
and Related Function Signaling
Complex Nuclear Transport

Nonsyndromic
COL4A3 NPHS (nephrin) ACTN4 INF2 WT 1 (Denys–Drash, PLCE1 TTC21B
Frasier)
COL4A4 NPHS2 (podocin) INF2 NUP95 TRPC6
COL4A5 CD2AP AHRGP24 NUP203
PTPRO (GLEPP1) AHRGDIA XP05 (exportin 5)
MYO1E NXF5 (nuclear
export factor 5)
PAX2
Clin J Am Soc Nephrol 12: 502–517, March, 2017

Syndromic
ITGB4 (epidermolysiss MYH9 (Esptein, INF2 (Charcot– WT1 (Denys–Drash, KANK4 SCARB2 (action
bullosa) Fechtner) Marie–Tooth) Frasier) myoclonus)
LAMB2 (Pearson) MT-TL1, MT-TL2 LMX1B (Nail-patella)
tRNA leucine
(MELAS)a
MT-TY, tRNA
tyrosine
(MELAS)a
COQ2 SMARCAL1 (Schimke
immune-osseous
dysplasia)
COQ6 NXF5
PDSS2 (Leigh) EYA1 (Branchio-oto-
renal)
ADCK WDR73 (Galloway–
Mowat,
nephrocerebellar
syndrome)
LMNA (partial
lipodystrophy)
5 5 5 7 11 3 1 1

Genetic FSGS can be categorized as susceptibility genes (not shown; e.g., APOL1) and genes with Mendelian and mitochondrial inheritance (38 genes shown above); genes for which casual
evidence is not yet entirely convincing or associations are with unbiopsied nephrotic syndrome are omitted. These gene products are located in various podocyte cell compartments, although some
proteins are present in more than one location (the number of genes in each compartment are tabulated in the last row). Nonsyndromic genes are those in which mutations are associated with
manifestations only in the kidney; syndromic genes are those in which mutations are also associated with extrarenal manifestations, in some cases with variable penetrance (some individuals with
certain mutations may have a purely renal phenotype). For some diseases, eponyms or syndromic names are provided in parentheses. Most genes affecting mitochondrial function are encoded by
nuclear genes. MELAS, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes.
a
The two MELAS genes are encoded by mitochondrial DNA and show mitochondrial inheritance.
FSGS, Rosenberg et al.
509
510 Clinical Journal of the American Society of Nephrology
particularly the collapsing glomerulopathy variant, al-
though other variants are also seen (79). The mechanisms
likely involve direct infection of podocytes (80). A similar
renal syndrome can be reproduced in transgenic mice
bearing HIV-1 Nef (81) or Vpr (82) accessory proteins,
suggesting possible mechanisms.
Interestingly, the effect of HIV on podocytes is strongest
in individuals with two APOL1 risk alleles, with an odds
ratio of 29 in the United States (83) and an odds ratio of 89
in South Africa (84). Most individuals with HIV-associated
nephropathy (HIVAN) have one or two APOL1 risk alleles.
Other viruses that have been implicated in causing FSGS
include cytomegalovirus, parvovirus B19, and Epstein-Barr
virus, with the evidence perhaps stronger for cytomegalovirus
compared with the others (reviewed in Chandra and Kopp [85]).
Certain parasites have also been associated with FSGS,
presumably by stimulating innate immune pathways in
ways that injure podocytes. These include Plasmodium
(malaria) (86), Schistosoma mansoni (87), and filiariasis (88),
although these seem to be rare events given the frequency
of these infections.
Medication-Associated FSGS
There is a relatively short list of medications that cause
FSGS. IFN-a, -b, or -g therapy has been associated with the
development of collapsing glomerulopathy in a case series
of 11 subjects (89).
Several other medications have been associated with
FSGS; a genetic predisposition is plausible but has not been
shown. Bisphosphonates are associated with podocyte
injury, including MCD, FSGS, and particularly, collapsing
FSGS (collapsing glomerulopathy) as first reported by
Markowitz et al. (89). As in HIVAN, the abundant cells in
Bowman’s space are derived from the parietal epithelium
(90). The mechanism by which bisphosphonates act re-
mains obscure. Lithium therapy has been associated with
MCD, which typically reverses within weeks after stopping
the medication, and FSGS, which may also be revers-
ible (91). The mechanism of podocyte injury, if that is the
mechanism, remains to be determined. Sirolimus, partic-
ularly when the plasma levels are high, has been associated
with FSGS (92) as well as exacerbating preexisting FSGS
(93). Anthracycline medications, including doxorubicin
(Adriamcyin) and daunomycin, have been associated
with FSGS (94), and doxorubicin, a podocyte toxin, has
been widely used to generate a mouse model of FSGS (95).
Emerging Pathologic Mechanisms: APOL1-Associated
FSGS
The identification of genetic variants in APOL1 in pa-
tients with FSGS has been an important discovery for FSGS
and related diseases. Unlike certain genes that have not
shown firm causality to FSGS, data are mounting for the
role of APOL1. Although confirmatory data are required,
the strength and consistency of the genetic association, the
exclusion of other genetic variants in this genomic region,
and the demonstration that the expression of the renal risk
variants (but not the common allele) causes FSGS in
transgenic mice (96) are highly supportive of the role of
APOL1 genetic variants as causal for FSGS.
APOL1-associated FSGS is a major form of FSGS in
countries with individuals of sub-Saharan African descent.
The effect is largely recessive, requiring two risk alleles,
although in certain situations (e.g., HIV-positive South
Africans), a single copy of a risk allele G1 has a significant
association with HIVAN (84). In the United States, ap-
proximately 40% of ESRD attributed to FSGS occurs in
blacks, and of this, 72% is associated with APOL1 genetic
variants (83); thus, approximately one third of FSGS in the
United States is associated with APOL1 variants.
APOL1-associated FSGS can present in various ways: it
may present as a primary FSGS, with severe nephrotic
syndrome, or as recurrence after kidney transplant, or it
manifest as adaptive FSGS with preserved serum albumin
and minimal edema. One setting in which the adaptive
processes drive APOL1 FSGS is perhaps the report that
APOL1 variants are associated with proteinuric sickle cell
nephropathy (97), although a systematic study of kidney
histology in APOL1-associated sickle nephropathy is still
lacking. APOL1 high-risk alleles are strongly associated with
collapsing glomerulopathy in several settings: (1) HIVAN, in
which 72% have two APOL1 high-risk alleles (83), and (2) the
use of exogenous IFN (98) and in lupus (99).
Emerging data support defining APOL1 FSGS as a sep-
arate category of FSGS. First, the APOL1 risk alleles repre-
sented confer susceptibility, but most subjects with two risk
alleles will not develop kidney disease; thus, APOL1 differs
from the high-penetrance genetic variants in most other
forms of genetic FSGS. Second, APOL1 FSGS is by far the
most common form of genetic FSGS in countries with
substantial African descent populations. Third, the diagnosis
of APOL1 FSGS may have implications for prognosis, with
more rapid progression to ESRD, and it may have impli-
cations for the selection of living donors. Fourth, novel
therapeutics may become available that target APOL1
variant–driven molecular pathways.
Therapeutic Approaches
Therapy should be individualized on the basis of the
particular form of FSGS as well as factors particular to the
patient, such as age and comorbidities. Therapy for pri-
mary FSGS and in rare instances, genetic FSGS, particularly
when nephrotic proteinuria is present, involves the use of
medications that are immunosuppressive but also have
direct effects on podocytes. These therapies are summa-
rized in Tables 4 and 5 and discussed below. A compre-
hensive analysis of approaches to steroid-sensitive and -resistant
FSGS is available from the Kidney Diseases Improv-
ing Global Outcomes initiative, and the reader is referred
to this initiative for a detailed and thoughtful discussion
(100) as well as recent reviews (13). FSGS may be re-
sponsive to therapy with glucocorticoids, although re-
lapses are typical. Randomized, controlled trials are few.
Interestingly, functional polymorphisms in the glucocorticoid
receptor encoded by NR3C1 have been associated with both
relapse and frequent relapse (101). Cyclosporin plus low-
dose prednisone was shown in a randomized, controlled trial
to be superior to prednisone alone in preserving renal
function assessed as creatinine clearance (102). Mycopheno-
late mofetil has not been tested as monotherapy for FSGS, but
it has been tested in combination with glucocorticoids in
Clin J Am Soc Nephrol 12: 502–517, March, 2017 FSGS, Rosenberg et al. 511

Table 4. Treatment recommendations for children with FSGS

Setting Therapy Comment

On presentation Prednisone: initially daily and then

alternate days
Frequently relapsing or Prednisone: initially daily and then
steroid dependent alternate days at lowest dose to prevent
relapse
Same, with steroid-related Alkylating agent (cyclophosphamide or No RCT comparing one agent with
adverse events chlorambucil), calcineurin inhibitor, another; listed in alphabetical
levamisole, mycophenolate mofetil order
Steroid resistant Calcineurin inhibitor Also ACE inhibitor and angiotensin
receptor blocker; sodium
restriction
If no remission, mycophenolate mofetil,
corticosteroids, or both

Recommendations from the Kidney Disease Improving Outcomes Global initiatives. Doses and durations of therapy are provided in
Lopez-Hellin et al. (46). In the nosology presented here, these recommendations would apply to nephrotic forms of primary FSGS, APOL1
FSGS, and certain rare forms of genetic FSGS. RCT, randomized, controlled trial; ACE, angiotensin-converting enzyme.

three trials against active comparators that were either
glucocorticoids or cyclosporin (reviewed in Senthil Nayagam
et al. [103]). None of the trials showed significant differences
between groups, and although sample sizes were small,
particularly for noninferiority trials, these data suggest efficacy.
Several Cochrane reviews are available covering treat-
ment of FSGS in adults (104) and children using not only
glucocorticoids (105) but also, other therapies, including
cyclophosphamide, azathioprine, levamisole, mizorbine,
and rituximab (106,107). Many other agents have been
tested in small trials or reported as case series, and they
have been the subject of recent reviews (13,108–111). These
agents include the following: adalimumab, an anti-TNF
mAb (112); pirfenidone, an antifibrotic agent that sup-
presses TGF-b signaling (113); fresolimumab, an anti–TGF-b
mAb (114); pulse steroids plus cyclophosphamide (115);
and saquinivir (116). Achtar gel is unusual in that it was
approved in the 1950s by the US Food and Drug Admin-
istration for nephrotic syndrome under criteria that were
less stringent than required today. Small case series suggest
limited efficacy of Acthar in some individuals with FSGS
(117,118) as has been reviewed (119); a randomized,
controlled trial is in progress. Galactose, proposed as ther-
apy for recurrent FSGS, has been shown to lack efficacy in
steroid-resistant primary FSGS in children (120). Sirolimus
may accelerate progression of FSGS and should be avoided
(93). Ongoing and recently completed phase 3 trials have
shown some efficacy with sparsentan, an irbesartan-like
molecule that also antagonizes endothelin receptor, and
abatacept, a CD80 antagonist (121).
There is considerable incentive for the pharmaceutical
and biotechnology industry to develop novel therapies for

Table 5. Treatment recommendations for adults with FSGS

Setting Therapy Comment

Nephrotic forms of primary FSGS,a
APOL1 FSGS, certain steroid-
sensitive genetic forms of FSGS
Steroid-resistant FSGS with
nephrotic syndromea
Refractory FSGS with nephrotic
syndromea
All forms of FSGS with subnephrotic
proteinuria
Prednisone, initially daily or Alternate for patients at high risk
alternate daysa for steroid complications:
calcineurin inhibitorsa
Calcineurin inhibitora
(cyclosporin and possibly,
tacrolimus)
Mycophenolate mofetil plus
high-dose dexamethasonea
ACE inhibitor and angiotensin Thiazide diuretic may potentiate
receptor blocker; dietary the antiproteinuric of RAAS
sodium restriction antagonism

Therapy doses are in ref. 46. Cyclosporin has been shown effective in randomized, controlled trials, whereas tacrolimus has not. In the
nosology presented here, these recommendations would apply, when nephrotic syndrome is present, to primary FSGS, APOL1 FSGS,
and certain rare forms of genetic FSGS that may be steroid sensitive. ACE, angiotensin-converting enzyme; RAAS, renin-angiotensin-
aldosterone system.
a
Recommendations from the Kidney Disease Improving Outcomes Global initiatives for idiopathic FSGS with nephrotic syndrome are
extended here to other forms of FSGS as shown.
512 Clinical Journal of the American Society of Nephrology
FSGS, a rare disease as defined by the US Food and Drug
Administration that lacks therapies that are both safe and
effective. Gipson and colleagues (122) have proposed a new
paradigm for therapeutics development that involves a deep
understanding of disease mechanisms in patient subsets,
enriching study populations for subjects most likely to
respond on the basis of those biologic insights, and adaptive
trial designs to improve efficiency (122,123).
Medication-associated FSGS can generally be managed
by stopping the offending medication, and virus-associated
FSGS can be best addressed by initiating antiviral therapy
with additional adjunctive therapies as indicated. Cur-
rently, therapy for APOL1 FSGS is directed toward ad-
dressing the other FSGS classes (e.g., primary, adaptive,
virus associated, or medication associated) that may coexist
with APOL1 FSGS. Future therapies for cell injury path-
ways initiated by APOL1 variant expression are likely to be
developed.
The customary definition of response is similar to that of
other nephrotic diseases and assumes baseline proteinuria
in the nephrotic range (i.e., urine protein-to-creatinine ratio
[uPCR] $2 g/g). First void urine is preferred, because that
uPCR most closely correlates with the 24-hour uPCR.
Complete remission (CR) is defined as uPCR,0.2 g/g, and
partial remission (PR) is defined as having 50% reduction
from baseline proteinuria and uPCR,2 g/g.
RAAS antagonism therapy is central to all progressive
CKD, and it is the treatment that directly addresses the
hemodynamic alterations in adaptive FSGS. RAAS antago-
nist therapy also has a role in genetic FSGS (evidence limited
to case reports [124]) and APOL1 FSGS (no published data),
particularly when adaptive hemodynamic mechanisms are
likely at work (e.g., an individual who was born prematurely
is now obese and has a normal serum albumin, despite
substantial proteinuria), and may reduce proteinuria in
primary FSGS adjunctive to immunosuppressive therapies.
RAAS antagonist monotherapy was shown in a retrospective
study to be superior to immunotherapy in a pediatric FSGS
cohort in Philadelphia (with 55% black subjects) (125). As
with all progressive CKD, attention to BP control, smoking,
obesity, and serum bicarbonate and urate are indicated, and
consideration should be given to statin therapy.
The effects of RAAS antagonist therapy are potentiated
by dietary sodium restriction and low-dose thiazide diuretic
(126). Although hydrochlorothiazide is the most widely used
thiazide diuretic, an alternative is chlorthalidone, which has
certain features to recommend its more widespread use: it
has longer duration of action, it is more kaliuretic (particu-
larly helpful when low GFR compromises potassium excre-
tion), and it has been shown to improve cardiovascular
outcomes, which other thiazides have not been shown to do.
The issue of combining an angiotensin-converting en-
zyme inhibitor (ACEi) and an angiotensin receptor blocker
(ARB) is fraught with uncertainty. A meta-analysis of this
combination therapy in IgA nephropathy suggested pro-
teinuria reduction compared with single therapy, but
only one study involved subjects with nephrotic-range pro-
teinuria (127). The Ongoing Telmisartan Alone and in
Combination with Ramipril Global End Point Trial Study
showed that this combination is associated with adverse
cardiovascular outcomes in an older population with a high
prevalence of cardiovascular disease (128); similarly, the VA
Diabetes in Nephropathy Study of diabetic nephropathy
(median age of 64 years old) showed a trend toward benefit
but was stopped early due to safety concerns (129). These
studies may have limited relevance to younger patients
with FSGS, particularly those with preserved GFR, who
may tolerate this combination better. RAAS antagonism and
particularly, the combination of ACEi and ARB will lower
GFR by reducing efferent arteriolar vascular tone and thus,
reducing intraglomerular capillary pressure, the driving
force for glomerular filtration. Thus, a modest decrease in
GFR may be tolerated, providing evidence that RAAS
antagonism has been achieved. Nevertheless, there are no
trials of suitable size to justify this approach from an
efficacy or safety standpoint.
An alternate approach to RAAS antagonism is to com-
bine an ACEi or ARB with an aldosterone antagonist (130).
This approach may have less effect on reducing glomerular
capillary pressure, but aldosterone antagonists are potent
antifibrotic agents. Recent data have shown that aldoste-
rone is positioned upstream of multiple profibrotic path-
ways and that angiotensin 2 is only one of many stimuli to
aldosterone production (131). This combination confers a
risk for hyperkalemia, particularly with reduced GFR; this
may be controlled with dietary restriction and diuretics,
although close monitoring may be required.
Glucocorticoids have some efficacy in primary FSGS,
although they have not been tested against placebo in a
randomized, controlled trial. Response rates, defined as CR
plus PR, tend to be higher in children (often approximately
50%) compared with adults. For APOL1 FSGS, response
rates to glucocorticoids are probably similar to those seen
in primary FSGS, although the data are limited (83). The
mechanism by which glucocorticoids affect podocytes are
poorly understood; these agents are known to have direct
effects on cultured podocytes (132). Recently, it has been
suggested that these agents can expand the population of
myeloid-derived suppressor cells that downregulate T cell
function (133). Reliable and validated biomarkers of steroid
responsiveness would be valuable. There are few data on
which to base a determination of the appropriate dose and
duration of glucocorticoid therapy. Biomarkers for respon-
siveness to glucocorticoid therapy would be valuable to
reduce or avoid the need to expose patients to drugs to
which they will not respond. Preliminary studies that await
validation in larger cohorts include the ratio of podocin
mRNA to synaptopodin mRNA, particularly when the
diagnostic uncertainty with regard to MCD versus FSGS
exists (134). Immunohistochemical detection of reduced
expression of synaptopodin and receptor-type tyrosine-
protein phosphatase O (PTPRO or GLEPP1) may be useful
in identifying steroid-resistant patients (135). Conversely,
reduced eGFR at presentation does not predict nonrespon-
siveness to glucorticoids (136).
Calcineurin inhibitors, including cyclosporin and tacro-
limus, are mainstays of FSGS therapy for both steroid-
sensitive individuals who cannot tolerate continued steroid
therapy and steroid-resistant FSGS. Cyclosporin was
shown superior to placebo in the North American collab-
orative trial of steroid-resistant FSGS, with the primary
outcome of CR or PR occurring in 70% with cyclosporin
and 4% with placebo (102). Similarly, an open label study
of cyclosporin in steroid-resistant nephrotic syndrome in
Clin J Am Soc Nephrol 12: 502–517, March, 2017
China showed a 75% response rate (137). The FSGS Clinical
Trial, which enrolled mostly children, showed that response
rates are similar for cyclosporin and mycophenolate mofetil
in blacks with and without high-risk APOL1 genotypes,
although group sizes were small (138). Although patients
may relapse when calcineurin inhibitors are discontinued,
many subjects remain in remission.
A number of novel therapies have been explored in small
trials. Some of these therapies have some promise, includ-
ing pirfenidone (113) and saquinivir (116). Other therapies
that have been shown to be ineffective or even harmful
include sirolimus (93), galactose (139), and adalimumab
(mAb directed against TNF) (139). Other immunosuppres-
sive agents that have been used include azathioprine and
mizoribine, although limited data for their success are
available.
Recently, there has been a surge of interest in developing
new therapies for FSGS and other primary glomerular
diseases, all of which are defined as rare by the US Food
and Drug Administration, and therefore, new therapies
have certain commercial benefits. This is an exciting time
for researchers of FSGS, and this is a time that patients
with FSGS and their families have reason for cautious
optimism. Ongoing or recently completed trials within the
United States include a phase 1 study of N-acetyl mannosamine
(metabolic precursor of sialic acid) and phase 2/3 studies
of sparsentan (a modified form of irbesartan that also antag-
onizes endothelin-1), abatacept (a fusion protein that targets
CD80), Acthar (pituitary extract), fresolimumab (mAb directed
against TGF-b), isotretinion (retinoic acid derivative), and
losmapimod (an mitogen-activated protein kinase inhibi-
tor). Trials in other countries are studying dapagliflozin
(Canada), lipoprotein removal (Japan), and mesenchymal
stem cell therapy (Iran). Given the diverse forms of FSGS and
the multiple molecular pathways involved in the pathogen-
esis of each form, it is critical that these trials and future trials
characterize subjects with sufficient depth to determine the
characteristics of responders and nonresponders.
FSGS comprises a complex set of syndromes, most with
multiple causes, and hence, FSGS represents a diagnostic
challenge that requires close and thoughtful collaboration
between patient, family, nephrologist, pathologist, and
geneticist to gather the necessary data. Information from
clinical history, laboratory testing, renal biopsy, and in
some patients, genetic testing can be used to identify which
syndrome is present, guide therapy, and provide prognos-
tic information. Many forms of FSGS tend to progress to
ESRD, but new therapies are being tested that may improve
the prognosis.
Acknowledgments
The authors gratefully acknowledge the editorial assistance of
Dr. Carla Nester, who improved the organization and clarity of
this manuscript.
This work was supported by the Intramural Research Program,
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health and the Departments of Pathology of
the Children’s National Medical Center and Johns Hopkins Medical
Institutions.
Disclosures
None.
FSGS, Rosenberg et al. 513
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This article contains supplemental material online at http://cjasn.
asnjournals.org/lookup/suppl/doi:10.2215/CJN.05960616/-/
DCSupplemental.
Published online ahead of print. Publication date available at www.
cjasn.org.
 IgA Nephropathy
Jennifer C. Rodrigues,* Mark Haas,† and Heather N. Reich*‡

Abstract
IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts
have led to important discoveries that have improved our understanding of some of the key steps involved
in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed
to rigorous design and execution of clinical trials that have provided important insights regarding
*Department of
immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN Medicine, University
research and describe how these novel findings will influence future strategies to improve the outcome of of Toronto and
patients with IgAN. Division of
Nephrology,
Clin J Am Soc Nephrol 12: 677–686, 2017. doi: https://doi.org/10.2215/CJN.07420716 University Health
Network, Toronto,
Ontario, Canada;
†
Department of
Epidemiology of IgA Nephropathy Pooled cohorts from the European Validation Study of Pathology and
The most common GN globally is IgA nephropathy the Oxford Classification of IgA Nephropathy (VALIGA) Laboratory Medicine,
(IgAN). Prevalence varies geographically, and esti- and North American cohorts indicate rates ESRD or Cedars-Sinai Medical
mates of disease burden vary according to whether Center, Los Angeles,
halving of eGFR of 27% at 10 years (7). There are regional
California; and
ascertained using biopsy registry data versus dialysis differences in the progression of disease, however these ‡
Gabor Zellerman
registries. Despite these caveats, biopsy and organ are difficult to ascertain given lead-time biases intro- Chair in Nephrology
replacement registries suggest geographic variation in duced by variation in biopsy practice. In our cohort of Research, University
disease burden with a higher incidence in Pacific of Toronto, Toronto,
669 patients, multivariable analysis demonstrated that Ontario, Canada
Asian regions. individuals of Pacific Asian origin have an increased
Biopsy registry data underestimate disease burden risk of ERSD (adjusted hazard, 1.56; 95% confidence in- Correspondence:
as patients with mild disease may not undergo biopsy, terval [95% CI], 1.1 to 2.22) (8). Dr. Heather Reich,
and in countries lacking screening programs disease Division of
may not be detected. Distinguishing the contribution Nephrology,
University Health
of ancestry and geography to differential disease sus- Disease Pathogenesis in IgAN Network, 200 Elizabeth
ceptibility using biopsy registry data is further chal- Susceptibility to IgAN and risk of disease progres- Street, Room 8N 849,
lenged by substantial geographic variation in biopsy sion are influenced by a confluence of genetic and Toronto, ON M5G
practice patterns (e.g., for clinical indication versus 2C4, Canada. Email:
environmental factors. The immunopathogenesis of
heather.reich@uhn.ca
mandatory military screening). A systematic review this disease is described as a multi-“hit” process (9).
of biopsy-based studies spanning multiple countries These “hits” reflect knowledge derived from popula-
suggests an overall population incidence of at least tion genetic studies and careful characterization of the
2.5 per 100,000 (1). Only one study in this review was IgA moieties found in biopsy specimens and circulation of
from Japan, and most were from Europe and North patients with IgAN. Figure 1 illustrates current under-
America. In children, the incidence in a Japanese biopsy standing of the pathogenesis of IgAN and steps where
registry study where broad screening programs were in therapeutic interventions may be targeted.
place was eight-fold higher compared with a Tennessee A central finding in patients with IgAN is the presence
program where biopsies were performed for-cause and of circulating and glomerular immune complexes com-
routine screening was not in place (4.5 versus 0.57 per prised of galactose-deficient IgA1, an IgG autoantibody
100,000/yr) (2,3). directed against the hinge region O-glycans, and C3. The
Compelling data from autopsy and donor registries presence of aberrantly glycosylated IgA1 is an heritable
support that there is a higher burden of IgAN in East trait (10). Galactose-deficient IgA1 levels are elevated in
and Pacific Asian countries. Lanthanic IgA deposition 25% of blood relatives of IgAN patients and segregation
is detected in 1.3% of autopsies of trauma victims in analysis suggests a major dominant gene with additional
Finland compared with 15.6% of deceased donor can- polygenic background (11). A recent review outlines
didates in Japan (4,5), suggesting that regional vari- the cellular mechanisms responsible for IgA glyco-
abilities in incidence are not simply attributable to sylation (12). The relative levels of galactose-deficient
variation in biopsy practices. These findings parallel IgA1 may also be partially influenced by environ-
geospatial differences in prevalence of genetic suscep- mental factors. For example, these antibodies are
tibility loci reported in global genome-wide association susceptible to bacteria-derived proteases (13). Re-
studies (6). cent data suggest that anti-glycan autoantibodies

www.cjasn.org Vol 12 April, 2017 Copyright © 2017 by the American Society of Nephrology 677
678 Clinical Journal of the American Society of Nephrology

Figure 1. | Understanding the pathogenesis of IgA nephropathy reveals therapeutic targets. (A) Mucosal IgA production by plasma cells
occurs by T cell–dependent and –independent processes. T cell cytokines such as APRIL promote B cell class switch to IgA1-producing plasma
cells. Inhibitors of these cytokines are potential therapeutic targets. B cell and plasma cell inhibitors (e.g., rituximab, bortezomib) may result in
decreased IgA production. (B) The IgA1 produced in patients with IgA nephropathy is underglycosylated (Gd-IgA1). Susceptible individuals will
also produce anti–Gd-IgA1 autoantibodies (auto-Ab), reviewed in (9). Antiproliferative drugs may affect production of anti-glycan autoanti-
bodies. The Gd-IgA1–auto-Ab immune complexes activate the alternative pathway of complement. Complement inhibitors may prevent
formation of immune complexes. (C) The immune complexes are nephritogenic, contributing to local inflammation, cellular proliferation, and
ultimately fibrosis. Broad-based targeting of processes implicated in glomerular and tubulo-interstitial injury (e.g., inflammation, fibrosis)
target these final common pathways of kidney damage. Anti-Gd-IgA1-auto Ab, autoantibody directed at galactose-deficient IgA1.

may be targeting IgA VH gene segments that occur as a
result of somatic hypermutation, and not sequences pre-
sent in the host germline (14).
These immune complexes are nephritogenic, contribut-
ing directly to glomerular inflammation and mesangial
proliferation. Activation of the local and systemic renin
angiotensin system and complement activation also ulti-
mately contribute to glomerulosclerosis and tubulo-inter-
stitial fibrosis, leading to loss of renal function. Coexistent risk
factors such as hypertension and smoking contribute to
disease progression, potentially through microvascular injury
(15). Maladaptive hyperfiltration injury and glomerulome-
galy attributed to obesity are also implicated in nonimmuno-
logically-mediated disease progression (16).
The triggers responsible for production of galactose-
deficient IgA1 are not known and the site of IgA produc-
tion in IgAN is not established. Experimental models suggest
environmental triggers may lead to excess production of
aberrantly-glycosylated IgA in mucosal-associated lymphoid
tissue. A B cell activation factor of the TNF family, BAFF, is
critical but not sufficient for development of an experimental
IgAN phenotype (17). In this model BAFF-overexpressing
mice reared in pathogen-free conditions develop a phenotype
similar to IgAN with detectable circulating and glomerular
underglycosylated IgA, whereas those housed in germ-free
cages do not. The related cytokine APRIL (a proliferation-
inducing ligand) shares some signaling receptors important
for B cell development with BAFF, is elevated in IgAN pa-
tients, and correlates with age, serum creatinine, and urine
protein-to-creatinine ratio (18).
These findings suggest that, at least in mice, exposure to
commensal or pathogenic bacteria is necessary for excess
IgA production, and this is facilitated by the presence of
mediators of B cell differentiation and proliferation BAFF
and/or APRIL. Although application to the pathophysiol-
ogy of IgAN in humans must be made with caution, this
schema is further supported by genome-wide association
studies and clinical studies of disease progression (19). It is
hypothesized that APRIL contributes to IgAN by promot-
ing B cell class switch to an IgA-producing plasma cell
through its dominant actions on the TACI receptor.
A polymorphism in the APRIL gene confers IgAN sus-
ceptibility (20) and several risk alleles associated with
IgAN are also associated with other diseases of mucosal
immunity and defense against mucosal microbial patho-
gens (21). Elevated circulating APRIL levels were docu-
mented in a cohort of 166 patients with IgAN, and
APRIL expression was correlated with a progressive clini-
cal phenotype and elevated circulating levels of galactose-
deficient IgA (19).
Recent studies suggesting immunotherapy primar-
ily results in reduction in proteinuria (without change in
long-term outcome) may call into question the role of anti-
glycan antibodies in disease immunopathogenesis. How-
ever, one must consider that these are short-term treatment
interventions, and the formation of anti-glycan antibodies is
only one part of a complex disease process. Genetically-
influenced and environmentally-determined defects in
mucosal immune function (and microbiota profiles) may
not be altered in a sustained fashion by a brief immuno-
modulatory intervention.
Activation of complement is regarded as an important
pathogenic contributor in IgAN. The lectin pathway of com-
plement activation is also implicated in IgAN pathogenesis.
Clin J Am Soc Nephrol 12: 677–686, April, 2017
Polymeric IgA1 is capable of activation of this pathway in vitro,
and mannose-binding lectin pathway elements are detected
in glomerular deposits (22,23).
Clinical and genetic studies link defects in regulation of the
alternative pathway of complement to IgAN immunopatho-
genesis (6). Circulating and immune complexes contain C3,
and this is evident on immunofluorescence of kidney biop-
sies (24). Properdin and complement factor H (CFH) are also
detected in immune deposits (reviewed by Gharavi et al.
[25]). Genome-wide association studies identify an allele
initially localized to the CFH gene that confers protection
against development of IgAN. Further analysis indicate
that deletion of complement factor H–related (CFHR) genes
one and three are in linkage disequilibrium with the iden-
tified risk allele. The CFHR1 and CFHR3 proteins titrate
CFH activity, and their absence is associated with altered
CFH levels and enhanced CFH activity (25,26).
Clinical-Pathologic Correlation in IgAN: Mesangial
hypercellularity (M), endocapillary hypercellularity
(E), segmental glomerulosclerosis (S), tubular atrophy
(T), MEST and Crescents
Through rigorous design of a structured, standardized,
and reproducible pathologic scoring system in IgAN,
pathologic evaluation now adds important prognostic
information beyond what is obtained from clinical var-
iables alone.
The Oxford classification schema was derived studying
patients with $0.5 g/d of proteinuria, eGFR$30 ml/min
per 1.73 m2 at renal biopsy, and $1 year of follow-up.
Histologic variables selected for inclusion demonstrated
a high degree of interobserver reproducibility and corre-
lated with predetermined clinical endpoints including a
composite outcome of ESRD or 50% reduction in eGFR
and rate of renal function decline. Four key pathologic
features were consistently independently-associated with
renal outcome including mesangial hypercellularity (M),
endocapillary hypercellularity (E), segmental glomerulo-
sclerosis (S), and tubular atrophy and interstitial fibrosis
(T) now known collectively as the MEST or Oxford score
(27). The absence/presence of .50% of glomeruli show-
ing mesangial hypercellularity is denoted M0/M1, respec-
tively; E1 indicates any endocapillary hypercellularity; S1
denotes any segmental glomerulosclerosis; and T0, T1, and
T2 reflect fibrosis involving 1%–25%, 26%–50%, or .50% of
the cortical area.
The clinical relevance and applicability of this score has
now been validated across multiple populations including,
most recently, the European (VALIGA) cohort (28). True
validation studies (such as described by Herzenberg et al.
[29]) applied the regression models derived in the original
Oxford cohort and verified the independent contribution
of each variable to the same clinical outcomes. Although
the individual components were not always indepen-
dently predictive in these validation studies the score over-
all consistently adds value to prognostication.
The largest validation study was performed in the VALIGA
cohort of 1147 patients. Unlike the original Oxford study,
entry criteria were less restrictive; patients at both ends of the
spectrum of disease severity were included. The cohort was
predominantly white (97.5%) and the combined end point of
IgA Nephropathy, Rodrigues et al. 679
ESRD or decrease in eGFR by 50% occurred in 26% of patients
at 10 years. Most of the histologic variables remained
independently associated with outcome, when adjusted for
baseline and longitudinal clinical variables. Interestingly, in
the low risk group with proteinuria,0.5 g/d only endoca-
pillary proliferation was associated with a rapid rate of re-
nal function decline by univariate analysis (hazard ratio
[HR], 5.2; 95% CI, 1.1 to 25.9), however, it was not signif-
icantly associated with outcome by multivariate analysis.
Mesangial and endocapillary proliferation were associated
with an increased risk of developing proteinuria$1 g/
d (HR, 2.3; 95% CI, 1.3 to 4.0) or $2 g/d (HR, 3.5; 95%
CI, 1.5 to 8.4). In patients with eGFR,30 ml/min per 1.73
m2 M1 and T1–2 were associated with a lower renal sur-
vival (HR, 2.3; 95% CI, 1.2 to 4.2) (28).
An important goal of deriving a histologic scoring sys-
tem is shortening the time frame of observation required
to accurately predict which patients are at risk of adverse
outcome. A recent pooled analysis of the 901 subjects from
the VALIGA, Oxford, and North American cohorts dem-
onstrated that incorporation of MEST score into predictive
algorithms provides timely and accurate predictive accu-
racy to identify patients at highest risk of poor outcome (7).
The addition of the MEST score to clinical data at biopsy
provided significant improvement in prediction compared
with considering only clinical data at biopsy (proteinuria,
creatinine, mean arterial pressure). Importantly, the com-
bination of MEST and cross-sectional clinical data at bi-
opsy predicted adverse outcome as well as using 2 years
of clinical data (proteinuria and mean arterial pressure av-
eraged over a 2-year period). This was true regardless of
treatment with renin-angiotensin system (RAS) blockade
or immunosuppression.
Elucidating the relationship between histologic class and
treatment response is an important next step. The MEST
studies suggest that response to corticosteroids may differ
according to histology. In the original derivation cohort,
use of corticosteroids confounded the relationship between
endocapillary proliferation, and adverse outcome (30). In
the VALIGA cohort, half of subjects received immunosup-
pression, mostly including corticosteroids. In a VALIGA
substudy, Tesar et al. (31) derived a propensity-matched
cohort of 184 pairs to evaluate additive benefits of cortico-
steroids above RAS blockade. Use of corticosteroids affor-
ded an improved renal survival, and the greatest reduction
in rate of renal function afforded by corticosteroids oc-
curred in subjects with mesangial proliferation, segmental
glomerulosclerosis, and tubulo-interstitial fibrosis. Al-
though it is difficult to make firm conclusions based
upon observational data, future therapeutic trials in
IgAN should include stratification based upon MEST score
to determine if histology can be used to tailor treatment
decisions.
The additive effect of crescents on prediction of outcome
remains a challenging question in IgAN, and new infor-
mation may shed some light on clinical implications of
these findings. Although crescents are a common finding
in IgAN biopsies, the presence of .30% of crescents is
not. Early studies initially suggested that patients with
crescents involving .50% of glomeruli are at high risk of
progression, with 75% reaching ESRD by 10 years (32).
Certainly, in the context of rapid progression of loss of kidney
680 Clinical Journal of the American Society of Nephrology
function, crescents portend a poor prognosis. Patients with
rapidly progressive courses were not included in the Oxford
study, therefore the study was underpowered to determine
if a high percentage of crescents is independently-associated
with adverse outcome (i.e., beyond the information that
would have been derived from clinical data alone). A meta-
analysis of the Oxford study and four validation studies did
suggest that the presence of crescents is associated with a
higher risk of adverse prognosis (HR, 2.3; 95% CI, 1.6 to
3.4; P,0.001) (33).
A working group formed in 2014 at the First Oxford Con-
ference on IgA Nephropathy examined the association
of crescents with renal outcomes in 3096 patients combined
from four published studies: the original Oxford cohort, the
VALIGA study cohort, and two large Asian cohorts, one
from China and the other from Japan. Biopsies from 1118
(36%) of the patients contained any cellular or fibrocellular
crescents; 440 (14%), 221 (7%), and 96 (3%) had crescents in
$1/10, $1/6, and $1/4 of glomeruli, respectively. Over-
all, the presence of any such crescents was a significant,
independent predictor of the likelihood of developing a
combined event of ESRD or a $50% reduction in eGFR.
Other independent predictors of the combined event were
eGFR at biopsy, time-averaged proteinuria and mean ar-
terial pressure, and Oxford M1, S1, and T1/T2 scores. The
predictive value of all histologic parameters (including
crescents) except T1/T2 was lost in patients receiving im-
munosuppression. However, the presence of cellular or
fibrocellular crescents in $1/4 of glomeruli was signifi-
cantly predictive of the combined event even in patients
receiving immunosuppression. On the basis of these find-
ings, the authors proposed adding crescent scores to the
Oxford (MEST) classification as follows: C0—no cellular or
fibrocellular crescents; C1—cellular/fibrocellular crescents
in ,25% of glomeruli, identifying patients at increased
risk of a poor outcome (compared with C0) among those
not given immunosuppressive therapy; and C2—crescents
in $25% of glomeruli, identifying patients at increased risk
of a poor outcome even if given immunosuppression (34)
(see Figure 2).
The MEST score does not replace the detailed and in-
formative information provided by the full pathology
report. One should be mindful that despite the statistically-
significant association with progression, the pathology score
combined with clinical data account for only a minority
(,30%) of the variability in outcome in patients with IgAN
(35). Therefore, a majority of the variability in outcome is
attributable to unmeasured factors which would hopefully
include therapeutic intervention.
Clinical Manifestations
The range of clinical manifestations of IgAN is broad,
from asymptomatic microscopic hematuria to rapidly pro-
gressive GN. The typical mode of presentation varies ac-
cording to age group and biopsy practice patterns.
Common Phenotypes: Asymptomatic Hematuria and
Progressive Kidney Disease
By far the two most common clinical presentations
are asymptomatic hematuria and progressive kidney
disease. Asymptomatic hematuria with minimal protein-
Figure 2. | A novel addition to the MEST classification system iden-
tifies patients at increased risk of poor outcome based on crescents: C0
(no crescents), C1 (<25% left panel), and C2 (‡25% right panel). The
biopsy specimen represented in the left panel had 21 total glomeruli of
which two had segmental crescents; of the six complete glomeruli
represented in the photomicrograph one shows a fibrocellular crescent
with segmental solidification of the tuft adjacent to the crescent. There is
also mild mesangial hypercellularity, and the MEST scores are M1, E0,
S1, T0. The biopsy represented in the right panel contained 14 total
glomeruli, of which five had segmental cellular crescents; two of the
latter glomeruli are represented in the photomicrograph. The glomeruli
also show mesangial hypercellularity, and the biopsy also showed focal
and segmental endocapillary hypercellularity (not shown in the photo-
micrograph); the MEST scores are M1, E1, S0, T0. Periodic acid–Schiff
stain; original magnification, 3100 (left panel), and original magnifi-
cation, 3200 (right panel).
uria (i.e., ,0.5 g/d) may be detected through screening
programs, such as those in countries with school screen-
ing, military draft screens, or insurance programs. Isola-
ted microscopic hematuria with minimal proteinuria is
regarded as having a favorable prognosis, particularly in
white populations (36). Nonetheless, a proportion will ul-
timately develop hypertension and significant proteinuria,
suggesting that long-term follow-up of these patients
should be instituted (37,38).
Progressive CKD is a common phenotype observed in
multiple cohorts. Renal survival ranges greatly according
to biopsy timing and introduction of lead-time bias.
Actuarial renal 10-year survival is reported to be 57%–
91% (39). In addition to pathologic findings, factors asso-
ciated with poor prognosis include hypertension, protein-
uria, and decreased eGFR at diagnosis (35,40). Race may
also be an important determinant of outcome (8).
Less Frequent Manifestations
Synpharyngitic macroscopic hematuria is a classic clin-
ical syndrome associated with first presentation of IgAN.
The presence of gross hematuria at the time of pharyngitis
or other infection is alarming to patients and often prompts
immediate medical attention and diagnosis. This syndrome
occurs in approximately 10%–15% of subjects (41) and pre-
dominantly in patients under the age of 40. Recurrent mac-
roscopic hematuria is associated with a favorable prognosis
in the short-term, potentially reflecting lead-time bias asso-
ciated with this finding in younger populations. However,
Clin J Am Soc Nephrol 12: 677–686, April, 2017
subsequent development of persistent proteinuria is well
documented and associated with potentially progressive
disease (42).
Although nephrotic-range proteinuria.3 g/d is not un-
common in IgAN, coexistence of the nephrotic syndrome is
rare (43,44). A rare clinical presentation more in keeping with
dual diagnoses of IgAN and minimal change disease is also
well described. Renal function is often preserved, and overt
nephrotic syndrome with edema, dyslipidemia, and hypoal-
buminemia is present. Steroid responsiveness and favorable
prognosis akin to minimal change lesions are reported (45),
although a steroid-sparing agent is often required to maintain
remission. In one cohort, only 306 patients of 11,885 with IgA
met criteria for this diagnosis—diffuse IgA-dominant mesan-
gial deposits with minimal changes in glomeruli on light
microscopy and .50% podocyte foot process effacement.
None of these patients reached ESRD at the end of a median
of 2.6 years (45).
IgAN with rapidly progressive course is rare and most
frequently associated with a pathologic finding of .50% of
glomeruli exhibiting crescents. The largest case series of
113 subjects described a rate of ESRD of 42.5% at 1 year
despite immunotherapy (46).
Treatment Strategies: Current Evidence and
Novel Therapies
In this section, the focus of discussion will be on treating
the most common clinical variants of IgAN.
Conservative Therapy
The importance of conservative therapy to reduce pro-
teinuria and slow the rate of renal function decline in IgAN
cannot be overemphasized. In the recent Supportive Versus
Immunosuppressive Therapy of Progressive IgA Nephrop-
athy (STOP-IgAN) trial, nearly one third of patients who
completed a 6-month run-in phase of intensive optimiza-
tion of conservative therapy no longer qualified for ran-
domization to immunosuppressive therapy (47).
The role of RAS blockade in IgAN is now well established.
Although dual RAS blockade may reduce proteinuria, reg-
ulatory agencies have recommended against use of combi-
nation therapy due to risks of hyperkalemia (48). Many trials
have examined the effects of statins in patients with CKD,
however few have focused on patients with IgAN. A small,
randomized, placebo-controlled trial of 21 patients with se-
rum creatinine ,1.8 mg/dl, with absence of severe lesions on
renal biopsy and without RAS blockade, received fluvastatin
or placebo for 6 months. A decrease in proteinuria was seen
after 6 months (baseline 837–1100 mg/24 hours in the pla-
cebo group versus 845–494 mg/24 hours, P,0.01) (49).
Obesity can contribute to proteinuria. In a cohort of 331
patients with IgAN in whom 44.1% were either overweight or
obese, the overweight/obese group were more likely to
be hypertensive (24.6% versus 52.9%, P,0.001), have worse
renal function (mean eGFR 69.1 versus 80.2, P50.003), and
have proteinuria$1 g/d (22.1% versus 39.7%, P50.003).
There was no difference in the endpoint of death/dialysis
between those with normal body mass index (BMI) and the
overweight/obese group, however the overweight/obese
group had a worse eGFR (59.3 versus 73.4, P,0.001) and a
greater prevalence of CKD stage 3 or greater (43.4% versus
IgA Nephropathy, Rodrigues et al. 681
21.0%, P 0.001) (50). Weight reduction may ameliorate pro-
teinuria in IgAN (51). Given the link between smoking and
progression, smoking cessation should also be promoted (15).
Corticosteroids
There are several clinical trials supporting that corti-
costeroids reduce proteinuria in IgAN. Although earlier
studies supported that this was associated with an im-
provement in clinical outcome, more recent large trials
question the sustained benefits of a brief period of immu-
nosuppression.
One of the first randomized trials suggesting a benefit of
corticosteroids was a study of 86 patients with biopsy-proven
IgAN with proteinuria 1–3.5 g/d for at least 3 months and a
serum creatinine #1.5 g/dl (52). Patients received steroid ther-
apy (1 g intravenously for 3 days at months 1, 3, and 5, and
oral prednisone at 0.5 mg/kg per day on alternate days for 6
months) or supportive therapy alone. Given the era of the trial,
use of RAS blockade was not uniform and there was no run-in
period of optimizing conservative therapy. In this study, 5-
year renal survival (defined as 50% increase in serum creati-
nine) was greater in the corticosteroid group (81% versus 64%,
P50.05) as was survival without a 100% increase in creatinine
(95% versus 74%, P50.001). In the multivariate analysis, re-
duction in proteinuria from baseline to 6 months was signifi-
cantly associated with renal survival (relative risk [RR], 0.48;
95% CI, 0.34 to 0.69; P,0.001). At 10 years, renal survival was
better in the steroid group as compared with controls (97%
versus 53%, P50.003; RR, 0.06; 95% CI, 0.01 to 0.44; P50.001).
More patients in the steroid group had a reduction in protein-
uria ,0.5 g/d after 1 year (26% versus 5%; RR, 5.50; 95% CI,
1.3 to 23; number needed to treat55; P50.01) (53). This finding
suggested that exposure to corticosteroids for a 6-month pe-
riod may have a “legacy effect,” with sustained reduction in
the risk of progressive renal dysfunction.
Similarly, a single-center, randomized, open-label trial of
97 patients with biopsy-proven IgAN, proteinuria$1 g/d,
and eGFR.50 ml/min per 1.73 m2 demonstrated benefits of
corticosteroids (54). After a 3-month run-in phase during
which they were required to discontinue RAS blockade pa-
tients were randomized to ramipril or ramipril plus predni-
sone 1.0 mg/kg per day for 8 weeks then tapered by 0.2 mg/
kg per day every month. The corticosteroid group had a
higher baseline proteinuria (2.5 versus 2 g/d). More patients
in the combined group failed to reach the combined end-
point of ESRD or doubling of serum creatinine at 8 years
(85.2% versus 52.1%, P50.003). Similar results were demon-
strated in a Chinese cohort of 63 subjects (55).
A subsequent meta-analysis of 536 patients in nine trials
with proteinuria.1 g/d demonstrated corticosteroids de-
creased the risk of kidney failure (RR, 0.32; 95% CI, 0.15 to
0.67; P50.002). The effects on renal outcome were dose-
dependent, requiring .30 mg/d or high-dose pulse and
were not surprisingly associated with an increased risk of
adverse events (56). Major criticisms of these studies have
been the lack of uniform use of RAS blockade for all pa-
tient groups (52) and small sample size, which may have
been underpowered to detect adverse events associated
with corticosteroids (56).
The STOP-IgAN study (47) recently further brought
into question the long-term benefits of a 6-month course
of corticosteroids. This study was designed to enroll
682 Clinical Journal of the American Society of Nephrology
approximately 380 subjects to determine the benefits of
immunosuppression compared with conservative therapy
in patients with persistent proteinuria and eGFR.30 ml/min
per 1.73 m2 after a 6-month run-in period that involved
adequate BP control and RAS blockade, as well as lipid con-
trol. Patients allocated to the immunotherapy would receive
corticosteroids if the eGFR was .60 ml/min per 1.73 m2
whereas those with eGFR of 30–59 ml/min per 1.73 m2
would receive steroid and cyclophosphamide, followed by
maintenance immunosuppression with azathioprine akin to
one of the few randomized trials in patients with severe but
not rapidly progressive disease (57). The study was powered
to evaluate the effect of immunotherapy on primary end-
points: “full clinical remission” (protein-to-creatinine ratio
of ,0.2 and stable renal function with a decrease in the
eGFR of ,5 ml/min per 1.73 m2 from the baseline eGFR)
and a decrease in the eGFR of .15 ml/min per 1.73 m2 from
the baseline. Secondary endpoints related primarily to eGFR
changes and slope.
After the intensive 6-month optimization of conserva-
tive therapy, nearly one third of patients no longer qualified
for randomization. Ultimately only 162 patients were ran-
domized. At 3 years, a larger proportion of patients who
received immunosuppression were in a full clinical re-
mission compared with patients who received only sup-
portive care (17% versus 5%, P,0.05). However, these
differences in remission were not associated with signifi-
cant difference in the rate of loss of kidney function. Not
surprisingly, more infections occurred in the immunosup-
pression group, including one sepsis-related death. Im-
paired glucose tolerance and significant weight gain
were also observed (47).
The interim results of the Therapeutic Evaluation of
Steroids in IgA Nephropathy Global Study were recently
presented as a late-breaking clinical trial abstract at the 53rd
meeting of the European Renal Association—European
Dialysis and Transplantation Association. This study
was designed to evaluate the effects of a 6–8 months
course of 0.6–0.8 mg/kg per day of oral methylpredniso-
lone versus placebo, with a target sample size of 1300 and
5 years of longitudinal follow-up. The primary outcome
was a composite of 40% decrease in eGFR, ESRD, or
death. An interim analysis of 262 patients was presented.
Although proteinuria was reduced with corticosteroid
treatment, and the composite outcome occurred in a lower
proportion of patients in the treatment arm (8% versus
15%, P50.02), there were concerning signals of risk with
corticosteroids at a mean follow-up of 1.5 years. Serious
adverse events were reported more frequently in the cor-
ticosteroid arm (relative risk, 4.63; 95% CI, 1.63 to 13.18;
P50.001) mostly due to excess serious infections (14.7%
versus 3.2%, P,0.001), including two fatal infections.
Based upon the interim analysis the investigators con-
cluded that renal benefit is likely but will need to be
weighed carefully against risk. Recruitment is currently
on hold pending protocol revision (ClinicalTrials.gov
NCT01560052).
Mycophenolate
Data regarding the efficacy of mycophenolate are mixed,
such that current clinical guidelines recommend against
use of this agent in IgAN (58). At one end of the spectrum
is applicability in patients with low-risk renal disease. In a
randomized, double-blind, placebo-controlled clinical trial,
44 patients with persistent proteinuria.0.6–0.8 g/g and
eGFR.50 ml/min per 1.73 m2 were randomly assigned
to mycophenolate mofetil (MMF) or placebo in addition
to conservative therapy. A significant number were ex-
cluded as they had a good response to conservative man-
agement during the run-in phase (36 of 184) and only
seven patients in the treatment group and ten patients in
the placebo group were analyzed at the end of the study
period after the trial was stopped early due to lack of
observed benefit (59).
At the other end of the spectrum is a study of myco-
phenolate in patients with more advanced and high-risk
disease. A double-blind, controlled trial of 32 patients with
$1g/d of proteinuria and at least two additional risk fac-
tors (male sex, hypertension, clearance,80 ml/min per
1.73 m2, glomerulosclerosis, tubulo-interstitial fibrosis, or
$25% of glomeruli affected by crescents) (60). Patients re-
ceived MMF or placebo in addition to RAS blockade. This
study was terminated early due to the finding of a trend in
worse renal outcome in the MMF group.
In contrast, in a small, randomized, nonblinded trial of
40 patients with .1 g/d of persistent proteinuria, more
patients in the MMF group demonstrated remission of
proteinuria (16 versus six) and had overall less proteinuria
(1.1460.23 g/24 hours versus 2.460.40 g/24 hours) (61).
Long-term follow-up demonstrated improved renal sur-
vival in MMF-treated patients (90% versus 55%, P50.01)
(62).
These studies are limited by small sample size. It also
remains possible there is race-specific variability in response
to MMF as in lupus nephritis (63). However systematic re-
views and meta-analyses of the randomized trials of MMF
also suggest mixed results (64–66).
Rituximab
Although evidence for rituximab in other glomerular
diseases is promising, early results in IgAN are not encour-
aging. A pilot trial evaluated the outcome of 34 patients with
proteinuria.1 g/d and eGFR,90 ml/min per 1.73 m2 ran-
domized to rituximab versus conservative management.
No effects on proteinuria or renal function were seen (67).
Combination Therapy
Combination therapy with corticosteroid plus an addi-
tional agent is generally reserved for patients with progressive
disease. A single-center, prospective, randomized, controlled
trial of 38 patients with “high-risk” IgAN (hypertension,
.15% rise in creatinine in prior year) demonstrated im-
proved renal survival after 2 years in patients receiving pred-
nisone and cyclosphosphamide/azathioprine as compared
with no immunotherapy (57).
In contrast, dual-agent immunotherapy does not always
afford an advantage. A multicenter, open-label, trial of 207
patients with creatinine,2.0 mg/dl and proteinuria$1.0 g/d
for at least 3 months randomized patients to corticosteroids
alone (1 g intravenously for three consecutive days at months
1, 3, and 5, and then continued at 0.5 mg/kg) or corticoste-
roids in addition to azathioprine 1.5 mg/kg. There was
no difference in primary outcome of time to 50% increase
in creatinine or secondary outcome of change in proteinuria
Clin J Am Soc Nephrol 12: 677–686, April, 2017
over time, however major side effects were seen more com-
monly in the azathioprine group (68). The same investigators
conducted a separate randomization for an additional 46 pa-
tients with advanced disease (creatinine$2.0 mg/dl) (69). There
was no difference in renal survival at 6 years, although multi-
variable survival analysis identified that azathioprine therapy
was associated with improved renal survival. A substantial
number of patients did not complete the study due to compli-
cations of therapy, highlighting the potential toxicity of immu-
nosuppression in patients with advanced renal insufficiency.
Novel Agents
A novel potential therapy for IgAN is a modified formulation
of oral budesonide (Nefecon). This agent is proposed to act
locally at the mucosal lymphoid tissue in the distal ileum and
proximal large intestine to modulate IgA production. High first-
pass metabolism also theoretically minimizes systemic effects
(70). The results of the phase 2 double-blind, placebo controlled
trial were recently presented. After a 6-month run-in phase, pa-
tients with proteinuria.0.5 g/g or 0.75 g/d and eGFR $45
ml/min per 1.73 m2 were randomized to receive placebo, 8,
or 16 mg/d of budesonide. There was a significantly greater
reduction in proteinuria in patients treated with the budesonide
—up to 27% reduction with a 3% rise in proteinuria in the
placebo group. In addition, there was a significant difference
in a secondary endpoint; the change in eGFR was less in the
budesonide group (24.7 ml/min per 1.73 m2 for placebo versus
0.32 and 1.95 ml/min per 1.73 m2 for 8 mg and 16 mg/d, re-
spectively P,0.05). More adverse events were seen in the bu-
desonide group, necessitating treatment cessation in 22% of
patients on this higher dose (ClinicalTrials.gov NCT01738035).
An open-label efficacy/safety study is currently recruiting
patients with eGFR.30 ml/min per 1.73 m2 with IgAN and
nephrotic syndrome who failed previous immunosuppres-
sion to treatment with Acthar gel, a purified form of adreno-
corticotropic hormone (ClinicalTrials.gov NCT02382523).
Another open-label pilot study is currently recruiting
for efficacy/safety in patients with .1 g/d of proteinuria
and no eGFR restriction of bortezomib, a proteasome in-
hibitor (ClinicalTrials.gov NCT01103778). Both studies exam-
ine proteinuria at 12 months as the primary outcome with
varying requirements for RAS blockade. A double-blind
safety/efficacy study in patients with .0.5 g/d of proteinuria
and eGFR.30 ml/min per 1.73 m2 randomized patients to
either fostamatinib, an oral spleen tyrosine kinase inhibitor,
or placebo with the primary outcome of proteinuria at
24 weeks (ClinicalTrials.gov NCT02112838). Additional ther-
apies are reviewed by Yeo et al. (71).
Reconciling Data and the Future of Clinical Trials in IgAN
Should corticosteroids be abandoned in IgAN? The
current landscape of evidence falls short of providing a
satisfactory answer to this question, and not surprisingly
no single randomized trial can adequately address indi-
vidual patient benefit. For example, one must be mindful
that patients with persistent proteinuria.3.5 g/d were ex-
cluded from STOP-IgAN, limiting generalizability. The
propensity-matching–based study of corticosteroids in
the VALIGA cohort suggests that the greatest benefits of
corticosteroids may be accrued in patients with the highest
degree of proteinuria, particularly .3 g/d (31). Taken to-
gether, there are insufficient data to refute current Kidney
IgA Nephropathy, Rodrigues et al. 683
Disease Improving Global Outcomes guidelines regarding
corticosteroid use in patients with .3 g/d of proteinuria
persisting despite conservative therapy, although treat-
ment is not without risk.
On the other end of the disease spectrum, 20% of subjects
ultimately randomized had under 1 g/d of proteinuria and
the rate of renal function decline in the study population
was low overall, as expected (72). The VALIGA analysis
suggests a graded benefit of corticosteroids according to
time-averaged proteinuria before treatment, with no differ-
ence in renal function decline below 1 g/d of proteinuria.
Therefore, patients with persistent proteinuria,1 g/d likely
do not derive significant benefit from addition of corticoste-
roids. The 1–3 g/d category remains a “gray zone.” Indeed, a
long duration of follow-up will be required to demonstrate
any potential benefit, based upon rates of renal function
decline typically observed in patients with this degree of
persistent proteinuria (72).
The rigor of design and execution of these multicenter
trials bring a most welcome evolution in the landscape of
clinical trials for IgAN. They have also highlighted urgent
needs in this realm. A lack of sensitive and specific early
surrogate markers of long-term outcome further challenges
execution of these studies. Although substantial observa-
tional data support an association between complete or partial
remission of proteinuria with improved renal survival, this
remains to be validated in controlled trials.
None of the information regarding the pathogenesis of
this disease suggests a curable time-limited event. Perhaps
there is a role for treatment to be divided into induction and
maintenance phases, with use of steroid-sparing mainte-
nance therapy to achieve sustained reductions in time-
averaged proteinuria that ultimately affect renal survival.
Furthermore, studies of immunotherapy in IgAN consis-
tently demonstrate significant risk of toxicity. Ultimately, it
is anticipated that improved understanding of the immu-
nopathogenesis of this disease will lead to development of
more targeted and less toxic treatment options.
Disclosures
M.H. discloses receipt of consulting fees from Shire Viro-
pharma (Lexington, MA) and Astra Zeneca (Wilmington, DE).
These disclosures are unrelated to the material presented in this
paper. H.N.R. has received speaker fees from Hoffman La-Roche
(Mississauga, ON, Canada) and participated in an advisory board
for Hoffman-La Roche and AMGEN (Mississauga, ON, Canada).
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 Update on Lupus Nephritis
Salem Almaani, Alexa Meara, and Brad H. Rovin

Abstract
SLE is a chronic inflammatory disease that affects the kidneys in about 50% of patients. Lupus nephritis is a major
risk factor for overall morbidity and mortality in SLE, and despite potent anti-inflammatory and immunosup-
pressive therapies still ends in CKD or ESRD for too many patients. This review highlights recent updates in our
understanding of disease epidemiology, genetics, pathogenesis, and treatment in an effort to establish a
Department of
framework for lupus nephritis management that is patient-specific and oriented toward maintaining long-term Internal Medicine, The
kidney function in patients with lupus. Ohio State Wexner
Clin J Am Soc Nephrol 12: 825–835, 2017. doi: https://doi.org/10.2215/CJN.05780616 Medical Center,
Columbus, Ohio

Epidemiology
SLE is a chronic inflammatory disease that can affect
any organ, but very often injures the kidney. SLE is
more prevalent in women than men across all age
groups and populations; the female-to-male ratio is
highest at reproductive age, ranging between 8:1 and
15:1, and is lowest in prepubertal children at about 4:3
(1–3). The prevalence of SLE and the chances of de-
veloping lupus nephritis (LN) vary considerably be-
tween different regions of the world and different
races and ethnicities (Table 1) (2,4–14). In the United
States, the higher frequency of LN in black popula-
tions persists after adjustment for socioeconomic fac-
tors (15). Additionally, black and Hispanic SLE
patients develop LN earlier (16), and have worse out-
comes than white patients with SLE, including death
and ESRD (10). This might explain why black indi-
viduals account for nearly half of those with ESRD
due to LN (17). The more aggressive disease course in
black individuals might be the result of a higher in-
cidence of diffuse proliferative LN, or the presence of
more high-risk features within the same LN histologic
class when compared with white individuals (18).
Those differences may arise due to genetic predispo-
sition as some “high-risk” genotypes and
autoantibodies are more frequent in black patients
(19–21). For example, black populations have a higher
frequency of the Fcg RIIA-R131 allele which is in-
volved in mediating phagocytosis of IgG2 immune
complexes (20). The APOL1 gene, which has been
implicated in the development of ESRD in black pa-
tients, has also been associated with progression and
development of ESRD in the LN population (22,23).
In LN patients with two risk alleles for APOL1 the
odds ratio (OR) for ESRD was 2.72 (95% confidence
interval [95% CI], 1.76 to 4.19; P,6.2310 26). An
HLA-DR2 subtype (HLA-DRB181503), characteristic
of black populations, was linked to worsening pro-
teinuria (24). Black individuals are also more likely to
have positive anti-Ro, anti-Sm, and anti-RNP anti-
bodies, which have a high association with LN (25).
Correspondence:
LN is a major risk factor for morbidity and mortality Dr. Brad H. Rovin,
in SLE and 10% of patients with LN will develop Nephrology Division,
ESRD (26). The risk of ESRD is higher in certain sub- Ohio State University
sets of LN. For example, in class 4 LN the risk may be Wexner Medical,
Ground Floor, 395 West
as high as 44% over 15 years (27). Patients with LN
12th Avenue,
also have a higher standardized mortality ratio (6–6.8 Columbus, OH 43201.
versus 2.4) and die earlier than SLE patients without Email: Rovin.1@osu.edu
LN (28–31). Importantly, 10-year survival improves from
46% to 95% if disease remission can be achieved (32).
Genetics and Pathogenesis
A detailed discussion of the genetics and patho-
genesis of LN is beyond the scope of this review, but
can be found in Munroe and James (33). Here we will
focus on recent findings that may be applicable to the
clinical management of LN.
Systemic Lupus versus LN
Given the morbidity associated with LN, the ability
to accurately identify SLE patients destined to develop
LN could shift the current management paradigm from
treatment to prevention. Although it is not likely that
CKD and ESRD can be avoided completely, because
many patients present with LN as the initial manifes-
tation of their SLE, a preventative management strategy
could significantly reduce CKD and ESRD. For exam-
ple, SLE patients destined to develop LN could be
followed much more closely, perhaps with home
monitoring of the urine so kidney biopsy and treat-
ment could be started without delay. Alternatively,
such patients could be considered for pre-emptive
therapy to attenuate autoimmunity before any clinical
manifestations of kidney involvement are apparent.
Although it is currently not possible to determine a priori
who with SLE will develop LN, several investigations
of lupus genetics have approached this question.
SLE arises in individuals with an appropriate ge-
netic background exposed to certain environmental
triggers. Several genes have been associated with SLE
susceptibility, most prominently in the human HLA

www.cjasn.org Vol 12 May, 2017 Copyright © 2017 by the American Society of Nephrology 825
826 Clinical Journal of the American Society of Nephrology
Table 1. Prevalence of SLE and frequency of lupus nephritis
Demographics Prevalence, Per 100,000
SLE
Region
United States, Canada 4.8–78.5
Europe (United Kingdom, Germany, 25–91
France, Italy, Spain, Scandinavia)
Australia 19–63
China 30–50
Japan 8–18
Lupus nephritis
Race/ethnicity
Black
White
Asian
Hispanic
loci. A meta-analysis of HLA-DRB1 alleles in SLE con-
cluded that carriers of HLA-DR4 and DR11 were protected
against LN with ORs of 0.55 (95% CI, 0.39 to 0.79; P,0.01)
and 0.6 (95% CI, 0.37 to 0.96; P,0.05), respectively (34).
Conversely HLA-DR3 and DR15 conferred an increased
risk of LN with ORs of 2.0 (95% CI, 1.49 to 2.7; P,0.05)
and 1.6 (95% CI, 0.37 to 0.96; P,0.05). These associations
were on the basis of 473 patients from five case-control
studies, and included mainly white and Asian patients.
Controls were healthy individuals. The mechanisms of
HLA-based disease susceptibility and protection remain
unknown. It has been suggested that this may be related
to the degree of stability of the interaction between self-peptide
and its HLA binding partner (35,36). More stable interactions
may lead to protection as in other autoimmune diseases like
rheumatoid arthritis.
In another approach, a meta-analysis of three genome-
wide association studies was done to identify risk alleles
for LN in patients already known to have SLE (37). All
patients were women of European descent (n52000) and
588 had LN. LN was defined by the American College of
Rheumatology criteria of persistent proteinuria and abnor-
malities of the urine sediment. Here the most significant
associations for LN mapped to the PDGF receptor A gene
(OR, 3.41; 95% CI, 2.10 to 5.54; P54.5231027) and the gene
for the sodium-dependent glucose cotransporter SLC5A11
(OR, 2.85; 95% CI, 1.93 to 4.22; P55.0831027). HLA loci
were less strongly associated with LN in this analysis, pos-
sibly because the comparison group had lupus, and there-
fore was already linked strongly to HLA. In LN, PDGF
may mediate kidney cell proliferation, matrix accumula-
tion, and intrarenal inflammation. The link between
SLC5A11 and LN is more convoluted. Several solute car-
rier (SLC) family genes have been associated with CKD
(38). Variants in SLC5A11 may mediate a decrease in se-
rum and an increase in urine myo-inositol, suggesting an
active role of SLC5A11 in proximal tubule inositol reab-
sorption (38). Additionally, or through inositol regulation,
SLC5A11 may mediate apoptosis through the program-
med cell death and TNF-a pathways (39).
The limitations of these and other genetic association
studies are the relatively small numbers of affected patients
available for analysis, and the limited racial and ethnic
Frequency, % References
Danchenko et al. (2)
Danchenko et al. (2)
Danchenko et al. (2)
Osio-Salido et al. (4)
Osio-Salido et al. (4)
69 Bastian et al. (8)
29 Bastian et al. (8)
40–82 Jakes et al. (99)
61 Bastian et al. (8)
diversity of the study cohorts, which to date have mainly
focused on white and Asian patients.
Pathogenesis
Clues as to how LN develops in SLE patients were
provided by a study of how the transcriptome of peripheral
blood cells changed over time in a cohort of pediatric LN
patients (40). LN occurred when the expression of neutro-
phil-associated genes increased. Neutrophil activation was
preceded by an increase in IFN and plasmablast-related
transcripts and was followed by upregulation of other my-
eloid cell and proinflammatory transcripts. These data
were synthesized in a model of lupus in which the disease
initiates preclinically with an IFN response and differentiation
of B cells into plasmablasts, and progresses to tissue-specific
(e.g., the kidney) and systemic inflammation as neutrophils
and myeloid cells activate.
Neutrophils can contribute to the pathogenesis of SLE
and LN even in death. When neutrophils die they often
release neutrophil extracellular traps (NETs), which are
composed of chromatin fibrils, histones, and neutrophil
antibacterial and immunostimulatory proteins. This type of
cell death, called NETosis, is normally a host defense mech-
anism to trap and kill microorganisms. However, NETs and
NETing neutrophils can also be found in the kidneys of
patients with SLE (41). NETs are a source of nuclear anti-
gens in SLE and may help to maintain antigen-specific au-
toantibody production. NETS and NETing neutrophils
facilitate inflammation, may cause endothelial damage,
and can induce plasmacytoid dendritic cells to produce
IFN-a (41), amplifying autoimmunity. Importantly, NET
degradation is impaired in patients with SLE, and mainly
in those with LN (42).
The C system is generally activated in LN and may
directly mediate kidney injury through the terminal path-
way, or indirectly increase renal inflammation by recruit-
ing leukocytes to the kidney. Because C also helps clear
apoptotic debris, it is important in reducing exposure to
autoantigens. In this regard, autoantibodies to C components
that are found in patients with lupus may be important in the
development of LN. In a cohort of 114 lupus patients, 23% of
patients had autoantibodies to C component C1q and to C3b
(43). In these dual-antibody–positive patients who were
Clin J Am Soc Nephrol 12: 825–835, May, 2017
prospectively followed, anti-C3b and anti-C1q levels ten-
ded to increase in the months leading up to renal flare.
In vitro experiments have shown that anti-C1q binds C1q
on early apoptotic cells and prevents their uptake by mac-
rophages (44). Anti-C1q also blocks immune complex binding
to red blood cells, a mechanism to safely clear immune
complexes. These data suggest anti-C1q antibodies may
enhance autoantigen exposure and may facilitate immune
complex deposition in target organs like the kidneys. Con-
sistent with this, it was shown that the absence of anti-C1q
autoantibodies was qualitatively associated with protection
against LN in a small cohort of lupus patients (45). Further-
more, C3b on immune complexes promotes immune complex
binding to red blood cells for clearance. This may be blocked by
anti-C3b, thereby augmenting the pro-LN effects of anti-C1q.
Finally, a recent investigation tied concepts important for
viral immunity to autoimmunity, providing insights into re-
lapsing autoimmune disease (46), a problem that is particularly
relevant to LN. CD8 T cells become “exhausted” in the setting
of persistent antigen exposure and the absence of CD4
T cell costimulation. These exhausted CD8 cells lose effec-
tor function and express inhibitory receptors at high levels.
This leads to an inability to clear viral infections, but can be
protective against relapsing autoimmune disease. In pa-
tients with SLE (not necessarily LN), a limited group of
upregulated coinhibitory receptors characterized exhausted
T cells, which translated to patients who had a nonrelapsing
course of lupus. The upregulated genes were 4–1BB, CTLA4,
PDCD1, LILRB4, and KLG1. The exhausted phenotype can
be rescued by costimulation, and certain genes, like KAT2B,
can facilitate this. KAT2B is antiapoptotic and mediates
protection against metabolic stress. In this paradigm of dis-
ease relapse, yet to be tested in LN, therapeutic interven-
tions to increase T cell exhaustion, perhaps by upregulating
inhibitory receptor expression, or blocking costimulation to
maintain the exhausted phenotype, may help prevent renal
flares. It is intriguing to speculate that stable HLA presenta-
tion of self-antigens results in T cell exhaustion and protection
in SLE, whereas unstable HLA associations with self-antigens
result in intermittent T cell activation, enhanced costimula-
tion, and suppression of the exhaustive (protective) T cell
phenotype.
Clinicopathologic Correlations
The clinical manifestations of LN are often subtle and
most commonly will be discovered by examination of the
urine as opposed to physical examination (Table 2). There-
fore, all patients with SLE should be evaluated for kidney
involvement at initial diagnosis and at least yearly there-
after even if they do not have symptoms of kidney disease.
It is also recommended that patients be re-evaluated for
LN if SLE flares. Evaluation is straightforward and should
include a urinalysis and measurement of kidney function,
generally a serum creatinine concentration or eGFR. Be-
cause SLE patients often have several concomitant medical
issues and may be on potentially nephrotoxic medications,
it is important to exclude nonlupus causes of renal insuffi-
ciency, especially if the urinalysis does not show abnormal
proteinuria and hematuria. If kidney involvement is
suspected a kidney biopsy should be considered (see below).
The clinical threshold for doing a kidney biopsy is not well
defined, but we suggest performing a biopsy if proteinuria
Update on Lupus Nephritis, Almaani et al. 827
Table 2. Prevalence of clinical manifestations in patients with
lupus nephritis
Approximate
Clinical Manifestation
Prevalence, %
Proteinuria 100
Nephrotic range proteinuria/ 50
nephrotic syndrome
Microscopic hematuria 80
Macroscopic hematuria ,5
Urinary red blood cell casts 30
Other urinary cellular casts 30
Renal insufficiency 60
Rapid decline in kidney function 15
Hypertension 30
Tubular abnormalities 70
$500 mg/d, with or without other clinical abnormalities,
or any level of proteinuria or hematuria with impaired kidney
function that cannot be attributed to another cause. There is
observational evidence that proteinuria of 500–1000 mg/d (or
lower) may be associated with significant kidney pathology
(47), and it has been well established that early diagnosis and
treatment of LN improves prognosis (48).
The Kidney Biopsy in LN
Although the decision to perform a kidney biopsy in SLE
patients when there is clinical evidence of renal involvement
seems straightforward, it has become somewhat controver-
sial because of a prevailing view that all forms of LN can be
adequately treated with corticosteroids plus mycophenolate
mofetil (MMF) (49). Nonetheless, the kidney biopsy is im-
portant to define the nature of renal involvement. Although
immune-complex–mediated GN is the most common cause
of kidney disease in SLE, there are other mechanisms that
result in renal injury which can only be diagnosed with a
biopsy, and require a different approach to management
than immune-complex LN. Examples include thrombotic
microangiopathy and lupus podocytopathy (defined as
nephrotic syndrome in SLE that on kidney biopsy shows
diffuse foot process effacement and no subendothelial or
subepithelial immune deposits), which can be seen in up to
24% and 1.3% of LN patients, respectively (50,51). The find-
ing of isolated tubulointerstitial nephritis is rare (52).
Immune-complex LN is described pathologically using
the 2003 International Society of Nephrology/Renal Pathology
Society (ISN/RPS) nomenclature (53). The ISN/RPS system
classifies LN on the basis of where immune complexes ac-
cumulate in glomeruli, the presence or absence of mesangial
or endocapillary proliferation, the overall extent of glomerular
involvement (focal or diffuse) and glomerular injury
(global or segmental), and whether glomerular injury is
active (inflammatory) or chronic (sclerotic) (Table 3). In a
general way, the ISN/RPS classes guide treatment decisions.
Patients with disease limited to the mesangium (class 2)
generally do not need specific therapy for their kidney dis-
ease but may need immunosuppressive treatment for ex-
trarenal SLE manifestations. Patients with mainly chronic
injury (any class) or end stage damage (class 6) also do not
need immunosuppression for LN, but may benefit from
828 Clinical Journal of the American Society of Nephrology

Table 3. The histologic classification of lupus nephritis

ISN/RPS
Histologic Findings Modifications to Histology Usual Clinical Findings
Class

1 Normal light microscopy; None relevant to the kidney

mesangial immune
complexes by
immunofluorescence
microscopy
2 Mesangial immune complexes/
mesangial cell proliferation
3 Mesangial and subendothelial
immune complexes/
segmental endocapillary
proliferation in ,50% of
glomeruli
4 Mesangial and subendothelial
immune complexes/
segmental or global
endocapillary proliferation in
$50% of glomeruli
5 Numerous subepithelial
immune complexes in .50%
of glomerular capillaries
6 Glomerulosclerosis in .90%
of glomeruli
Lesions can be active, chronic,
or have elements of both
Lesions can be active, chronic,
or have elements of both
so rarely diagnosed or
biopsied
Hematuria, low-grade
proteinuria; renal
insufficiency, nephrotic
syndrome not expected
Hematuria, proteinuria
seen in most patients;
renal insufficiency,
nephrotic syndrome not
unusual
Hematuria, proteinuria
seen in most patients;
renal insufficiency,
nephrotic syndrome not
unusual
Proteinuria, often nephrotic
range; hematuria
possible; usually no renal
insufficiency
Renal insufficiency;
proteinuria and
hematuria often present

ISN/RPS, International Society of Nephrology/Renal Pathology Society.

antiproteinuric, renoprotective measures. The proliferative
classes (3 and 4) are often treated with potent immunosup-
pression, whereas nonproliferative, membranous LN (class
5) may be managed conservatively (antiproteinuric ther-
apy) if patients have subnephrotic proteinuria, or with im-
munosuppression if patients have nephrotic range
proteinuria.
As the therapy of LN moves beyond the currently avail-
able nontargeted immunosuppressive regimens of high-dose
corticosteroids plus cyclophosphamide or MMF to inter-
ventions that focus on specific immune pathways, a more
comprehensive picture of kidney pathology through mo-
lecular imaging of the kidney biopsy may be desirable. The
immune pathways active in the kidney at the time of LN
diagnosis vary considerably between patients. For example,
when glomeruli were dissected from human LN biopsies
and subject to transcriptomic analysis, patients segregated
into groups showing dominant expression of B cell genes,
myelomonocytic genes, IFN-inducible genes, or fibrosis-
related genes (54). Similar pathways have been shown to
be activated in the kidneys of lupus-prone mice (55). These
molecular variations may reflect the intrinsic heterogeneity
of LN or may occur because patients are biopsied at differ-
ent points in the course of a disease that rapidly evolves.
Regardless of how LN heterogeneity arises, these molecular
differences suggest that a targeted therapy is not likely to
work for all patients, but only those with activity in a specific
autoimmune or inflammatory pathway. The applicability of
molecular analyses of the kidney biopsy to LN treatment is
illustrated by a recent survey of transcript expression of im-
mune genes in kidney biopsies done at LN flare. Patients
who had early complete clinical renal responses to standard-
of-care induction therapies could be distinguished from non-
responders on the basis of transcript expression profiles (56).
A similar approach could conceivably be applied to patients
being treated with novel therapies to define which patients
are likely to respond to a particular treatment.
The role of protocol repeat kidney biopsies in LN is con-
troversial, but emerging data suggest serial biopsies may
inform ongoing treatment decisions and predict long-term
renal prognosis. Repeat biopsies have demonstrated con-
siderable discordance between clinically- and histologically-
defined disease activity. After completing 6–8 months of
immunosuppressive therapy, 20%–50% of complete
clinical renal responders still had histologic evidence of
ongoing active inflammation, and 40%–60% of patients
with no histologic evidence of disease activity still had
persistent, high-grade proteinuria (57,58). Even after sev-
eral years of immunosuppressive treatment, histologic ac-
tivity was found in about 20% of patients who had been in
sustained clinical remission. Conversely, 40% of patients in
complete histologic remission after long-term treatment
had persistent clinical findings (59). These results suggest
that an immediate application of repeat biopsies could be
to evaluate a patient for withdrawal of maintenance immu-
nosuppressive therapy. Presently there are no evidence-
based guidelines concerning the duration of LN maintenance
therapy (60).
Clin J Am Soc Nephrol 12: 825–835, May, 2017
The prognostic value of the diagnostic kidney biopsy for
predicting long-term renal health in LN has been disap-
pointing (61). However, repeat biopsies after at least
6 months of immunosuppressive therapy appear to provide
better prognostic information. Persistent histologic evidence
of glomerular and interstitial inflammation, glomerular
capillary immune complexes, and macrophages in tubular
lumens after completing induction therapy were risk factors
for future doubling of the serum creatinine concentration
(62,63). Increasing chronic damage on the postinduction bi-
opsy also predicted long-term renal outcomes in some stud-
ies (57,58). The National Institutes of Health (NIH) activity
and chronicity indices (64) were measured in repeat biopsies
12–18 months after starting treatment, while patients were
on maintenance immunosuppression (65). After 10 years of
follow-up, the probability of doubling serum creatinine was
about 56% for patients whose second biopsy had persistent
activity (an activity index .2), compared with 20% for
patients who had an activity index #2 (P,0.001). Simi-
larly, 10-year renal survival was .90% if the chronicity in-
dex of the repeat biopsy was ,3, but 55% if the chronicity
index was .6 (P50.10).
Repeat kidney biopsies are also done in LN for clinical
indications, with the assumption that the biopsy could
support changes in therapy. Most of the time this is due to
LN flare, persistent proteinuria, or declining kidney func-
Figure 1. | A proposed algorithm for when to perform a kidney biopsy in patients with lupus nephritis (LN).
Update on Lupus Nephritis, Almaani et al. 829
tion (66–70). Considering these investigations together,
some generalizations about clinically-indicated repeat bi-
opsies may be drawn. Patients who originally had prolif-
erative LN often show proliferative LN at flare, whereas
many patients who originally had membranous LN often
develop a proliferative component at flare. Similarly, in
patients who had class 2 LN it is not unusual to find a
more aggressive injury pattern at repeat biopsy. These
findings suggest repeating a kidney biopsy for flare is
most beneficial for patients with previous class 2 or 5 LN
because there is a reasonable likelihood therapy may be
intensified. Biopsies for persistent or worsening protein-
uria or an increase in serum creatinine concentration do
not necessarily reflect active LN; a biopsy diagnosis of
chronic damage and inactive disease may allow a reduc-
tion in therapy.
On the basis of the current evidence of how a kidney
biopsy may contribute to the management of LN, a sug-
gested algorithm for initial and repeat kidney biopsies in
lupus is provided in Figure 1.
The Treatment of LN
Management Strategy
The overarching goal of LN treatment is to prevent CKD
and ESRD. As adverse kidney outcomes occur far more
830 Clinical Journal of the American Society of Nephrology

frequently in proliferative LN, we will focus on the
treatment of classes 3 and 4. To prevent CKD and ESRD,
short-term treatment strategies have focused on complete
or partial reversal of the clinical signs of kidney injury
discussed previously. By the time LN is clinically apparent
the kidney is already modestly or severely inflamed due to
the accumulation of autoantibody-containing immune
complexes. Therefore, patients are treated with an anti-
inflammatory agent to immediately attenuate intrarenal
inflammation and allow healing to begin, coupled with a
potent immunosuppressive agent to interrupt autoimmune
pathways that could reignite renal immune complex
formation and start the cycle of inflammatory injury again
(renal flare). This induction phase of treatment generally
lasts 3–6 months and is followed by a prolonged, but less
intense maintenance phase, often lasting years. It is not
clear when maintenance therapy can be withdrawn. A repeat
kidney biopsy showing histologic remission during main-
tenance in patients who have achieved complete clinical
remission, or who have stable but persistent proteinuria,
may help in making a decision to taper off therapy. A ran-
domized clinical trial is currently being done to address the
question of duration of maintenance therapy (Clinicaltrials.
gov identifier: NCT01946880).
The report card for this management strategy is mixed.
Induction and maintenance therapies have improved over-
all patient survival to about 80% at 5 years, however, 12-
month complete renal response rates are only 10%–40%,
and as many as 30% of LN patients will still progress to
ESRD (71–75). Furthermore, although there are no estimates
of how many LN patients are left with CKD after treatment,
the number is likely to be large. For example, kidney
biopsies after induction therapy with high-dose corticoste-
roids and cyclophosphamide or MMF generally show an
increase in chronic damage, even in those patients who
achieved a complete clinical remission to induction alone
(57). LN flare is also an important risk factor for CKD and
CKD progression (76) and flares may occur in 25% of pa-
tients (77,78). These outcome statistics suggest there is con-
siderable room for improvement in the treatment of LN.
Current Approaches to Treatment
All current widely-accepted treatment regimens for LN
(summarized in Figure 2) incorporate high-dose corticoste-
roids for rapid control of inflammation and either MMF or
cyclophosphamide to control inflammation and autoim-
munity (60,79). All patients (unless contraindicated)
should be treated with an antimalarial given the evidence
that lack of antimalarial use may be associated with an
increase in LN treatment failures (80). Cyclophosphamide
can be given orally or intravenously, and if intravenous in
either standard-dose (designated the NIH regimen) or low-
dose (called low-dose or Euro-lupus regimen). High intensity
immunosuppression is given for the first 3–6 months and
then replaced by MMF (or a lower dose of MMF if it was
used for induction) or azathioprine to maintain suppression of
autoimmunity and inflammation, and thereby prevent flare.
Standard-dose cyclophosphamide (either oral or NIH)
improved the long-term kidney survival compared with
corticosteroids alone and set the standard-of-care for LN
treatment (81). Because of toxicity concerns surrounding
cyclophosphamide, MMF and NIH cyclophosphamide

Figure 2. | Current induction and maintenance treatment choices for proliferative lupus nephritis. Patients are considered to have severe
lupus nephritis if they have functional kidney injury with an elevated serum creatinine and/or heavy proteinuria, evidence that the loss of renal
function occurred over a relatively short period of time and active histologic injury with glomerular crescents and necroses affecting several
glomeruli. AZA, azathioprine; CSA, cyclosporine A; MMF, mycophenolate mofetil; TAC, tacrolimus.
Clin J Am Soc Nephrol 12: 825–835, May, 2017
were directly compared in a large randomized controlled
trial and found to be equivalent for the induction of renal
responses after 6 months of treatment (73). Although the
MMF arm had a similar number of adverse events as the
cyclophosphamide arm, and its long-term ability to pre-
serve renal function was not clear, MMF has replaced cy-
clophosphamide as first-line induction therapy for LN in
many areas. The increased exposure of LN patients to
MMF has raised some concerns as to whether it is equiv-
alent to cyclophosphamide induction with respect to long-
term kidney outcomes (77). A recent meta-analysis
showed that between the 1970s and the 1990s the risk of
ESRD from LN declined and plateaued, and this was co-
incident with cyclophosphamide treatment becoming rou-
tine (27). In the 2000s, as MMF was becoming a dominant
induction drug for LN, the risk of ESRD increased, and
was highest at 44% over 15 years in patients with diffuse
proliferative LN.
In another attempt to reduce the long- and short-term
toxicity of cyclophosphamide, low-dose, Euro-lupus cyclo-
phosphamide was found to be equivalent to NIH cyclo-
phosphamide for remission induction and preservation of
renal function at 5 and 10 years, but with fewer adverse
effects (78). The original Euro-lupus trial was done in a
mainly white cohort with LN of mild-to-moderate sever-
ity, but recently, low-dose cyclophosphamide was found
to be effective in a multiethnic/multiracial cohort with
more severe LN (82).
The duration of corticosteroid administration in LN remains
controversial and nonevidence-based. A small but interest-
ing pilot study to assess the feasibility of doing a definitive
trial on whether maintenance corticosteroids are needed in
LN was done (83). The trial included 15 patients with pro-
liferative (6membranous) LN induced with cyclophospha-
mide or MMF who achieved at least a partial response and
had been tapered down to #20 mg of prednisone. After
3 weeks, prednisone was decreased to 5–7.5 mg/d in eight
patients, and that dose was maintained. Prednisone was
completely withdrawn in seven patients by week 17. Patients
were followed for a median of 12 months, and the end point
was renal or major nonrenal relapse. Relapse occurred in
only one patient from the withdrawal group (14%; one renal
flare), but in 50% of the low-dose prednisone patients (three
renal and one major nonrenal flare). These data, although
inconclusive, are provocative.
Opportunities in LN Management
To reduce the incidence of ESRD it will be necessary to
prevent CKD. Preventing CKD will require more rapid and
complete control of inflammatory kidney injury and minimi-
zation of LN flares. There are several opportunities to imple-
ment such a paradigm, which include developing methods
for earlier diagnosis and treatment, improving patient compli-
ance, and applying novel therapies. Here we will focus on
creating opportunities with novel therapeutic approaches.
Controlling Renal Inflammation in LN
Historically, intrarenal inflammation has been controlled
during induction by high-dose corticosteroids, which are
effective but toxic (81). It is likely that many of the adverse
outcomes that occur during the first year of LN treatment
Update on Lupus Nephritis, Almaani et al. 831
can be attributed to corticosteroids, and their side effects often
challenge patient compliance. Borrowing existing therapies
used for other diseases to treat renal inflammation may re-
duce or eliminate the need for corticosteroids. In this context,
C inhibitors, quinolone immunomodulators, and proteasome
inhibitors should be considered for LN clinical trials.
Several animal studies have demonstrated a beneficial
effect of blocking the alternative C pathway in LN (84).
Although little work has been done with C inhibition in
human LN, effective inhibitors are available, including a
monoclonal antibody against C5 (eculizumab) and a small
molecule C5a receptor blocker (CCX168) (85). Interest-
ingly, the ability of corticosteroids to attenuate intrarenal
C activity in LN is not clear, but at least in some clinical
settings, such as hemodialysis, they do not block C activa-
tion (86). Thus, C inhibitors may synergize with steroids to
permit significant steroid dose reduction. Blocking the al-
ternative C pathway can potentially attenuate renal in-
flammation and injury by inhibiting the chemotactic and
leukocyte activating properties of C5a, and preventing the
formation of C5b-9 (the membrane attack complex) which
may directly injure renal cells.
Laquinimod, a quinolone, is a small molecule that blocks
activation of NF-kB, a transcription factor important in the
expression of proinflammatory cytokines that has been
studied in human multiple sclerosis (87) and murine LN
(88). A small phase 2 trial in LN showed improved kidney
function and reduced proteinuria at 6 months when laqui-
nimod was added to standard-of-care, including corticoste-
roids (89). These findings need to be replicated in a larger
trial, but suggest synergy with steroids and offer the possi-
bility of steroid dose reduction.
The proteasome inhibitors are used mainly to treat plasma
cell malignancies, but their mechanism of action may of-
fer efficacy at two steps in the pathogenesis of LN and kidney
injury. The overall effect of the boronic acid proteasome
inhibitors (for example, bortezomib and carfilzomib) is to kill
plasma cells, so these drugs could immediately attenuate
autoantibody production. This would be expected to halt or
decrease immune complex production and thus ongoing
immune complex–mediated renal injury. More directly rele-
vant to inflammation, the proteasome inhibitors block activa-
tion of NF-kB, and so may also be anti-inflammatory. This
class of drugs has successfully treated murine LN (90).
Minimizing LN Flares
In contrast to the many recent clinical trials of novel
induction therapies in LN, flare prevention has received
relatively little attention. However, several of these in-
duction trials included follow-up and the effects of the
experimental drugs on flare rate were determined. An
interesting example is the abatacept and cyclophosphamide
combination efficacy and safety study (ACCESS) trial which
studied the effect of blocking the CD28/CD80 costimula-
tory pathway in LN with abatacept, a CTLA4-Ig construct.
Although abatacept did not offer any benefit for induction
of remission when added to low-dose cyclophosphamide,
patients in the abatacept arm that reached a complete renal
remission at 6 months were followed for another 6 months
without any maintenance immunosuppressive therapy. At
12 months the patients in the abatacept arm had fewer SLE
flares than patients in the placebo arm who did receive
832 Clinical Journal of the American Society of Nephrology
maintenance azathioprine. This study was not powered to test
abatacept in maintenance of remission, and the flare rates
were not significantly different, but the results suggest that
abatacept may be worth investigating as a maintenance agent
to prevent flares. Importantly, no important safety signal for
abatacept was detected in the ACCESS trial.
Similarly, a post hoc analysis of belimumab, a monoclonal
antibody directed against the B cell survival factor BLyS,
trials in nonrenal lupus showed a dose-dependent trend
toward a decreased rate of renal flares in patients who had
received belimumab (91). This analysis suggested that
belimumab may be effective in preventing renal flares
in patients who have inactive or stable LN. In contrast, another
anti-BLyS monoclonal antibody, tabalumab, also trialed in
nonrenal SLE, did not prevent renal flares (92). The effects of
BLyS blockade in LN are being directly tested in an ongoing
trial (NCT0139330), so resolution of these conflicting results
may need to wait until the trial is finished.
Other Emerging Therapies
IFN-a seems to be a central regulatory cytokine in SLE
and especially in LN, and may promote development of au-
toreactive plasma cells, helper and memory T cells, and several
proinflammatory cytokines (93–95). Blocking the effects of
IFN-a may therefore ameliorate inflammation and attenuate
autoimmunity and prevent future LN flares. Anifrolumab, a
monoclonal antibody against the IFN-a type 1 receptor, was
found to be effective in nonrenal lupus and is currently un-
der evaluation in a randomized clinical trial in LN
(NCT02547922).
The calcineurin inhibitors (CNIs) cyclosporine A and tacro-
limus have been tested extensively in LN, especially in Asia,
with very encouraging results. CNIs attenuate inflamma-
tion by preventing release of inflammatory cytokines from
leukocytes, and also block T cell activation (96), and there-
fore could have an effect to maintain remission. CNIs have
been used as part of a multitarget approach to treating LN,
added to a regimen of MMF and corticosteroids, and have
been shown to be superior to cyclophosphamide in induc-
ing remission by 6 months (97). A multitarget approach is
appealing as the pathogenesis of SLE involves several im-
mune pathways. CNIs plus corticosteroids alone have also
been used for LN induction and found to be as effective as
MMF for proliferative LN (98). At this time, CNI studies
need to be viewed cautiously. Unexpectedly, in the multi-
target study patient withdrawals due to adverse events
were higher in the CNI arm than the cyclophosphamide
arm (97). The effects of CNIs in more racially and ethnically
diverse cohorts must be studied. Additionally, most of the
studies to date are fairly short-term, and long-term preserva-
tion of kidney function needs to be verified. Finally, because
proteinuria is the major contributor to current criteria of LN
response, and CNIs can affect proteinuria by mechanisms un-
related to immune modulation, it is not clear that proteinuria
is an appropriate end point for comparing CNIs to drugs with
different mechanisms of action. In this setting a kidney biopsy
should be considered to verify histologic improvement/
resolution.
Conclusions
LN continues to be a major source of morbidity and
mortality for SLE patients. Most patients develop LN
during the prime of their lives, and this adversely affects
their livelihoods and families, affecting all of society. An
improved understanding of disease pathogenesis has not
yet resulted in major therapeutic advances. However, the
availability of a variety of novel drugs to modify the immune
system, coupled with a thoughtful approach to clinical trial
design, is anticipated to overcome this slow progress in
advancing LN management.
Disclosures
B.H.R. has consultancy agreements and has received honoraria
from Lilly, Genentech-Roche, and Mallinckrodt, and has received
research funding from the National Institute of Diabetes, Digestive
Diseases and Kidney Diseases (NIDDK), Mallinckrodt, and Genen-
tech.
This work was supported in part by NIDDK U01 DK096927 (to
B.H.R.)
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Primary Membranous Nephropathy
William G. Couser

Abstract
Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic
nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and
20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN.
Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy
Division of Nephrology,
evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels Department of Medicine,
(15%), or serum anti-THSD7A (3%–5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A University of Washington,
antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Seattle, Washington
Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of
patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about Correspondence: Dr.
one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third William G. Couser,
Division of
progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for Nephrology,
months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All Department of
patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein Medicine, University
excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who of Washington,
Medicine, 16050
fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome,
169th Avenue,
should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, Woodinville, WA
calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the 98072. Email: wgc@
subsequent 10 years. uw.edu
Clin J Am Soc Nephrol 12: 983–997, 2017. doi: https://doi.org/10.2215/CJN.11761116

Introduction empirically on clinical consequences of immune injury

About 20% of all cases of membranous nephropathy
(MN) are associated with other diseases or exposures
(secondary MN) that are listed in Table 1. Secondary
MN is not discussed further in this review. Primary
membranous nephropathy (PMN) is a kidney-specific,
autoimmune glomerular disease that presents with
increased protein in the urine associated with a pa-
thognomonic pattern of injury in glomeruli (Figures
1–3). Both clinical and pathogenetic aspects of the
disease have been recently reviewed elsewhere (1–8).
PMN is the commonest cause of idiopathic nephrotic
syndrome in nondiabetic adults worldwide, repre-
senting between 20% and 37% in most series and rising
to as high as 40% in adults over 60 (1,2,7). MN is rare
in children (1%–7% of biopsies) (3). Most PMN is
mediated by antibodies to the M-type phospholipase
A2 receptor (anti-PLA2R) (85%), thrombospondin type
1 domain containing 7A (THSD7A) (3%–5%), or by
other as yet unidentified mechanisms (10%) (1,2,4–8).
The recognition that PMN is an autoimmune disease
has dramatically altered both the diagnostic and ther-
apeutic approach to what was previously called idio-
pathic MN. Patients with immunologically active
disease can now be separated from those with inactive
disease and therapeutic initiatives in active disease can
be adjusted to the presence and levels of the patho-
genic antibody causing the disease rather than relying
to the glomerulus such as proteinuria or reduced GFR
(1,4–7).
Epidemiology
In the United States, the incidence of MN is
estimated at about 12/million per year with a mean
age between 50 and 60 and a 2:1 male predominance
(1–4). The incidence of ESRD due to MN in the United
States is about 1.9/million per year (1). Because only
10%–20% of patients with PMN currently progress to
ESRD, the real incidence may be as high as 20/million
per year. PMN is most common in whites followed by
Asians, blacks, and Hispanics (1,2).
Pathogenesis
Studies in the past decade have dramatically im-
proved understanding of the pathogenesis of PMN
(1,2,4–8). Current concepts derive in large part from
earlier studies carried out in the Heymann models of
MN in rats which revealed that the pathognomonic,
exclusively subepithelial deposits of IgG resulted
from in situ immune complex formation involving
megalin, a rat podocyte membrane antigen, and that
the associated proteinuria was mediated primarily by
complement through the membrane attack complex

www.cjasn.org Vol 12 June, 2017 Copyright © 2017 by the American Society of Nephrology 983
984 Clinical Journal of the American Society of Nephrology
Table 1. Recognized causes of anti-PLA2R/THSD7A–negative secondary membranous nephropathya
Cause
Infections (1,2,27,56,90)
Malignancy (20% in patients .57,
4%,57) (1,2,14–18,55,58,66)
Autoimmune diseases (1,2,4,56–58,91)
Alloimmune diseases (1,4,7,58,82)
Drugs/toxins (92)
HBV, hepatitis B; HCV, hepatitis C; CLL, chronic lymphocytic leukemia; MN, membranous nephropathy; NSAIDs, non-steroidal anti-
inflammatory drugs.
a
Most of these associations are on the basis of multiple case reports or small series. Causative roles are implied but generally not proven.
b
Common.
C5b-9 (9). The first confirmation that PMN in man involved
an analogous mechanism came from Debiec et al. in Paris
in 2002, who showed that alloimmune MN in babies of
neutral endoproteinase (NEP)–deficient mothers was me-
diated by maternal anti-NEP antibody that formed immune
complexes in situ with NEP on the podocyte membranes of
Figure 1. | Glomerulus from a patient with primary membranous
nephropathy showing the pathognomonic “spikes” of basement
membrane projecting from the outer surface of the glomerular
basement membrane (arrows) when stained with silver-methenamine
(original magnification, 340). (Provided by Dr. Charles Alpers, De-
partment of Pathology, University of Washington, Seattle, WA.)
Examples
b
HBV, HCV, HIV, parasites (filariasis, schistosomiasis, malaria),
leprosy, syphilis, hydatid disease, sarcoid
b
Solid tumors (lung 26%, prostate 15%, hematologic [plasma cell
dyscrasias, non-Hodgkin lymphoma, CLL] 14%, colon 11%),
mesothelioma, melanoma, pheochromocytoma; some benign tumors
b
SLE (class V), thyroiditis, diabetes, rheumatoid arthritis, Sjogren
syndrome, dermatomyositis, mixed connective tissue disease,
ankylosing spondylitis, retroperitoneal fibrosis, renal allografts
Anti-GBM disease, IgAN, ANCA-associated vasculitis
IgG4 disease
Membranous-like glomerulopathy with masked IgG k deposits (90)
Graft versus host disease, autologous stem cell transplants, bde novo MN
in transplants/transplant glomerulopathy
b
NSAIDs and cyclooxygenase-2 inhibitors, gold, d-penicillamine,
bucillamine, captopril, probenecid, sulindac, anti-TNFa, thiola,
trimetadione, tiopronin
Mercury, lithium, hydrocarbons, formaldehyde, benvironmental air
pollution (China)
Cationic BSA (infants)
the infant (10). In 2009, a seminal paper from Beck et al. in
Boston reported that about 70% of adult patients with PMN
have IgG4 antibodies to podocyte-expressed PLA2R that
are present in the circulation and also deposited in
glomeruli (11), a finding since confirmed, with a range of
52%–78%, by many other laboratories (1,4–8).
A second IgG4 antibody specific for THSD7A, another
podocyte membrane antigen with similar properties to
PLA2R, was later identified in a smaller number of
patients with PMN (2%–5%) (Table 2) (12). About 10%
of patients with typical PMN are negative for both
antibodies, making it probable that more autoantibodies
to podocyte antigens will be found. Dual expression of
antibodies to both PLA2R and THSD7A has been report-
ed but is rare (13).
Most statements in this review are assumed to apply to
patients with either antibody, designated in this paper as
anti-PLA2R/THSD7A, unless otherwise specified. The
only significant clinical difference identified so far is a
female predominance and a higher frequency of associ-
ated malignancies with THSD7A (14,15). THSD7A is ex-
pressed in those tumors most frequently associated with
PMN (16). Twenty percent of THSD7A-positive patients in
one series had coexistent malignancy, usually detected
within 3 months (14,17). The observation that THSD7A was
expressed in the tumor in two cases suggests one potential
mechanism for the well established association between
MN and malignancy (14,17,18). The pathogenicity of anti-
PLA2R has not yet been confirmed because PLA2R is not
expressed in rodents. However, human anti-THSD7A has
recently been shown to transfer MN with proteinuria in
mice (19).
PLA2R/THSD7A-mediated disease can also be confirmed
by the presence of PLA2R/THSD7A staining colocalized
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 985

Figure 2. | Immunofluorescence microscopy in primary membranous nephropathy (PMN). (A) Finely granular staining for IgG, predominately
IgG4, present uniformly in a subepithelial distribution in all glomeruli in a patient with PLA2R-associated PMN (original magnification, 340)
(generously provided by Dr. Charles Alpers, Department of Pathology, University of Washington, Seattle, WA). (B) Finely granular staining for
PLA2R antigen that colocalizes with IgG4 in a patient with PMN. The presence of PLA2R indicates that anti-PLA2R antibody was present and
forming deposits in glomeruli at the time of biopsy or within the past several weeks. (original magnification, 340) (generously provided by Dr.
Charles Alpers, Department of Pathology, University of Washington, Seattle, WA). (C) Finely granular staining for the complement membrane
attack complex, C5b-9, in a patient with active PMN (original magnification, 340). Reprinted from reference 89, with permission.

with IgG4 in glomerular deposits (Figure 2B) (17,20–25).
Staining persists for weeks to months after antibody
disappears (5–9,19,20). Most antibody-positive, and about
70% of antibody-negative, patients have positive PLA2R/
THSD7A staining in glomeruli, suggesting that up to
85%–90% of all cases of PMN are anti-PLA2R/THSD7A–
mediated (21) (Table 2). However, occasional anti-PLA2R–
positive, or presumed positive, patients, especially early in
the course, have been reported without staining for PLA2R
antigen in glomeruli (23–25). As summarized in Table 2,
patients presenting with PMN include those who are free of
systemic disease and are anti-PLA2R (70%) or THSD7A

Figure 3. | Electron micrograph of chronic primary membranous nephropathy showing discontinuous, electron-dense deposits representing
aggregates of PLA2R–anti-PLA2R immune complexes formed in situ along the outer surface of the glomerular capillary wall beneath a layer of
effaced podocyte foot processes (arrows). BM, basement membrane; CL, capillary lumen. Original photomicrograph generously provided
by Dr. Charles Alpers, Department of Pathology, University of Washington, Seattle, WA.
986 Clinical Journal of the American Society of Nephrology
Table 2. Interpretation of serum anti-podocyte antibody and glomerular antigen staining in primary membranous nephropathy
(4,21,23–26)
Serum Glomerular
Antibody (6) Antigen (6)
Anti-PLA2R (1) PLA2R (1)
Anti-PLA2R (2) PLA2R (1)
Anti-THSD7A (1) THSD7A (1)
Anti-THSD7A (2) THSD7A (1)
Anti-PLA2R/THSD7A (2) PLA2R/THSD7A (2)
1, positive; PMN, primary membranous nephropathy; 2, negative.
a
Patients with nephrotic syndrome due to PMN without evidence of PLA2R/THSD7A antibody or glomerular staining are presumed to
have autoimmune PMN mediated by a different, still unidentified, anti-podocyte antibody.
(3%–5%) positive, those who are anti-PLA2R/THSD7A
negative but have positive glomerular staining for PLA2R/
THSD7A (another 15%), and those without PLA2R/THSD7A
antibody or glomerular staining (10%) who may: (1) develop
detectable anti-PLA2R/THSD7A antibody later, (2) have
disease mediated by a different anti-podocyte antibody, or (3)
develop another autoimmune disease to which the MN
might be considered secondary.
Initiation of an antibody response likely precedes devel-
opment of proteinuria in PMN by weeks or months (pre-
clinical disease) (22,26) and may occur following several
etiologic events in the presence of immunogenetic risk
alleles (see below). There is one report of homology
between genes for PLA2R and the LTLENCK domain in
some gram-positive bacterial enzymes (27). Viral infections
including hepatitis B virus, hepatitis C virus, and HIV have
been reported in association with anti-PLA2R/THSD7A,
but these may represent patients who have coincidental
PMN (4–8,22) (Table 1). Other potential etiologic factors,
e.g., exposures to environmental toxins such as drugs,
mercury, formaldehyde, and air pollutants, have been
identified (Table 1) but generally the anti-PLA2R/THSD7A
status in these patients is not known. For example, a recent
report from China correlated the rising incidence of MN in
that country with increasing levels of air pollution (28).
Over time, a threshold quantity of IgG4 and C5b-9
deposition is reached in some patients that is sufficient
to cause enough podocyte injury/activation to increase
urine protein excretion and lead to nephrotic syndrome
(5–7,22,26). Just as appearance of proteinuria lags behind
initial antibody production by weeks/months, so resolu-
tion of proteinuria (clinical remission) also lags behind
antibody disappearance (immunologic remission) by
week/months. This offset between immunologic and clin-
ical remissions reflects the prolonged time required to form
sufficient deposits to cause proteinuria initially and the
time required to clear subepithelial deposits, repair podo-
cyte and capillary wall damage, and restore glomerular
permselectivity (5). Thus, proteinuria is a poor clinical
Percent of Patients Who
Diagnosis
Underwent Biopsy, %
70 PLA2R-mediated PMN
(active)
15 PLA2R-mediated PMN
(inactive)
3–5 THSD7A-mediated PMN
(active)
Unknown THSD7A-mediated PMN
(inactive)
10 Non-PLA2R/THSD7A–
mediated (pathogenesis
unknown)a
biomarker for the pathogenetic disease processes that are
targeted by current immunosuppressive therapies (IST).
C activation leading to sublytic C5b-9 attack on podo-
cytes has been established to be the primary mediator of
anti-podocyte antibody–induced cellular injury and pro-
teinuria in most studies of the Heymann rat models (5,9,29–
31). Currently available serologic and immunohistochemical
data in PMN are most consistent with complement
activation by under-glycosylated IgG4 through the man-
nose binding lectin pathway, but roles for the classic and
alternate pathways have not been entirely excluded (29–
31). In the rat models, the complement effect involves a
sublytic agonistic effect of C5b-9 insertion on the podocyte
membrane to activate several signaling pathways that lead
collectively to increased production of oxidants, proteases,
growth factors, and extracellular matrix components as
well as to slit diaphragm disruption, apoptosis, auto-
phagy, remodeling of the actin cytoskeleton, DNA damage
with cell cycle arrest, and detachment of damaged cells
(29,30). A similar role for complement in human PMN is
suggested by the facts that C3, C4d, and C5b-9 (but not
C1q) are prominent in glomerular deposits; complement
activation products are elevated in the serum (M.H. Zhao,
personal communication); and serum and urine C5b-9
seem to parallel disease activity (28–30). However, pro-
teinuria in some human PMN may also be C-independent
as suggested by some studies of the Heymann models by
Hall and colleagues (32), the transfer of anti-NEP alloim-
mune MN without complement activation (10), and an in
vivo transfer study with human anti-THSD7A where
heterologous phase proteinuria appears to precede detect-
able complement deposition (19).
Genetics of PMN
Genetic findings in PMN are reviewed in more detail
elsewhere (4–8,33–35). Familial MN is rare and usually seen
in children (3,33,34). Genome-wide association studies
(GWAS) implicate risk alleles in HLA genes, particularly
HLA–DQA1, that increase the risk for PMN three-fold in
Clin J Am Soc Nephrol 12: 983–997, June, 2017
white patients (27). GWAS studies have also identified
single nucleotide polymorphisms in noncoding regions of
the PLA2R gene (27,36–38). Homozygosity for high-risk
alleles in both HLA and PLA2R genes increases the odds
ratio for PMN almost 80-fold in white patients and ten-fold
in Chinese patients and is associated with higher levels of
antibody production, strongly suggesting interaction be-
tween HLA and PLA2R genes (36–38). Two recent GWAS
studies in Chinese patients have identified additional in-
dependent HLA risk alleles including DRB1*1501/
DRB1*0301 (37) and DRB3*02:02 (38) and suggested that
DRB1 may be more important in generating the HLA signal
than DQA1 in that population. Ninety-nine percent of
PLA2R-positive patients carry at least one of these HLA risk
alleles, and the presence of one HLA risk allele increases the
odds ratio for developing PMN almost 100-fold (35)
However, risk alleles identified so far are common in the
general population, and studies to date are also consistent
with a predisposition to autoimmunity conferred by HLA
genes and an environmental trigger rather than any unique
coding variant in PLA2R genes (33).
Structure of the PLA2R Antigen
PLA2R is a transmembrane glycoprotein member of the
mannose receptor family, which has a conserved extracellular
structure consisting of the cysteine-rich (Ricin B) domain
(Cys-R), a fibronectin II domain, and a tandem repeat of 8 C-
type lectin domains (CDLD 1–8) (1,4–7,39,40). Anti-PLA2R–
reactive epitopes are conformation-dependent and have been
identified in three domains: Cys-R, CTLD1, and CTLD7
(1,4,39,40). The potential for these different epitopes to be of
clinical significance is suggested by the finding that patients
with anti-PLA2R directed at the Cys-R epitope, which is
recognized by 100% of anti-PLA2R antibodies, may have less
severe disease and undergo more spontaneous remissions
than those with antibodies primarily reactive with the CDL1
and CDL7 domains, and that epitope spreading beyond the
Cys-R domain may confer a worse prognosis, but this
observation requires confirmation (36). The small contact
residues that bind the antibody, and would be essential to
developing specific peptide-based immunotherapies, have
not yet been identified.
Pathology
In most centers a diagnostic renal biopsy remains the
standard of care, even in anti-PLA2R/THSD7A–positive
nephrotic patients. The characteristic morphologic changes
in PMN are described elsewhere (41) and are illustrated in
Figures 1–3. By light microscopy, glomeruli may appear
entirely normal in early disease despite nephrotic-range
proteinuria. With time, changes in basement membrane,
with thickening and formation of subepithelial “spikes” of
basement membrane on the outer surface of the capillary
wall, become apparent using an extracellular matrix stain
such as silver methenamine (Figure 1). Immunofluores-
cence microscopy (Figure 2) in anti-PLA2R/THSD7A–
positive patients usually reveals diffuse, uniform, finely
granular deposits of IgG4 along the outer surfaces of all
capillary walls (Figure 2A) (41). Lesser amounts of IgG1
and IgG3 may also be seen, particularly in early disease
(21,22,26). The antigen PLA2R or THSD7A (Figure 2B)
Membranous Nephropathy, Couser 987
colocalized with IgG4 may be seen by immunofluores-
cence microscopy with appropriate antigen enhance-
ment techniques and persist for weeks to months after
serum antibody is undetectable and immune complex
formation has ceased (4–8,20–23). Complement components
including C3, C4d, and C5b-9 (Figure 2C) are also commonly
present, but not C1q (29,30,41). Although these findings
describe the typical case, they are not universal, and
occasional patients with IgG4-dominant deposits but without
detectable PLA2R/THSD7A antibody or staining have been
described (20,21).
Electron microscopy in PMN confirms the exclusively
subepithelial localization of electron-dense deposits pro-
duced by capping and shedding of immune complex
lattices formed on the podocyte membrane, which then
accumulate beneath slit pores (Figure 3). Glomerular
basement membrane thickening is seen with progression,
and the deposits are gradually incorporated within new glo-
merular basement membrane and become more electron-
lucent as they are resorbed before eventually disappearing
in patients with earlier complete remissions (41).
Additional biopsy findings that should prompt careful
search for secondary causes (Table 1) include electron-
dense deposits in subendothelial or mesangial locations;
significant mesangial or endothelial cell proliferation; cres-
cents; tubular basement membrane staining; dominant de-
position of IgG1/IgG3, IgM, IgA, or C1q; and endothelial
tubuloreticular inclusions by electron microscopy (1,2,4–
7,21,22,41). One report has described an association between
MN with intraglomerular inflammatory cell infiltrates and
cancer (18).
Clinical Manifestations
All adult patients with idiopathic nephrotic syndrome
should be screened initially for anti-PLA2R/THSD7A anti-
bodies as well as for the common causes of secondary MN
including hepatitis B and C, lupus, and sarcoid (Figure 4,
Table 1). Although the specificity of the anti-PLA2R assay
for PMN is essentially 100%, this finding has somewhat
blurred the distinction between primary and secondary
disease because some patients with secondary diseases
such as hepatitis B and C, cancer, and sarcoid have been
found to be anti-PLA2R–positive suggesting the coinciden-
tal presence of PMN in some patients with an unrelated
systemic disease rather than MN as a manifestation of, or
secondary to, the systemic disease (4–8). Observational
correlations between the anti-PLA2R/THSD7A pathogenic
mechanisms discussed above and clinical features of PMN
that now support incorporating anti-PLA2R/THSD7A into
clinical decision-making are summarized in Table 3.
The most common clinical features at onset and during
the course of PMN are presented in Table 4. The most
prominent is nephrotic syndrome and its associated man-
ifestations including various degrees of edema, hypoalbu-
minemia, and hyperlipidemia (1,2,42–45) (Table 4). About
80% of patients with PMN present with nephrotic-range
proteinuria (.3.5 g/d) and the remaining 20% have
subnephrotic proteinuria, but 61% of these latter patients
later become nephrotic, usually within the first year, and
especially if anti-PLA2R antibody is present (1,26,27,43–
45). Although the peak incidence is between ages 50 and
988 Clinical Journal of the American Society of Nephrology

Figure 4. | Antibody-guided diagnosis and treatment algorithm for primary membranous nephropathy (PMN). Patients who undergo biopsies
for proteinuria of uncertain cause who have MN should initially be classified as anti-PLA2R/THSD7A–positive (active disease) or negative (Table
2). Patients who are antibody-negative should have the absence of a PLA2R/THSD7A-related mechanism further excluded by the absence of
PLA2R/THSD7A staining in glomeruli and usually the dominance of IgG1–3 in the biopsy sample. Most of these latter patients have secondary
MN and require other tests to identify the cause. They are treated with supportive care and therapy for their underlying systemic disease. Patients
who are negative for anti-PLA2R/THSD7A in the serum but have PLA2R or THSD7A antigen staining in the biopsy sample, and usually
predominately IgG4 deposition in glomeruli, have inactive anti-PLA2R/THSD7A–mediated PMN and should be treated with supportive care
while monitoring anti-PLA2R levels for 4–6 months. They would be considered for ISTonly if anti-PLA2R becomes positive or proteinuria.3.5 g/
d persists after 6 months of supportive care. Patients with elevated anti-PLA2R levels (with positive PLA2R staining and [usually] predominantly
IgG4 in the biopsy sample) and proteinuria ,3.5 g/d have active anti-PLA2R/THSD7A–mediated PMN but would receive supportive care with
monthly anti-PLA2R monitoring because most of these patients will undergo spontaneous remission. If patients have, or develop, elevated anti-
PLA2R levels and .3.5 g/d of proteinuria they have active, anti-PLA2R/THSD7A–mediated PMN and would be considered for immediate IST. IST
options would be selected on the basis of characteristics of individual patients with dose and duration of therapy (Table 6) guided by regular
monitoring of anti-PLA2R levels. About 10% of patients with anti-PLA2R/THSD7A–negative antibody and glomerular staining have PMN
presumably mediated by a different anti-podocyte antibody rather than secondary MN and would be treated with traditional restrictive care
(4,52,53). Occasional patients with negative anti-PLA2R antibody but dominant IgG4 in the biopsy sample have also been reported and should
be monitored for later development of positive circulating anti-PLA2R antibody. ANA, anti-nuclear antibody; HBV, hepatitis B; HCV, hepatitis C;
IST, immunosuppressive therapy; MN, membranous nephropathy. Modified from other schemas in references 1 and 4, with permission.

60, 23% or more are over 60 (2,43–45). Renal function is
normal at presentation in .90% (2,42–45) (Table 4).
Spontaneous remissions occur in about 32% in an average
of 14 months and up to 62% by 5 years, and occur more
commonly in patients with low anti-PLA2R/THSD7A
levels (46–48). Anti-PLA2R/THSD7A levels generally cor-
relate with proteinuria, clinical course, and outcomes
(Table 3) (4–8,22,46–51).
The clinical consequences of PMN can be considered as
both short and long term. In the short term, they include
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 989

Table 3. Clinical and translational correlates of circulating levels of anti-PLA2Ra

70%–80% of patients with PMN have anti-PLA2R/THSD7A antibody (4–6,11)

Anti-PLA2R antibody is about 80% sensitive and 100% specific for PMN (although rare patients with sarcoid, HBV, HCV,
HIV, and cancer have been reported) (4,7,8,20,22)
Anti-PLA2R antibody can be present for many months before proteinuria appears (22,26)
In non-nephrotic patients, low, or declining, anti-PLA2R levels predict spontaneous remission and high levels predict
progression to nephrotic syndrome (47,48,51)
Anti-PLA2R–negative patients can become positive later (4,47,48)
High antibody levels (before and after treatment) correlate with proteinuria, response to therapy, and (after therapy)
long-term outcomes (4–8,50,51,70,71)
Patients with higher antibody levels require more prolonged immunosuppression to achieve remission rates comparable
to those with lower levels (63,70)
Expansion of the specificity of anti-PLA2R antibody to include additional epitopes (epitope spreading) correlates with a
worse prognosis (36)
Patients with IgG4 antibody directed only at the cysteine-rich epitope of PLA2R have a higher rate of spontaneous
remission (36)
Anti-PLA2R levels go down in remission and return with relapse (4–8,47,48)
Elevated anti-PLA2R levels after treatment predict relapse (5–8,47,48)
Elevated anti-PLA2R levels at the time of transplantation predict recurrence (especially if DQA1a05:01/05 positive)
(71,83–85)
Disappearance of anti-PLA2R antibodies (immunologic remission) precedes renal remission (disappearance of
proteinuria) by weeks to months (5–8)
Patients previously positive for anti-PLA2R/THSD7A who become negative will exhibit positive glomerular staining for
weeks to months (5–8,13,20,21)
.50% of cases of pediatric PMN are PLA2R-positive (3)

PMN, primary membranous nephropathy; HBV, hepatitis B; HCV, hepatitis C.

a
Although established in only a few cases, most of these associations are likely similar in anti-THSDA–mediated PMN.

complications of nephrotic syndrome such as development
of thrombotic and thromboembolic events that are pro-
portional to the degree of hypoalbuminemia and increase
significantly below albumin levels of about 2.8 g/L (1,2,42,
52–54) (Table 4). There is also an increased risk of infection,
due primarily to urinary loss of Igs, and of cardiovascular
disease (42,49). An association with malignancies is well
documented (55). Cancer may be seen within 3 years in up
to 20% of patients over 60 and may be more common in the
anti-THSD7A group where up to 20% have had a malig-
nancy detected within 3 months (14–16).
The most feared long-term consequence of MN is
progressive loss of renal function as occurs in 60% of
untreated patients with about 35% eventually develop-
ing ESRD within 10 years (1,2,4,44–46). Patients
who never become nephrotic virtually never progress
(1,2,4,43–45). Other established risk factors for progres-
sion include age, male sex, decreased GFR on presenta-
tion, increased excretion of some low molecular weight
markers such as b 2 microglobulin, persistent elevation of
anti-PLA2R levels after therapy, C3 staining in the biopsy
sample, and increased urinary excretion of C3dg and C5b-9
(1,2,43–45).
Treatment
Selection of patients for IST
Traditional approaches to treatment of PMN begin with
supportive care alone and withhold IST until the patient
meets certain criteria that predict progression (restrictive
therapy). Supportive care should be initiated in all patients
at the time of diagnosis and continued for the course of
the disease. It includes careful BP control, angiotensin-
converting enzyme inhibitor/angiotensin receptor blocker
therapy to minimize proteinuria and enhance chances of
a spontaneous remission, statins for hyperlipidemia, salt
restriction and diuretics to control edema, and a low
protein diet allowing for replacement of urinary protein
losses (1,2,4,56–60) Some patients are also anticoagulated if
serum albumin is ,2.5 g/L in the presence of other risk
factors and a favorable risk/benefit ratio as defined by
online calculators (54).
Current criteria for adding IST to supportive care (SC)
are based on either evidence of progressive loss of GFR
(usually .50% increase in serum creatinine or a level
.1.5 mg/dl) or proteinuria refractory to 6 months of SC
as defined by the Toronto risk score (56). The latter
approach divides patients after 6 months of supportive
care into three categories: low risk (,4 g/d, stable GFR),
moderate risk (4–8 g/d with stable GFR), or high risk
(. 8 g/d, ,50% decrease from baseline or .30% decline in
GFR since baseline) categories. Initiation of IST is recom-
mended in most patients in the moderate- and high-risk
categories unless factors that reduce the chance of a good
response are present, such as GFR,30 ml/min, serum
creatinine .3.5 mg/dl, small fibrotic kidneys, or an abun-
dance (.50%) of sclerotic glomeruli. Other situations that
would dictate early initiation of IST would include pro-
teinuria.10 g/d or failure to reduce proteinuria below 8 g/d
after 3 months, complications of nephrotic syndrome such as
990 Clinical Journal of the American Society of Nephrology

Table 4. Clinical manifestations of primary membranous nephropathy at presentation and during the course of the disease
(1,2,42,43,56,58)

Clinical Manifestations Initially During Course Comments

Nephrotic syndrome
Proteinuria.3.5 g/d 60% 75% Anti-PLA2R antibody predicts
later development of
nephrotic syndrome
Edema 60% 75% Less severe than minimal
change nephrotic syndrome
or primary FGS
Hypoalbuminuria 60% 75% Inversely related to
proteinuria
Hyperlipidemia 50% 65% Inversely related to serum
albumin levels, associated
with cardiovascular disease
Thromboemboli ,1% 7% Risk increases with serum
albumin ,2.8 g/dl
Hematuria 50% 60% Red blood cell casts rare
Reduced GFR 20% 40% Seen only in nephrotic patients
ESRD NA 10%–20% (treated) to Requires .10 yr follow-up if
33% (untreated) ESRD is used as a clinical
end point in studies of
therapy
Hypertension 30% Up to 50% Usually associated with
progression
Risk alleles HLA-DQR1; PLA2R1 Presence of risk alleles for both
HLA and PLA2R raises the
risk for PMN up to 79-fold
Anti-PLA2R antibody 70%–80% 85% May be present before
proteinuria and resolve
weeks to months before
proteinuria resolves
Anti-THS7DA antibody 2%–7% ? Similar to anti-PLA2R, but
may be associated with more
extrarenal cancer
Associated with cancer 10% overall, 20% age .57 PMN usually follows cancer
diagnosis, anti-PLA2R
usually negative, issue of
causality versus coincidence
still unresolved

FGS, focal glomerular sclerosis; NA, not applicable; PMN, primary membranous nephropathy.

thromboembolic events, anasarca due to severe hypoalbumi-
nemia, or unexplained loss of GFR.
Definitions of terms conventionally used to classify
responses to therapy of PMN are presented in Table 5
(4,52,53). Goals of therapy would be complete or partial
remission. Thompson et al. have recently presented evi-
dence supporting the validity of considering complete and
partial remissions of proteinuria in PMN as surrogate
markers of good outcomes and consequently as valid goals
of therapy or end points for therapeutic trials (43).
For decades, clinicians have treated PMN with nephrotic
syndrome with potentially toxic IST using the above
proteinuria/GFR-based guidelines, because there was no
way to distinguish patients with immunologically active
disease from those with inactive disease who have persis-
tent proteinuria despite immunologic remission. Table 6
provides an overview of IST regimens of established benefit
in preserving renal function in PMN.
Figure 4, and the legend to Figure 4, outline a different
approach to IST applicable to all patients with protein-
uria.3.5 g/d, normal or stable GFR and active disease,
defined as ongoing glomerular immune deposit formation
indicated by elevated circulating levels of anti-PLA2R/
THSD7A. Based on the data reviewed above, such patients
have active immunologic disease and should be consid-
ered for immediate IST without waiting 6 months on
supportive care alone as prescribed by restrictive therapy
protocols. Although much remains to be learned about
translating anti-PLA2R/THSD7A levels into predictive
clinical algorithms, patients with anti-PLA2R levels in
the highest tertile have only a 4% chance of undergoing
spontaneous immunologic remission while being treated
with SC alone (47,48,50,51,59,60). Informed consent should
always be obtained before IST is initiated.
Both supportive care and IST should continue with antibody
monitoring every 1–2 months until anti-PLA2R/THSD7A
Clin J Am Soc Nephrol 12: 983–997, June, 2017
Table 5. Definitions of clinical responses in primary
membranous nephropathy (4,56–58)a
Clinical Response Definition
Complete remission Proteinuria ,0.3 g/d
Partial remission .50% reduction from baseline
and between 0.3 and 3.5 g/d
With stable GFRb
No remission ,50% reduction or .3.5 g/d
Relapse Recurrence of .3.5 g/d after
remission
ESRD GFR,15 ml/min or
requirement for dialysis/
transplant
a
Measurements of proteinuria for clinical decision-making
should be done on 24-hr collections. Overnight or random
samples can be used for monitoring.
b
Decline of ,15%.
levels become undetectable (or fall below some as yet
undefined level below which progression is unlikely),
recognizing that a response in proteinuria (clinical re-
mission) may only occur several weeks to months after an
immunologic remission is achieved (4,6,7). Considering the
current high cost of anti-PLA2R assays, obtaining levels at
the time of diagnosis and when a clinical decision point is
reached (e.g., after 6 months of IST) would be acceptable if
cost to the patient is a limiting factor. However, monitor-
ing levels initially every 1–2 months may justify shorter
courses of therapy and better predict remissions and
relapses. In most anti-PLA2R/THSD7A–positive patients,
circulating antibody disappears after 4–6 months of IST,
which should then be tapered and discontinued even if
some proteinuria persists (4,6,56–60). If antibody levels
persist but show a downward trajectory after 4–6 months,
the IST regimen can be maintained until antibody disap-
pears (immunologic remission). If no substantial reduction
in antibody levels is seen after 4–6 months or GFR falls
(.30% increase in serum creatinine on two determinations)
and nephrotic-range proteinuria persists at .50% of baseline,
changing to an alternate IST regimen would be justified
(Figure 4).
In the 10% of patients with PMN who are PLA2R/
THSD7A antibody– and glomerular antigen–negative, and
therefore have uncertain immunologic activity, initiation
of IST should follow the current restrictive proteinuria or
GFR-based guidelines outlined above (56,57) (Figure 4).
Clinical outcomes using these restrictive therapy protocols
have been equivalent to earlier results achieved by initi-
ating IST in all patients with PMN at the time of diagnosis
while sparing about 50% of patients with PMN the toxic
effects of IST (61). However, using the current recommen-
dations of 6 months of SC alone, nephrotic syndrome
resolves more slowly, patients are exposed to the nephrotic
state for longer periods of time and therefore are at greater
risk for developing complications of nephrotic syndrome
such as thromboembolic disease (Table 4), and some
nephrons will inevitably be damaged or destroyed while
waiting for a spontaneous remission to occur (4–6).
Membranous Nephropathy, Couser 991
The quantitative ELISA assay for PLA2R (Euroimmune
AG, Luebeck, Germany), or the recently developed cell-
based ALBIA assay (Mitogen Advanced Diagnostics Lab-
oratory, Calgary, Canada) should be used for monitoring
antibody levels (4–7). As we move more toward antibody-
guided therapy, it is essential that measurements be
standardized between commercial laboratories and that
the threshold antibody level below which IST does not
provide sufficient benefit to offset potential risks be de-
fined. In the ELISA assay, levels .20 RU/ml are considered
positive, and available data indicates a relationship be-
tween anti-PLA2R levels and clinical outcomes with pa-
tients in the lowest tertile frequently undergoing
spontaneous remission and levels in the highest tertile
associated with progression and rarely (,5%) with spon-
taneous remission (4,47,50,51).
IST regimens in PMN
Table 6 presents an overview of the IST regimens of
established benefit in PMN. Current data do not permit an
evidence-based choice between these IST protocols on the
basis of differences in their efficacy in suppressing anti-
PLA2R/THSD7A production. The three most utilized regi-
mens (cyclophosphamide/steroids, calcineurin inhibitors
[CNIs]/steroids, and rituximab) appear similar in their
effect on anti-PLA2R levels (1,4,59–63). Small studies have
shown that a combination of a CNI and rituximab was more
effective in suppressing antibody than cyclophosphamide/
steroids (63), that cyclophosphamide/steroids was more
effective than mycophenolate mofetil (MMF) (64), and that
tacrolimus (TAC) and cyclophosphamide/steroids were of
similar efficacy (62). However, each of these studies is small
and short-term. All three regimens lead to marked reductions
in circulating antibody in most patients within 3–4 months,
followed by disappearance of antibody within 6–9 months,
and remission of proteinuria in 12–24 months in .80% of
patients (4,63). Thus, IST prolonged for 6 months may not be
necessary in all patients, whereas longer courses might be
required in others.
Most current therapeutic guidelines, on the basis of older
randomized controlled trials (RCTs), recommend initiating
IST in patients with proteinuria resistant to supportive care
after 6 months utilizing a modified Ponticelli regimen of 6
months of alternating pulse steroids and cyclophosphamide
(56–60,65). This leads to remissions of proteinuria in about
50%–60% of patients at 1 year and 70%–80% at 2–3 years,
versus about 30% of controls treated with supportive care
only (2,56–60,65). Development of ESRD 10 years later is
reduced from 30%–40% to 10% or less when all patients with
PMN are treated at the time of diagnosis with alkylating
agents/steroids (65). Proteinuric relapses, seen in about 25%
of patients, are not predicted by any clinical parameter, but
usually follow the return of anti- PLA2R/THSD7A antibody
and are treated by repeating the same therapy that induced
the initial remission (1,2,56–60). A course of cyclophospha-
mide should be repeated only once because cumulative
doses .36 g are associated with an increased incidence of
malignancy (55), although increased incidence ratios for
malignancy have been reported in PMN at all levels of
cumulative cyclophosphamide dose (66). Advantages of the
Ponticelli regimen include the well established efficacy,
992 Clinical Journal of the American Society of Nephrology

Table 6. Summary of the most common IST protocols for treating patients with primary membranous nephropathy (56–60,93)

IST Regimen Drug, Dose Comments

Cytotoxic drugs KDIGO first choice

Modified Ponticelli Months 1, 3, 5: 1 g methylprednisolone Monitor Uprotein and WBC weekly
iv on days 1, 2, and 3 followed by oral 38, then every 2 mo; daily oral
prednisone, 0.5 mg/kg daily for 27 d prednisone and
cyclophosphamide may have
similar efficacy. Increased risk of
malignancy above 36 g
Months 2, 4, 6: 2.0–2.5 mg/kg oral Relapse rate 20%–30%
cyclophosphamide daily
Dutch protocol Months 1, 3, 5: 1 g MP days 1–3 followed Same as above
by oral prednisone, 0.5–1.0 mg/kg for
6 mo, then taper
Oral cyclophosphamide, 1.5–2.0 mg/kg
daily for 12 mo
CNIs KDIGO second choice
Cyclosporin 3.5–5.0 mg/kg daily in divided doses Used in patients resistant to cytotoxic
adjusted to level of 120–200 mg/L for drugs but can be used as initial
12–18 mo and tapered therapy. Taper slowly
Prednisone 5–10 mg/kg daily or alt days Discontinue at 6 mo if no response
Relapse rate 40%–50%
Tacrolimus 0.05–0.075 mg/kg daily in two divided Same as above
doses adjusted to level of 3–5 mg/L for
12–18 mo and taper slowly
Prednisone 5–10 mg/kg per day daily or Preferable in young women
alt days
B cell depletion Used for patients resistant to
cytotoxic drugs or CNIs
Utility as initial therapy not yet
established by RCTs
Rituximab 375 mg/kg weekly times 4 Follow CD20 counts and repeat dose
375 mg/kg once and follow CD20 if counts rise before remission in
counts proteinuria or relapse occurs
1000 mg on days 1 and 15
ACTH
Tetracosactrin 1 mg IM every 2 wk for 6–12 mo
(Synacthen)
(synthetic)
Corticotropin 80 U IM every 2 wk for 6–12 mo
(ACTHAR) (purified)

IST, immunosuppressive therapy; KDIGO, Kidney Disease Improving Global Outcomes; WBC, white blood cells; MP, methylpred-
nisolone; CNI, calcineurin inhibitor; alt, alternate; RCT, randomized controlled trial; ACTH, adrenocorticotrophic hormone; IM,
intramuscular.

including reduction in ESRD, lower relapse rate (25%), and
considerable experience with its use (4,59,60,62). Disad-
vantages include a relatively high adverse event rate (25%)
that includes infection, need for close monitoring of
hematologic parameters, infertility, and later malignancy
(56,57,62,66).
CNIs (cyclosporin [CSA] or tacrolimus [TAC]), used
either as monotherapy or combined with low-dose steroids,
which is thought to improve response and reduce nephro-
toxicity, have also been shown to decrease proteinuria,
reduce the rate of loss of renal function, and decrease anti-
PLA2R levels in PMN (1,2,4,56–60). In the United States,
many clinicians prefer to initiate therapy with CNIs to avoid
the more severe adverse events associated with alkylating
agents and higher doses of steroids. Most studies show
about equal efficacy between TAC and CSA (1,4,56–60).
Advantages of CNIs include the lower incidence of in-
fection and malignancy compared with cytotoxic drugs
and the efficacy of monotherapy if steroids are not used
(1,56,58). Disadvantages include long-term nephrotoxicity
with consequent need to closely monitor drug levels,
increased incidence of hypertension and diabetes, espe-
cially with TAC, and some recent concerns about whether
CNIs are effective at all in preventing ESRD in the long
term (67). The relapse rate with CNIs (40%–50%) is also
higher than with cyclophosphamide (25%) but may di-
minish with longer periods of therapy (1,59,60), and some
have advocated using low-dose CSA as maintenance
therapy to reduce or prevent relapses. CNIs have been
shown to not only reduce anti-PLA2R levels (62,63) but also to
Clin J Am Soc Nephrol 12: 983–997, June, 2017
have a direct effect to stabilize the podocyte actin cytoskeleton,
which reduces protein filtration (68). CNIs induce partial or
complete remissions in up to 80% of cases of PMN within 12
months and could be employed if cyclophosphamide/steroid
treatment fails, previous cumulative doses of cyclo-
phosphamide approach 36 g, there is inability to tolerate
cytotoxic drugs, or issues such as osteoporosis
or preservation of fertility are present (1,56–60). However,
CNIs have not yet been established by proper RCTs to
reduce the long-term development of ESRD, although a
strong case can be made that complete and partial
remissions of proteinuria can serve as surrogate markers
of failure to progress to ESRD in PMN (44). The limited
data comparing cytotoxic drug therapy directly to CNIs
suggests they have similar short-term clinical efficacy
(1,44,56–60). However, in one recent RCT, the response
to CNIs was not different from the response to SC alone
(67). An excellent initial response rate to CNIs (80%) has
been reported in some patients who failed the Ponticelli
regimen and, conversely, some patients who have failed
CNIs may respond to the Ponticelli regimen (59,60,69).
MMF monotherapy has not been established to be
effective in PMN (64). In one study only 44% of patients
receiving MMF were in remission at 23 months versus
75% in the cyclophosphamide group (63).
B cell depletion using the anti-CD19/20 monoclonal
rituximab as monotherapy has recently emerged as a less
toxic approach, with efficacy equivalent to cytotoxic drugs
and CNIs but with a significantly lower adverse event rate
(58,70–72). Rituximab was initially given weekly for 4
weeks as doses of 375 mg/M2 intravenously (iv) or, more
recently, as two iv doses of 1000 mg, or 375 mg/m2, 15
days apart (71). Rituximab, 375 mg/M2 as a single dose
repeated only when B cell counts return (B cell–driven
therapy), has also been established to reduce anti-PLA2R
antibody levels and to induce remission of proteinuria in
about 64% of patients in a mean of 7 months, but that
figure increases over 3–4 years and the safety profile is
better than that of cyclophosphamide or CNIs (1,70–72).
Also, similar effects on proteinuria have been reported in
PLA2R/THSD7A antibody–negative patients, suggesting
that these patients too may have an antibody-mediated
disease (71). Advantages of B cell–driven therapy include
the freedom from steroids, low adverse event rate, ability to
monitor B cell levels to assess efficacy and predict remission
and relapse, and modest cost when only a single dose is given
(71). Disadvantages include the lack of confirmation that
early reductions in proteinuria predict a lower incidence of
ESRD (with the caveat mentioned above that remissions of
proteinuria in PMN may be acceptable surrogate markers for
ESRD in PMN [44]). The response rate closely parallels CD
19/20 B cell counts and anti-PLA2R levels, and seems similar
in patients treated initially and those in whom rituximab
was used later as rescue therapy (70–72). The relapse rate in
rituximab responders is about 30%, associated with return
of circulating B cells and anti-PLA2R antibody, and relapse
can sometimes be associated with development of anti-
rituximab antibodies (72). Most patients who relapse respond
to another dose (70–72). A recent RCT (Evaluate Rituximab
Treatment for Idiopathic Membranous Nephropathy Study)
comparing supportive care alone to supportive care plus
rituximab, 375 mg/M2 iv on days 0 and 8 in patients with
Membranous Nephropathy, Couser 993
persistent nephrotic syndrome after 6 months of supportive
care, demonstrated much greater efficacy of rituximab in
reducing anti-PLA2R levels (56% versus 4% at 3 months,
P,0.05) and more complete and partial remissions of pro-
teinuria at a mean of 17 months in the rituximab group (65%
versus 34%, P,0.01), with short-term adverse event rates
similar to those in the group receiving SC alone (72). Analysis
of the cost of therapy over the course of the disease using a
Markov decision analysis model suggests it is lower than the
cost of cyclophosphamide/steroids (73). Thus, experience to
date supports considering rituximab monotherapy as a third
option for induction therapy, as well as a popular choice for
maintenance or rescue therapy (71).
Adrenocorticotrophic hormone monotherapy, usually
given as 1 mg twice a week for a year (Table 6), has also
been shown in one small randomized controlled study to
reduce anti-PLA2R levels and produce results (.80%
remission at 6 months) equivalent to cyclophosphamide/
steroids, with minimal adverse events (Table 6) (74–75).
However, another study comparing the two using histor-
ical controls favored cyclophosphamide (75). The cost of
adrenocorticotrophic hormone is very high, and its place
in the therapeutic armamentarium for PMN remains to be
established (76).
Another treatment option is to utilize combinations of
drugs in lower doses (multidrug therapy), usually ritux-
imab plus a cytotoxic drug or CNI to retain efficacy and
reduce adverse events, especially those due to steroids.
For example, a recent observational study using rituximab
with low-dose cyclophosphamide and an accelerated taper
of steroids reported a 100% remission rate over a mean
follow-up of 37 months (77). Another, using a combination
of rituximab and CSA, achieved remissions in 92% and
antibody depletion in 100% in 9 months (78), and a
combination of rituximab and plasma exchange showed
promise in a third small study (79). These studies all require
confirmation, and RCTs comparing these approaches to
conventional IST reviewed above are necessary before
multidrug therapy can be recommended as an established
approach to initial therapy in PMN.
Transplantation in PMN
Renal transplantation is effective in the 10%–20% of
patients who do reach ESRD from PMN (1,4,75–78). In anti-
PLA2R–positive patients, subepithelial deposits can ap-
pear in the allograft within 6 days (70,80,81). As deposits
increase, clinical recurrence (proteinuria) is seen within 13–
15 months in about 40%–50% of allografts and can diminish
allograft survival (70,80–85). The recurrence rate of sub-
epithelial deposits in patients positive for anti-PLA2R
antibodies at the time of transplantation may approach
90% (70,80,81). Delaying transplantation until anti-PLA2R/
THSD7A is no longer detectable seems advisable unless
there are clinical reasons for greater urgency. Anti-PLA2R–
negative de novo MN is also a common cause of transplant
nephrotic syndrome, affecting about 2% of all renal trans-
plant recipients whose original disease was not MN, and is
about equal in frequency to recurrent MN in patients with
PMN (82–85). In these patients, IgG1 deposits often pre-
dominate, anti-PLA2R/THSD7A is negative, and the
mechanism(s) involved are not yet known, although the
994 Clinical Journal of the American Society of Nephrology
lesion is believed to be related to graft rejection (82). Anti-
PLA2R positivity has a sensitivity of 83% and specificity of
.90% in differentiating between recurrent and de novo MN
in transplants (78–80,84).
Because patients with recurrent subepithelial deposits
do not all go on to manifest clinical recurrence, treatment
for recurrent MN is usually considered only when protein
excretion reproducibly exceeds 1 g/d in patients with PMN
or 4 g/d in patients with de novo MN (82–85). However, an
approach analogous to the one recommended above for
PMN in native kidneys would suggest initiating additional
IST in patients with PMN with elevated anti-PLA2R/
THSD7A levels and nephrotic-range proteinuria post-
transplant. Based entirely on observational data, rituximab
is usually added to regular immunosuppressive protocols,
which often already include CNIs (70,82–84). The doses
employed have ranged from one dose of 200 mg to the older
375 mg/M2 given four times at weekly intervals with
monitoring of CD20 counts. Because these patients are
being treated early and are already on IST for the trans-
plant, lower doses are probably preferable. Use of pretrans-
plant rituximab has been attempted in antibody-positive
patients, and may have been effective in preventing re-
currence in some patients with a history of recurrent PMN
in previous allografts (84). In patients receiving CNIs and
resistant to rituximab, cyclophosphamide, 2 mg/kg per
day, is usually employed after other antimetabolites such as
MMF or azathioprine are discontinued (78,82–84).
Gaps and Shortfalls in Current Therapy
Despite the numerous translational observations that
have already been made (Table 3), many questions remain
unanswered (86). Some of the more clinically relevant ones
include: What is the best way to measure anti-PLA2R,
and, in the future, anti-THSD7A, antibody? How do
antibody levels translate into risk of progression and are
there levels below which IST is not worthwhile? If therapy
is antibody-directed, will this achieve better clinical out-
comes or fewer adverse events in patients with active
disease compared with current restrictive therapy regi-
mens? Is it important for prognosis or treatment to know
the pathogenic epitopes and molecular configurations of
the PLA2R peptides against which antibodies in individual
patients are directed? Does a biopsy contribute to im-
proved outcomes in typical anti-PLA2R/THSD7A–positive
PMN with nephrotic syndrome? If a patient has apparent
secondary MN with another systemic disease, but also has
elevated anti-PLA2R/THSD7A antibody or positive glomer-
ular staining, should such a patient be treated for PMN? If
a biopsy is done in antibody-negative patients, is positive
glomerular staining for IgG4 and PLA2R/THSD7A suffi-
cient to establish anti-PLA2R/THSD7A–related PMN and
exclude secondary causes?
Can multidrug therapy protocols combining currently
available drugs reduce adverse events without sacrificing
efficacy as has been done in lupus nephritis? Can outcomes
be further improved if complement inhibitors are added to
current IST protocols, especially during the interval of
active disease between initiation of IST and disappearance
of the antibody? Can routine maintenance therapy reduce
relapses and the need for retreatment?
New Therapies on the Horizon
Current knowledge of the roles of autoantibody IgG and
complement in the pathogenesis of PMN make better B
cell–depleting agents and complement inhibitors of par-
ticular interest. New therapeutic approaches to suppress
antibody production or interfere with antibody-induced
podocyte injury include improved B cell–depleting agents,
B cell depletion targeted specifically to anti-PLA2R re-
active cells, and suppressors of B cell activation. A recent
pilot study of belimumab, an inhibitor of B cell activation,
in 11 anti-PLA2R–positive patients reported a 90% re-
duction in anti-PLA2R levels and a (delayed) 70% re-
duction in proteinuria in patients receiving monthly iv
doses of the drug over a period of 28 weeks (87). Other
approaches under development include antibody traps or
decoys and efforts to directly protect the podocyte itself
from consequences of immune injury such as endoplasmic
reticulum stress, autophagy, and oxidant injury (88).
Pending identification of PLA2R peptides that neutralize
antibody, peptide-blocking agents will likely also be de-
veloped. Although one trial of the C5 inhibitor eculizumab
was negative in PMN, adequate complement -inhibiting
doses were not used, and other trials with newer comple-
ment inhibitors, including oral agents, recombinant com-
plement regulatory proteins, small molecules, new
monoclonal antibodies, small interfering RNA agents,
and approaches that upregulate natural complement in-
hibitors, are in progress or under development (31).
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Anti-Glomerular Basement Membrane Disease
Stephen P. McAdoo and Charles D. Pusey

Abstract
Anti–glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects the capillary
beds of the kidneys and lungs. It is an archetypic autoimmune disease, caused by the development of directly
pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of
these organs, although the inciting events that induce the autoimmune response are not fully understood. The
Renal and Vascular
recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including Inflammation Section,
infection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespread Department of
glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%–60% will have Medicine, Imperial
concurrent alveolar hemorrhage. Treatment aims to rapidly remove pathogenic autoantibody, typically with the use College London,
London, United
of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and
Kingdom
tissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early,
the majority of patients will have good renal outcome, although presentation with oligoanuria, a high proportion of Correspondence: Dr.
glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrent Stephen P. McAdoo,
disease after kidney transplantation are both uncommon, although de novo anti-GBM disease after transplantation Renal and Vascular
for Alport syndrome is a recognized phenomenon. Copresentation with other kidney diseases such as ANCA- Inflammation Section,
Department of
associated vasculitis and membranous nephropathy seems to occur at a higher frequency than would be expected by
Medicine, Imperial
chance alone, and in addition atypical presentations of anti-GBM disease are increasingly reported. These observations College London,
highlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, and Hammersmith
how to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors. Hospital Campus, Du
Cane Road, London
Clin J Am Soc Nephrol 12: 1162–1172, 2017. doi: https://doi.org/10.2215/CJN.01380217
W12 0NN. Email:
s.mcadoo@imperial.
ac.uk

Nomenclature and History
Anti–glomerular basement membrane (anti-GBM)
disease is a rare small vessel vasculitis that affects
glomerular capillaries (where it may result in glo-
merular necrosis and crescent formation), pulmonary
capillaries (where it may cause alveolar hemorrhage),
or both. It is characterized by the presence of circu-
lating and deposited antibodies directed against
basement membrane antigens, and as such is classified
an immune-complex small vessel vasculitis in the
Revised International Chapel Hill Consensus Confer-
ence Nomenclature of Vasculitides (1). The Consensus
acknowledges the relative misnomer of anti-GBM
disease, given the frequent involvement of alveolar
basement membranes, although recognizes the widely
accepted use of anti-GBM disease to describe this
condition with or without lung involvement.
The eponymous term “Goodpasture disease” is also
used to describe this condition, first being used by
Australians Stanton and Tange in 1958 (2), in their
report describing nine cases of GN associated with
lung hemorrhage. They credited Ernest Goodpasture,
an American pathologist, with the first description of
the syndrome in his 1919 paper describing a fatal case
of GN and lung hemorrhage that was, at the time,
attributed to an atypic influenza infection (3). We do
not know, however, if any of these patients had anti-
GBM disease as we recognize it today, because it was
not until the development of immunofluorescence
techniques in the 1960s that it became possible to de-
tect anti-GBM antibodies in kidney tissue (4), and to
demonstrate their pathogenic potential upon elution
and transfer to nonhuman primates (5). The detection
of circulating anti-GBM antibodies in patients quickly
followed (6), and the first comprehensive clinical de-
scription of “anti-GBM antibody–induced GN” was by
Wilson and Dixon (7). It is of historical interest to note
that Goodpasture’s original description of lung and
kidney disease in association with intestinal and splenic
inflammation, after a subacute clinical presentation, was
perhaps more in keeping with a diagnosis of ANCA-
associated vasculitis (AAV) than anti-GBM disease, and
that Goodpasture himself is said to have rejected the
eponymous use of his name.
The term “Goodpasture disease” has persisted, how-
ever, being generally reserved for patients with demon-
strable anti-GBM antibodies, whereas “Goodpasture
syndrome” may be used to describe copresentation
with GN and pulmonary hemorrhage of any cause.
We will use the term “anti-GBM GN” when referring
specifically to the kidney involvement seen in this
condition, and “anti-GBM disease” when referring to
the broader spectrum of kidney and lung disease.
Epidemiology and Etiologic Associations
Given its rarity, definitive observations regarding
the incidence of anti-GBM disease are lacking. It is

1162 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 July, 2017
Clin J Am Soc Nephrol 12: 1162–1172, July, 2017
often said to have an incidence of ,1 per million population/yr
in European populations, largely on the basis of single-center
biopsy- or serology-based series, although accurately defining
populations at risk in such studies is difficult. A recent study
from Ireland is notable for being the first to define a nationwide
disease incidence, by identifying all cases over a decade via
reference immunology laboratories and a nationwide pathol-
ogy database (8). It reported a disease rate of 1.64 per million
population/yr, higher than previous estimates. The disease is
well recognized in other white and in Asian populations (9–12),
although is thought to be rarer in African populations (13).
Anti-GBM GN accounts for 10%–15% of all cases of
crescentic GN in large biopsy series (14), although it ap-
pears to be a rare cause of ESRD (15). A common observation
from larger series of anti-GBM disease is that of a bimodal
age distribution, with peak incidences in the third decade,
where a slight male preponderance and presentation with
both kidney and lung disease is observed, and in the sixth to
seventh decades, where presentation with isolated kidney
disease is more common (16–18).
Some series have reported disease “outbreaks” and
seasonal variation in incidence (16,17), and the Irish study
identified spatial and temporal clustering of disease, sug-
gesting that environmental factors may be important
triggers for disease onset, although they are yet to be
accurately defined (8,19). Infectious associations, particu-
larly with influenza A, have been the subject of anecdotal
reports (20,21), and may account for the aforementioned
seasonal or geographic “clustering” of anti-GBM disease
cases, and a recent study described a high prevalence of
prodromal upper and lower respiratory tract infection in a
cohort of 140 Chinese patients (22). The causative nature
of these associations, however, is not proven and remains
speculative.
A more conclusive environmental association is that with
cigarette smoking and the development of lung hemor-
rhage in anti-GBM disease (23). Similarly, inhalation of
hydrocarbons has also been implicated in disease onset
(24). It is suggested that localized inflammation induced
by inhaled toxins may increase capillary permeability, or
potentially disrupt the quaternary structure of the alveolar
basement membrane, exposing usually sequestered anti-
gens and allowing access to pathogenic autoantibodies.
A more recently identified trigger for anti-GBM disease
is treatment with the anti-CD52 mAb, alemtuzumab, a
lymphocyte-depleting agent that is increasingly used in the
treatment of relapsing multiple sclerosis (25). It is thought
that loss of regulatory T cell subsets, or abnormal immune
cell repopulation after depletion, may account for the in-
creased incidence of many autoimmune diseases, including
anti-GBM disease, after exposure to this agent.
It is likely that these environmental triggers act in genet-
ically susceptible individuals to induce disease onset. Anti-
GBM disease has a strong HLA-gene association, with
approximately 80% of patients inheriting an HLA-DR2
haplotype. A hierarchy of associations with particular DRB1
alleles has been identified, some positively associated with
disease (DRB1*1501, DRB1*0401) and some conferring a
dominant-negative protective effect (DRB1*07), which
might be attributed to the higher affinity of the latter alleles
for binding peptides from the target autoantigen (26). The
DRB1*1501 association has been replicated in Asian
Anti-GBM disease, McAdoo et al. 1163
populations (27,28). It should be noted, however, that these
susceptibility alleles are common in most populations and
that they are also associated with other autoimmune
diseases (including multiple sclerosis, perhaps contributing
to the association with alemtuzumab treatment), highlight-
ing that other factors are necessary to incite anti-GBM
disease, and thus HLA-gene testing is not routinely used in
the clinical work-up of these patients.
Polymorphisms and copy number variation in non-HLA
genes have also been implicated in disease susceptibility,
such as the genes encoding Fcg-receptors (29,30), consis-
tent with the role of pathogenic autoantibodies in disease
onset. On the basis of a small study, polymorphisms in
COL4A3, the gene encoding the Goodpasture autoantigen,
are not thought to be involved in disease predisposition
(31). To the best of our knowledge, there has not been an
undirected genetic study in anti-GBM disease.
Immunopathogenesis
In its native form, the GBM consists of a network of type
IV collagen molecules, each made up of triple-helical
protomers of a3, a4, and a5 chains (Figure 1). The principal
target of the autoimmune response in anti-GBM disease
has been identified as the noncollagenous (NC1) domain
of the a3 chain of type IV collagen (a3[IV]NC1; the
“Goodpasture autoantigen”) (32,33). The clinical pattern of
reno-pulmonary disease reflects the restricted expression of
this antigen to the basement membranes of glomerular and
alveolar capillaries (and to a lesser extent, the retina, choroid
plexus, and cochlea, where it is generally not associated
with clinical disease [34]). Two principle autoantibody (B cell)
epitopes within the autoantigen have been identified, desig-
nated EA and EB (35), which in native GBM are usually
sequestered within the quaternary structure of the noncol-
lagenous domains of the triple helix of a3, 4, and 5 chains.
Sera from all patients with anti-GBM disease appear to
react to a3(IV)NC1, although a proportion will also have
antibodies directed against other collagen chains, including
a5 and a4, identified either in serum or upon elution from
kidney tissue, and thought to arise via a process of “epitope
spreading” after a primary response to the a3 chain (36).
The directly pathogenic potential of these antibodies was
clearly demonstrated by Lerner and colleagues in 1967,
when they administered antibodies eluted from the kid-
neys of patients with anti-GBM disease to nonhuman
primates, leading to the development of crescentic GN in
the recipients (5). The pathogenicity of these antibodies has
since been confirmed in a number of other species and
animal models.
Clinical observations support a pathogenic role for these
antibodies; antibody titer, subclass, and avidity have each
been correlated with disease outcome (37–40). In addition,
the rapid removal of circulating antibodies by plasma
exchange is associated with better outcome, and if kidney
transplantation is performed in the presence of circulating
antibodies, disease is likely to recur rapidly in the allograft
(7,41).
In addition to humoral responses, T cells also have a role
in disease pathogenesis. Data from animal models sug-
gest that T cells may contribute directly to cell-mediated
glomerular injury, which can occur in the absence of
1164 Clinical Journal of the American Society of Nephrology

Figure 1. | Structure of the glomerular basement membrane. In its native form, the collagen IV network in the glomerular basement membrane
consists of triple-helical protomers of a3, a4, and a5 chains (shown individually in [A]). The carboxy-terminal domains of these a3 a4 a5
protomers form a trimeric “cap” (B), end-to-end association of which results in the formation of the hexameric NC1 domain (C). The quaternary
structure of this hexamer is stabilized by hydrophobic and hydrophilic interactions across the planar surfaces of opposing trimers, and reinforced
by sulfilimine bonds crosslinking opposing NC1 domains. Two key autoantibody epitopes within a3(IV)NC1 have been described, designated EA
(incorporating residues 17–31 toward the amino terminus) and EB (residues 127–141 toward the carboxy terminus), which in the native form are
sequestered at the junction with a4 and a5 chains within the triple helical structure. Binding through 7s domains (shown in orange) completes
the lattice-like structure of the type IV collagen network (D). Reprinted from reference 102.

significant humoral immunity (42,43), and glomerular T
lymphocytes may be observed in kidney biopsy samples
taken from patients with active disease (44,45). The strong
HLA association and the presence of high-affinity, class-
switched autoantibodies also indicate a necessity for T cell
help in the development of the autoimmune response.
Notably, mononuclear cells from patients proliferate in
response to a3(IV)NC1 at much higher frequency than do
cells from healthy controls, and the frequency of auto-
reactive T cells correlates with disease activity (46–48). The
pathogenic T cell epitopes in humans, however, have not
been consistently defined.
That these autoreactive T cells can be identified in
healthy individuals, along with low-level natural autoan-
tibodies (49), suggests that tolerance to the a3(IV)NC1
antigen is not fully achieved during immunologic develop-
ment. In addition, a rising titer of anti-GBM antibodies has
been shown to predate the onset of clinical disease by
several months (50), highlighting that several tolerance
mechanisms must be disrupted before disease occurs. One
such breach of “peripheral” tolerance is disruption of the
quaternary structure of the Goodpasture autoantigen, and
in particular disruption of the sulfilimine crosslinks that
stabilize the association of opposing NC1 domains on
individual collagen chains (Figure 1). This may result in
modification or exposure of usually hidden epitopes, which
is suggested to be a key event in the pathogenesis of disease
(36). This may account for the association with etiologic
factors that may disrupt alveolar (e.g., smoking, inhalation
of hydrocarbons) or GBM (such as lithotripsy [51,52], and
the other kidney pathologies discussed below).
The recovery phase of anti-GBM disease is associated
with a progressive fall in autoantibody titers (even in the
absence of immunosuppression) and a lower frequency of
T cells reactive to a3(IV)NC1. The emergence of a CD251
suppressor T cell subset that may inhibit responses to a3
(IV)NC1 has been described (53), suggesting that immu-
nologic tolerance to a3(IV)NC1 can be re-established. This
may explain the rarity of clinical relapses in anti-GBM
disease, and the association with lymphocyte-depleting
therapy with alemtuzumab.
Clinical Presentation and Diagnosis
The majority of patients (80%–90%) will present with
features of rapidly progressive GN. Forty percent to 60%
Clin J Am Soc Nephrol 12: 1162–1172, July, 2017
will have concurrent lung hemorrhage, and a small mi-
nority of patients may present with isolated pulmonary
disease. “Atypical” presentations are well recognized, and
discussed in more detail below. Central to the diagnosis of
anti-GBM disease is the identification of anti-GBM anti-
bodies, either in serum or deposited in tissue, along with
pathologic features of crescentic GN, with or without evi-
dence of alveolar hemorrhage.
Serologic Testing
In current practice, circulating anti-GBM antibodies are
usually detected using commercially available enzyme
immunoassays or bead-based fluorescence assays, which
typically use purified or recombinant human or animal
GBM preparations as antigenic substrate. Western blotting,
using similar GBM preparations, may be a more sensitive
method for antibody detection, although it is not
widely available outside research laboratories. Indirect
immunofluorescence using normal kidney tissue is an
alternative method, although this requires additional
input from a kidney pathologist and is prone to giving
false negative results. A proportion of patients who
have demonstrable deposition of IgG on the GBM by
immunofluorescence, but who are negative for circu-
lating antibodies by these conventional techniques,
may be positive when tested by highly sensitive bio-
sensor assay (54). In anti-GBM disease, the pathogenic
antibodies are usually of the IgG class, with IgG1 and
IgG3 subclasses predominating (37,38), although rare
cases of IgA- and IgG4-mediated disease have been
described (55,56). These antibodies may not be detected
on routine assays.
Serologic testing for anti-GBM antibodies is, by defini-
tion, an urgent laboratory test, and we recommend that
results should be available within 24 hours for patients
presenting with RPGN, particularly when there are contra-
indications to kidney biopsy, because initiating treatment
before developing a need for RRT may have a significant
effect on outcome. It should be noted, however, that
approximately 10% of patients do not have identifiable
circulating antibodies with conventional assays, and so
serologic testing should not be the sole method of diagnosis
when kidney biopsy is available.
Deposited Antibody
Direct immunofluorescence for Ig on frozen kidney
tissue has high sensitivity for detecting deposited anti-
bodies, and is the gold-standard for diagnosis of anti-GBM
disease, typically showing a strong linear ribbon-like
appearance (Figure 2). An important caveat is that fluo-
rescence may be negative or unclear in cases with severe
glomerular inflammation, where the underlying architec-
ture is so disrupted that the linear pattern may not be
recognized. Other causes of linear fluorescence should be
considered (including diabetes, paraproteinemias, lupus
nephritis, and rarely fibrillary GN). Immunoperoxidase
techniques using paraffin-embedded tissue may also be
used, but may be less sensitive. Lung biopsy samples are
not routinely used in the diagnosis of anti-GBM disease,
and, in our experience, immunofluorescence on lung tissue
is rarely informative.
Anti-GBM disease, McAdoo et al. 1165
Figure 2. | Kidney biopsy sample immunofluorescence for IgG re-
vealing linear deposits along the glomerular basement membrane,
and weaker staining of Bowman’s capsule and tubular basement
membranes.
Conventional direct immunofluorescence techniques
will identify all IgG subclasses, although will not differ-
entiate the antigenic target of the kidney-bound antibody.
Noncollagen chain antigens, such as entactin, have been
identified in historical case series, although their signifi-
cance is not well characterized. In addition to detecting
deposited anti-GBM antibody, immunofluorescence may
demonstrate the presence of C components, in particular
C3 and C1q, along the GBM (17). A proportion of patients
may also demonstrate Igs or C deposition along tubular
basement membranes.
Renal Biopsy Findings
Crescent formation is the histopathologic hallmark of
anti-GBM disease (Figure 3). Large biopsy series suggest
that 95% of patients will have evidence of crescent
formation on kidney biopsy, and that in 80% of patients
.50% of glomeruli will be affected. The average proportion
of affected glomeruli is approximately 75% (14,57). The
proportion of crescents observed in the biopsy sample
correlates strongly with the degree of renal impairment at
presentation (17,18). These crescents will typically be of
uniform age (Figure 3F), in contrast to other causes of
RPGN, such as AAV, where a mixture of cellular, fibro-
cellular, and fibrous crescents may be seen. Crescentic
glomeruli are likely to have areas of fibrinoid necrosis in the
underlying glomerular tuft. Noncrescentic glomeruli may
similarly have segmental fibrinoid change (Figure 3A),
although often they may appear completely normal. In
early or mild disease, segmental proliferative change
may be seen, with infiltrating neutrophils or mononu-
clear lymphocytes. In severe disease, rupture of Bowman’s
capsule, peri-glomerular inflammation (Figure 3E), pro-
gressing to granuloma formation with multinucleate giant
cells, may be observed in a proportion. Given the acuity of
disease onset, interstitial fibrosis and tubular atrophy are
uncommon in anti-GBM disease (unless there is preexisting
kidney pathology) although interstitial inflammation may
be observed.
1166 Clinical Journal of the American Society of Nephrology

Figure 3. | Renal histopathology in anti–glomerular basement membrane (anti-GBM) GN. (A–C) Hematoxylin and eosin–stained sections
demonstrating (A) segmental fibrinoid necrotizing lesion in early anti-GBM GN; (B) small, circumscribed cellular crescent; and (C) large,
circumferential cellular crescent. (D–E) Demonstrate the use of Jones methylamine silver stain to delineate glomerular and tubular basement
membranes, clearly identifying a segmental area of extracapillary proliferation (D). (E) Demonstrates obliteration of the glomerular architecture
and rupture of Bowman’s capsule, with extravasation of red blood cells into the urinary space, and significant peri-glomerular inflammation.
(F) Adjacent glomeruli with synchronous cellular crescent formation typical of anti-GBM disease.

Electron microscopy is of limited additional value in the
diagnosis of anti-GBM disease, showing nonspecific fea-
tures of crescentic GN including rupture of the GBM and
extracapillary localization of fibrin and proliferating cells.
Electron-dense deposits are not seen in isolated anti-GBM
disease, although electron microscopy is necessary to ex-
clude concomitant glomerular pathologies, such as mem-
branous GN, and may identify other diseases that may
cause linear fluorescence (such as fibrillary GN and di-
abetic GBM thickening).
Diagnosis of Alveolar Hemorrhage
Diffuse alveolar hemorrhage may be evident clinically,
or identified by radiologic examination. Broncho-alveolar
lavage may identify hemosiderin-laden macrophages, a
characteristic feature of alveolar bleeding, and may also be
useful to exclude other pathologies, such as atypical in-
fection. In addition, pulmonary function testing, in partic-
ular the determination of the alveolar carbon monoxide
transfer factor (KCO) may assist with the differentiation
of alveolar hemorrhage from other causes of pulmonary
infiltration. The utility of both bronchoscopy and func-
tional testing, however, may be limited by the clinical
condition of the critically unwell patient.
Treatment
Standard treatment for anti-GBM disease includes plas-
mapheresis, to rapidly remove pathogenic autoantibody,
along with cyclophosphamide and corticosteroids, to in-
hibit further autoantibody production and to ameliorate
end-organ inflammation. The use of this combination of
therapies was first described in 1976 (58), and they remain
the core recommendation of the latest Kidney Disease
Improving Global Outcomes guideline for treating anti-
GBM GN (59). We have reproduced a recommended
treatment schedule in Table 1 (13).
The inclusion of plasmapheresis is supported by obser-
vational studies that suggest improved renal and patient
survival compared with historical cohorts treated with
immunosuppression alone (18,60). In addition, a large
contemporaneous Chinese study of 221 patients suggested
better outcomes in patients who received plasmapheresis
in addition to cytotoxic and corticosteroid therapy (61). To
date, there has only been one randomized trial in anti-GBM
disease, which compared the addition of plasma exchange
to cyclophosphamide and steroids. Although this study
was small (n517), the groups not ideally matched at
randomization, and its treatment regimens not represen-
tative of current practice, its findings supported the use of
plasma exchange in anti-GBM disease (62). In particular, it
demonstrated a much more rapid fall in circulating anti-
GBM antibodies and improved kidney function in patients
receiving plasmapheresis.
Immunoadsorption is an alternative form of extracor-
poreal therapy that may be more efficient than plasma
exchange for the removal of pathogenic autoantibody
(although conversely it may not remove proinflammatory
or procoagulant factors). In small series, it appears to have
comparable outcomes to plasma exchange therapy (63,64),
and we note that a prospective, open-label study is planned
to study the kinetics of anti-GBM antibody removal using
Clin J Am Soc Nephrol 12: 1162–1172, July, 2017 Anti-GBM disease, McAdoo et al. 1167

Table 1. Initial Treatment of Anti-GBM Disease

Agent Details and Duration Cautions

Plasma exchange Daily 4 L exchange for 5% human Monitor and correct as required: platelet
albumin solution. Add fresh human count, aim .70 3 109/L; fibrinogen,
plasma (300–600 ml) within 3 d of aim .1 g/L (may require
invasive procedure (e.g., kidney biopsy) cryoprecipitate supplementation to
or in patients with alveolar hemorrhage. support PEX); hemoglobin, aim for
Continue for 14 d or until antibody levels .90 g/L; corrected calcium, aim to
are fully suppressed. Monitor antibody keep in normal range
levels regularly after cessation of
treatment because plasma exchange may
require reinstatement if antibody levels
rebound.
Cyclophosphamide 2–3 mg/kg per d given orally for 2–3 mo. Stop if leukocyte count falls to ,4 3 109/
Reduce dose to 2 mg/kg in L and restart at reduced dose when
patients.55 yr. recovered. Insufficient evidence to
recommend use of IV
cyclophosphamide.
Corticosteroids Prednisolone 1 mg/kg per d (maximum 60 There is no evidence to support the use
mg) given orally. Reduce dose weekly to of methylprednisolone, and it may
20 mg by 6 wk, then gradually taper until increase the risk of infection
complete discontinuation at 6–9 mo.
Prophylactic treatments Prophylaxis against oropharyngeal fungal H2 receptor antagonists in those who are
infection (e.g., nystatin, amphotericin, or intolerant of PPI. Cotrimoxazole may
fluconazole) while on high-dose steroids. contribute to leukopenia; monitor
Peptic ulcer prophylaxis (e.g., with PPI) leukocyte count. Alternatives include
while on high-dose steroid treatment. nebulized pentamidine.
Prophylaxis against PCP (e.g.,
cotrimoxazole) while receiving high-
dose corticosteroids and
cyclophosphamide. Consider acyclovir
for CMV prophylaxis. Consider
prophylaxis against HBV reactivation
(e.g., lamivudine) in patients who have
evidence of previous infection (HBV cAb
positive).

Modified from reference 13, with permission. GBM, glomerular basement membrane; PEX, plasma exchange; IV, intravenous; PPI,
proton pump inhibitor; PCP, Pneumocystis jiroveci pneumonia; CMV, cytomegalovirus; HBV, hepatitis B virus; cAb, core antibody.

this technique (NCT02765789), which may be considered an
alternative depending on local availability.
In AAV, the equivalence of daily oral and pulsed intra-
venous cyclophosphamide in induction therapy has been
established in a large randomized controlled trial (65).
Nearly all published experience in anti-GBM GN, however,
has used daily oral dosing, and so we recommend this as
the first-line approach in this disease. Because the risk of
relapse is very low, and approximately only 3 months of
cytotoxic therapy is usually required, concerns about total
cumulative dose of cyclophosphamide are less relevant
than in AAV. In our experience, high-dose intravenous gluco-
corticoids are not required in the treatment of anti-GBM
disease, provided the other components of therapy, in
particular plasma exchange, can be initiated promptly (18).
The use of other immunosuppressive therapies in anti-
GBM disease is less well described. There are several
reports of rituximab use, as either “add-on” to standard
therapy or as a substitute for cyclophosphamide in patients
who are intolerant (66). Similarly, the use of mycophenolate
mofetil and cyclosporine has been reported in individual
cases or small series (67–69). There is insufficient evidence,
at present, to recommend their use in first-line therapy,
although they may be considered in patients who have
contra-indication or intolerance to conventional treatment.
In addition to targeted immunotherapy, patients may
require immediate organ support; in larger series, approx-
imately half of patients require hemodialysis at the point of
initial presentation (18). There are limited data on how
frequently artificial ventilation is required, although one
small series estimated that this occurred in 11% of patients
with lung hemorrhage (70). There are case reports of
successful use of extracorporeal membrane oxygenation in
patients with very severe lung disease (71–73).
Outcome and Prognosis
Long-term follow-up of the largest cohort of patients
(n571) all treated with the combination of plasma ex-
change, cyclophosphamide, and corticosteroids, from the
Hammersmith Hospital, London, United Kingdom, sug-
gests that it is effective in treating lung hemorrhage in
1168 Clinical Journal of the American Society of Nephrology
.90%, and in preserving independent kidney function in
the majority of patients, including those who present
with severe kidney dysfunction (18). In patients presenting
with creatinine values ,500 mmol/L, renal survival was
95% and 94% at 1 and 5 years, respectively. In patients
presenting with creatinine .500 mmol/L, but not requiring
immediate dialysis, renal survival was 82% and 50% at
the same respective time-points. In patients presenting
with an initial requirement for dialysis, however, renal
recovery occurred in only 8% at 1 year. Other reports have
described similarly low levels of renal recovery in patients
presenting with dialysis-dependent kidney failure, with the
highest rate of approximately 20% recovery in one series (66).
Predictors of poor renal outcome include severity of
renal dysfunction at presentation, the proportion of glomer-
uli affected by crescents, and oligoanuria at presenta-
tion (17,18,74). In the Hammersmith series, no patient who
required hemodialysis and had 100% crescents on kidney
biopsy recovered renal function, and so withholding treat-
ment (and its incumbent toxicity) is often considered in these
cases. An isolated case of renal recovery despite these
findings (75), however, highlights the need to consider all
cases for treatment, with specific attention to other features
that might predict renal recovery on biopsy (such as
concomitant acute tubular injury) and the ability of patients
to tolerate each component of therapy. A short trial of early
treatment may be considered, and rapidly tapered if there is
no evidence of renal recovery within 2–4 weeks. In addition,
the potential benefit of a period of immunosuppression to
expedite autoantibody clearance, thus allowing earlier kid-
ney transplantation, should be considered in suitable pa-
tients. We have used rituximab monotherapy, for example,
in patients with ESRD who have an identified live-donor
for transplantation, but remain anti-GBM antibody–positive,
although controlled evidence for this indication is lacking.
A recent retrospective study (an Australia and New
Zealand Dialysis and Transplant Registry [ANZDATA]
study) analyzed the long-term outcomes of 449 patients
with ESRD due to anti-GBM disease, and found that their
survival was comparable to patients with ESRD of other
causes, whether they remained on dialysis or underwent
kidney transplantation (15). Chronic respiratory sequelae
after alveolar hemorrhage are uncommon (70).
Relapse is rare in anti-GBM disease, occurring in ,3% of
patients in the Hammersmith series (18). It is usually as-
sociated with ongoing exposure to pulmonary irritants
such as cigarette smoke and hydrocarbons (76,77), and
avoidance of these precipitants is an essential part of
long-term management of these cases. We recommend
repeat kidney biopsy in cases of relapse with kidney
involvement, in order to secure an accurate diagnosis and
to exclude concomitant pathologies such as AAV and
membranous nephropathy (discussed below). In confirmed
cases, standard retreatment with cytotoxics and corticoste-
roids is usually indicated. In a patient with multiply
relapsing alveolar hemorrhage we have found treatment
with rituximab beneficial.
Kidney Transplantation after Anti-GBM Disease
Kidney transplantation performed in the presence of
anti-GBM antibodies results in a high likelihood of disease
recurrence in the allograft, at frequencies of up to 50%
in historical series (41). Most centers therefore recommend
a period of at least 6 months’ sustained seronegativ-
ity before undertaking transplantation in patients who
have reached ESRD due to anti-GBM disease (59). Under
these circumstances, and with current immunosuppres-
sive regimens, recurrent disease is rare; the ANZDATA
registry study found that 6 of 449 (2.7%) patients de-
veloped biopsy-proven recurrent anti-GBM disease,
which led to graft failure in two cases (15). The frequency
of other causes of graft failure was similar to patients
transplanted for ESRD of other causes, and overall patient
and renal survival in anti-GBM disease was similar to
other groups in this study. These findings were somewhat
in contrast to a previous European study that suggested
patient survival was favorable in patients transplanted for
anti-GBM disease compared with those transplanted for
other primary kidney diseases (although significant dif-
ferences in age at transplantation may account for this
apparent difference in patient survival) (78). The Euro-
pean study also reported a higher frequency of recurrent
disease (14%), although this may reflect differences in
immunosuppressive use during an earlier era, and the
study did not comment on anti-GBM titers and their
relationship to timing of transplantation. In the current
era, isolated case reports of recurrent disease still exist
(79).
Post-Transplant Anti-GBM Disease in Alport
Syndrome
Mutations in any of the genes which encode the a3, a4, or
a5 chains may result in a failure to produce the normal type
IV collagen network present in GBM, and thus lead to
progressive kidney disease in Alport Syndrome. Mutations
in the COL4A5 gene located on the X chromosome are most
common, giving rise to typical X-linked Alport syndrome,
although autosomal recessive and dominant disease are
recognized with COL4A3 and COL4A4 mutations. After
kidney transplantation, these patients may develop anti-
GBM antibodies as an alloimmune response to the neo-
antigens contained in “normal” a3, a4, or a5 chains in the
kidney allograft. In X-linked disease, these antibodies do
not recognize the individual EA and EB epitopes of the a3
chain recognized by sera from Goodpasture patients, but
rather a distinct, composite epitope on the a5 chain, that is
not sequestered within the native hexamer of the Goopas-
ture antigen (36). It should be noted that commercially
available anti-GBM assays, which are optimized to detect
reactivity to the a3(IV)NC1 antigen, may fail to detect
circulating antibodies in this setting. Anti-GBM anti-
bodies may be detected in 5%–10% of Alport patients
after transplantation, although the development of overt
GN in the allograft is less frequent (perhaps owing to the
effects of maintenance immunosuppression). When GN
develops, however, it usually occurs early and carries a high
risk of graft loss (80,81). Repeated transplantation in this
setting almost invariably leads to more aggressive disease
recurrence and rapid graft loss, and is undertaken at very
high risk (82). Individuals with large COL4A5 gene dele-
tions are at increased risk of post-transplant anti-GBM
disease, and recent guidelines encourage the use of genetic
Clin J Am Soc Nephrol 12: 1162–1172, July, 2017
testing to inform discussions regarding the risk of de novo
anti-GBM disease after transplantation (83).
Other Variant Forms of Anti-GBM Disease
Double-Positive Anti-GBM and ANCA-Associated GN
The concurrence of ANCA and anti-GBM antibodies is
recognized to occur at much higher frequency than ex-
pected by chance alone. In some series, almost half of
patients with anti-GBM disease have detectable ANCA
(usually recognizing myeloperoxidase [MPO]), and up to
10% of patients with ANCA also have circulating anti-GBM
antibodies (84–86). The mechanism of this association is
unclear, although it has been shown that ANCA may be
detected before the onset of anti-GBM disease, suggesting
that ANCA-induced glomerular inflammation may be a
trigger for the development of an anti-GBM response,
perhaps by modifying or exposing usually sequestered
disease epitopes in GBM (50). Conversely, a recent study
found that up to 60% of anti-GBM cases also had anti-
bodies directed against linear epitopes of MPO, versus 24%
recognizing intact MPO. The authors hypothesize that
MPO-ANCA recognizing linear and conformational epi-
topes may arise sequentially, via a process of inter- and
intramolecular epitope spreading (87). We recently ana-
lyzed the outcomes of a large cohort of these “double-
positive” patients from four centers in Europe, and found
that they experience the early morbidity and mortality of
anti-GBM disease, with severe kidney and lung disease at
presentation, requiring aggressive immunosuppres-
sive therapy and plasma exchange (88). During long-term
follow-up, they relapsed at a frequency comparable to a
parallel cohort of patients with AAV, suggesting they
warrant more careful long-term follow-up and maintenance
immunosuppression, unlike patients with single-positive
anti-GBM disease.
Anti-GBM Disease Associated with Membranous
Nephropathy
There are several reports of anti-GBM disease associated
with membranous nephropathy, occurring as a preceding,
simultaneous, or succeeding diagnosis (89,90). As with
the ANCA association, it is postulated that disruption of
glomerular architecture by one disease reveals hidden
epitopes that allow the second process to occur. A rapid
decline in kidney function in a patient with known
membranous nephropathy should raise suspicion of the
development of superimposed crescentic nephritis or anti-
GBM disease, and rebiopsy is recommended. We suggest
that these cases are treated initially as for anti-GBM disease,
although how they should be managed in the long-term is
not clear. The authors of a recent case report suggest that
rituximab may be a useful agent to treat both pathologies
simultaneously (91).
“Atypical” Anti-GBM Disease
Unusual presentations of anti-GBM disease have been
recognized for as long as the disease itself. Wilson and
Dixon’s original 1973 report, for example, included the
case of a male 14-year-old who had the incidental finding
of linear IgG deposition on a kidney biopsy sample taken
Anti-GBM disease, McAdoo et al. 1169
during splenectomy for hypersplenism and a diag-
nostic workup for optic vasculitis, who was treated with
steroids only, and who had normal renal function after
1 year follow-up (7). There have been a number of series of
“atypical” cases published in recent years, often with less
severe renal involvement than is seen in the classic pre-
sentation of anti-GBM disease, although it not always clear
whether these represent distinct clinical subphenotypes or
heterogenous cases on a spectrum of disease severity (92–95).
The largest of these series, reported by Nasr and
colleagues, described 20 patients with mild and indolently
progressive renal impairment, who had linear Ig deposi-
tion on kidney biopsy, but without predominant features of
crescentic GN, and without overt lung hemorrhage (95).
Circulating anti-GBM antibodies were not detected using
conventional assays, and both patient and renal prognosis
were good, with 90% and 85% survival at 1 year, re-
spectively. They estimated that these atypical cases ac-
counted for approximately 10% of anti-GBM cases at their
center. Notably, half of the cases had light-chain restric-
tion on immunofluorescence, although the authors suggest
that the pathologic features were not in keeping with
proliferative GN with monoclonal Ig deposition. They
suggest that differences in the antigen specificity, Ig sub-
class, and/or the ability to fix C and recruit inflammatory
cells, of these atyptical compared with “classic” anti-GBM an-
tibodies, account for the less severe disease phenotype seen.
Another small but well characterized series with a
distinct clinical phenotype was recently described in
Sweden; it included four young females, who had severe
lung disease and minimal kidney involvement, who were
found to have IgG4 subclass anti-GBM antibodies that were
not detectable with conventional anti-GBM assays (56). That
two of these patients demonstrated higher signal in the anti-
GBM ELISA when using a nondenaturing buffer suggests
that differences in epitope specificity might also account for
the negative testing seen with the routine assays, and
supports the hypothesis that differences in clinical pre-
sentation might be related to differences in the subclass or
target of the anti-GBM antibody.
Future Directions
Despite being one of the better characterized autoim-
mune diseases, unanswered questions remain regarding
the pathogenesis of anti-GBM disease, which may have
important clinical implications. These include the need to
further characterize the variant forms of disease, and how
differences in antibody subclass or specificity might influ-
ence presentation, the appropriate use of treatment, and
outcomes. Better understanding of T cell functions, and in
particular the role of regulatory cells that may suppress
disease, may have therapeutic significance, both in anti-
GBM disease and other autoimmune conditions. The
induction of immunologic tolerance using mucosal admin-
istration of GBM antigen has been described in experimental
models (96), which may likewise have therapeutic potential.
Finally, the inciting events that cause autoimmunity to GBM
antigens remain unclear. Idiotype–anti-idiotype interactions
have been invoked in a recent study (97), and the role of
infectious triggers that might operate via a similar mechanism
in clinical disease induction could be explored further.
1170 Clinical Journal of the American Society of Nephrology
As a rare disorder requiring immediate treatment, co-
ordinating large, prospective studies in anti-GBM disease is
challenging. In addition, the efficacy of current treatment
regimens, when started early enough, is widely accepted.
Future therapeutic studies, therefore, should perhaps focus on
identifying “add-on” treatments that might improve outcomes
in severe disease. We have recently shown that treatment with
fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, effec-
tively reverses crescent formation in rodent models of anti-
GBM disease (98,99) (and that intraglomerular SYK can be
detected in patient kidney biopsy samples [100]), so it would
be of interest to explore the use of this agent in advanced
clinical disease. Another interesting agent that has shown
efficacy in experimental models is IdeS (IgG-degrading en-
zyme of Streptococcus pyogenes), an enzyme that is able to
cleave both circulating and membrane-bound Ig (101). IdeS
was safe and tolerable in early-phase human studies, and a
clinical study in severe anti-GBM disease, where it may
promote rapid clearance of pathogenic IgG, has been proposed
(EudraCT number: 2016–004082–39). Finally, large multicenter
studies might aim to identify clinical and histopatho-
logic indicators that reliably predict failure to respond to
treatment, so that the toxicities associated with intensive
immunosuppression may be avoided in futile cases.
As an archetypal autoimmune disorder, such studies of
anti-GBM disease and its experimental correlates are likely
to provide fresh insights into the mechanisms of renal
autoimmunity. However, it is the alarming clinical pre-
sentation, and the need for emergency treatment, often in
critically unwell patients, that underscores the need for
clinicians to be mindful of this rare condition, the pitfalls
associated with its diagnosis, particularly in atypical and
variant presentations, and the early and appropriate use of
immunosuppressive and extracorporeal therapies, in order
to prevent morbidity and to improve survival.
Acknowledgments
We acknowledge support from the National Institute for Health
Research Imperial Biomedical Research Centre.
Disclosures
None.
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cjasn.org.
 Viral-Associated GN: Hepatitis C and HIV
Warren L. Kupin

Abstract
Viruses are capable of inducing a wide spectrum of glomerular disorders that can be categorized on the basis of the
duration of active viremia: acute, subacute, or chronic. The variable responses of the adaptive immune system to
each time period of viral infection results mechanistically in different histologic forms of glomerular injury. The
unique presence of a chronic viremic carrier state with either hepatitis C (HCV) or HIV has led to the opportunity
Division of
to study in detail various pathogenic mechanisms of viral-induced glomerular injury, including direct viral Nephrology, Miami
infection of renal tissue and the development of circulating immune complexes composed of viral antigens that Transplant Institute,
deposit along the glomerular basement membrane. Epidemiologic data show that approximately 25%–30% of all University of Miami
HIV patients are coinfected with HCV and 5%–10% of all HCV patients are coinfected with HIV. This situation Miller School of
Medicine, Miami,
can often lead to a challenging differential diagnosis when glomerular disease occurs in this dual-infected pop-
Florida
ulation and requires the clinician to be familiar with the clinical presentation, laboratory workup, and patho-
physiology behind the development of renal disease for both HCV and HIV. Both of these viruses can be Correspondence:
categorized under the new classification of infection-associated GN as opposed to being listed as causes of Dr. Warren Kupin,
postinfectious GN as has previously been applied to them. Neither of these viruses lead to renal injury after a latent University of Miami,
period of controlled and inactive viremia. The geneses of HCV- and HIV-associated glomerular diseases share a Miami Transplant
Institute, 1801 NW
total dependence on the presence of active viral replication to sustain renal injury so the renal disease cannot be
9th Ave, #568, Miami,
listed under “postinfectious” GN. With the new availability of direct-acting antivirals for HCV and more effective FL 33136. Email:
combined antiretroviral therapy for HIV, successful remission and even regression of glomerular lesions can be wkupin@med.miami.
achieved if initiated at an early stage. edu
Clin J Am Soc Nephrol 12: 1337–1342, 2017. doi: https://doi.org/10.2215/CJN.04320416

Introduction concomitant with the host immune clearance of viremia

Since their initial discovery in 1898, viruses have
challenged their human hosts with a greater degree of
foreign genomic diversity than any other infectious
organisms (1). Over 5000 DNA and RNA viruses
have been structurally defined, and either by their
own direct intracellular virulence or through the
stimulation of natural host adaptive immune defense
mechanisms they often lead to significant tubule-
interstitial and glomerular injury (2).
One proposed schema that can be used to classify
viral-induced GN can be on the basis of the duration
of active viremia. Patients with recent self-limited
acute viremia (days to weeks) develop significantly
different forms of glomerular pathology as compared
with patients with subacute viremia (weeks to months)
and those with chronic persistent viremia (years). An
outline of the most well documented viruses that fit into
each of these categories and their individual glomerular
lesions that have been described in the literature is
shown in Table 1.
In order to link a viral illness with a specific form of
GN, certain supporting criteria must be met: (1) dem-
onstration of the presence of active quantifiable vire-
mia primarily through serologic PCR testing, (2) the
identification of viral proteins/nucleic acid residues
within renal tissue and/or within immune complexes
deposited in the glomerular basement membrane, and
(3) resolution/regression of the glomerular lesion
or eradication of viremia through antiviral therapy.
However, recent emerging data has proposed a new
relationship of GN associated with occult viral disease
which is defined as the presence of viral nucleic acid
in renal tissue and in peripheral blood mononuclear
cells but with complete absence of detectable systemic
viremia by standard PCR amplification techniques
(3). Occult hepatitis C (HCV) has been detected in
30%–50% of patients with idiopathic membranous
nephropathy, IgA, FSGS, ANCA positive vasculitis,
and membranoproliferative GN (MPGN) (4). Simi-
larly, occult hepatitis B (HBV) infection has been de-
scribed with documented HBV antigens found in
renal tissue but with absent viremia in selected cases
of idiopathic membranous nephropathy and IgA (5).
In many of the cases, viremia could only be identified
by intensive ultracentrifugation of plasma. Possibly
fulfilling the cause and effect nature of this finding,
there is anecdotal evidence that antiviral therapy in
select cases of occult HCV or HBV has led to resolu-
tion of the previously diagnosed “idiopathic” glomer-
ular disease (6). Future research is needed to define
the role of occult viremia from undetectable intracel-
lular reservoirs with clinical renal disease.
This review will detail the pathophysiology, histo-
pathology, and clinical syndromes associated with
clinically active viral diseases, which will be pre-
sented in two separate parts. This issue (part 1)

www.cjasn.org Vol 12 August, 2017 Copyright © 2017 by the American Society of Nephrology 1337
1338 Clinical Journal of the American Society of Nephrology

deposition. The classic pathologic hallmark of HCV renal

Table 1. Viruses associated with GN disease is type 1 MPGN as a consequence of type 2 mixed
cryoglobulinemia (MC), although the same renal lesion
Predominant
Virus Type may also develop from noncryoglobulinemic immune
Glomerular Histology
complexes (9). In addition, HCV is also an important cause
Acute of polyarteritis nodosa (PAN) from immune complex de-
Dengue ICGN, MsPGN position in medium size blood vessels leading to renal
Hantavirus HFRS-MsPGN ischemia and infarction similar to HBV PAN and idio-
Varicella-zoster DPGN pathic PAN (10). Other forms of glomerular immune com-
Parvovirus ICGN, PAN, MPA, TMA, IgA plex deposition have been described in HCV patients,
HAV ICGN, MsPGN including mesangial proliferative and focal proliferative
HBV DPGN
GN and IgA nephropathy (Figure 1).
CMV cFSGS, MN, IgA, HSP, ICGN,
MPGN, TMA It is important to note that renal dysfunction in a patient
EBV ICGN, MN, MsPGN with HCV is rarely a result of GN (,10%) and hospital ad-
Coxsackie B RPGN missions for MPGN from HCV have been decreasing for
Subacute the past decade (11). The majority of renal diseases in
Parvovirus cFSGS HCV patients with liver disease are a consequence of
EBV cFSGS, MN acute tubular necrosis, hepatorenal syndrome, prerenal
HBV PAN azotemia, and CKD and therefore it is essential to be fa-
HCV PAN miliar with the typical presentation and characteristics of
Chronic acute GN in HCV patients and how to differentiate them
HBV MN, Type I MPGN, MPGN1MC,
from the more common diagnoses causing AKI in this
PAN, IgA, FSGS
HIV HIVAN, HIVICK, TMA population.
HCV Type I MPGN1MC, Type I
MPGN, PAN, IgA, MN
HEV MN Type 1 MPGN with MC
HCV provides a unique opportunity to study the effects
ICGN, immune complex glomerulonephritis; MsPGN, me-
of a hepatotropic virus that also has unique lymphotropic
sangial proliferative GN; HFRS, hemorrhagic fever and renal potential (12). In the absence of this lymphotropism, HCV
syndrome; DPGN, diffuse proliferative GN; PAN, polyarteritis would be indistinguishable from a pathogenic standpoint
nodosa; MPA, microscopic polyarteritis; TMA, thrombotic mi- from HBV and HIV in the development of typical IgG–
croangiopathy; HAV, hepatitis A virus; HBV, hepatitis B virus; viral particle immune complexes of varying size and vir-
CMV, cytomegalovirus; cFSGS, collapsing FSGS; MN, mem- ulence. In approximately 20% of type 1 MPGN cases
branous glomerulopathy; HSP, Henoch Shoenlein purpura; caused by HCV, this standard sequence results in the pro-
MPGN, membranoproliferative GN; EBV, Epstein-Barr virus; duction of noncryoglobulin immune complexes (13). How-
RPGN, rapidly progressive glomerulonephritis; HCV, hepatitis ever, in the majority of type 1 MPGN lesions, HCV is
C virus; MC, mixed cryoglobulinemia; HIVAN, HIV-associated
capable of specifically binding to CD51 CD811 B cells
nephropathy; HIVICK, HIV immune complex disease of the
kidney; HEV, hepatitis E virus.
which subsequently leads to polyclonal type 3 and even-
tually monoclonal type 2 cryoglobulin synthesis of IgMk.
This IgMk monoclonal antibody is a unique effect of HCV-
driven B cell clonal proliferation and carries rheumatoid
will focus on the glomerular syndromes associated with
long-term chronic HCV and HIV carrier states. In the
second issue (part 2) the focus will concentrate on the
glomerular diseases seen with chronic HBV infection and it
will also cover glomerular diseases seen with a variety of
acute and subacute viral infections including cytomegalo-
virus, parvovirus, Epstein–Barr, hantavirus, and dengue.

HCV
With the current availability of direct-acting antivirals
(DAA) which can achieve a viral remission of .95% for most
HCV genotypes, the prevalence of glomerular disease in this
population should progressively decline in the coming de-
cade (7). Chronic HCV viremia is present in 150–170 million
people worldwide (3% of the global population) and in 3.2
million people in the United States. Approximately 2–3 mil-
lion new cases of HCV occur each year with 75%–90% of
these patients becoming chronic carriers (8). Figure 1. | Glomerular disease in patients with chronic HCV infection.
Similar to HBV, HCV-associated glomerular disease is Ag, antigen; HCV, hepatitis C virus; MC, mixed cryoglobulinemia; MN,
primarily a consequence of viral antigen – immune com- membranous glomerulopathy; MPGN, membranoproliferative GN;
plex formation with glomerular basement membrane PAN, polyarteritis nodosa.
Clin J Am Soc Nephrol 12: 1337–1342, August, 2017
factor activity. Additional receptors that mediate HCV
B cell stimulation involve the scavenger receptor SR-B3 and
toll receptor TRL4 (14).
The entire cryoglobulin complex consists of monoclonal
IgMk binding to the Fc portion of non-neutralizing HCV-
specific IgG1 and IgG3 that have ineffectively bound the
structural E2 or nonstructural NS3 proteins of HCV or the
actual HCV RNA itself. It is not surprising, given the sheer
size of this complex, that it lodges along the subendothelial
space creating large crystalline intraluminal thrombi com-
pletely distinct from a typical subendothelial immune com-
plex as in SLE. Cryoglobulinemia is unusual (,5%) in all
other forms of viral hepatitis (HBV, hepatitis A virus), HIV
carriers, cytomegalovirus, parvovirus B19, and Epstein-
Barr virus which reinforces the unique role of the HCV/B
cell interaction (15).
The development of MC and type 1 MPGN requires a
considerable duration of viremia and a select host response.
After a minimum of 5–10 years, 35%–50% of HCV carriers,
regardless of HCV genotype, develop type 3 MC which
carries a minimal risk of GN. After 10–15 years of viremia
approximately 10% of patients within this subgroup tran-
sition and develop type 2 MC and systemic small vessel
vasculitis (16). These patients demonstrate the characteris-
tic skin rash (palpable purpura), polyneuropathy, gastro-
intestinal/pulmonary/cardiac/central nervous system
vasculitis, and in 30% of patients a type 1 MPGN.
From a nephrologic standpoint, these patients may present
with hypertension and the nephritic syndrome but impor-
tantly 20% of type 1 MPGN patients present only with the
nephrotic syndrome, making a renal biopsy essential for
diagnosis.
The mechanisms behind the transition from type 3 to
type 2 MC in a small fraction of HCV patients are not well
defined. Host factors may play an important role with
.65% of HCV-positive patients worldwide being men but
there is a reversed female predominance in patients that
develop type 2 MC. The response by sex to chronic anti-
genemia is different, with women showing a TH2 response
and a greater likelihood of autoimmunity compared with
a more typical TH1 response in men. In HCV patients,
autoantibody production is especially prevalent with
66% showing anti-smooth muscle antibodies and 40%
with a positive anti-nuclear antibody. Between 40% and
75% of HCV patients have some form of extrahepatic au-
toimmune complication (17).
Hypocomplementemia of the classic pathway is a
distinguishing feature of type 2 MC with type 1 MPGN
with C4 being low in 93% of patients, whereas C3 is
depressed in only 53% due to both its role as an acute
phase reactant and the possible activation of the alternate
C pathway in some patients. At this stage of their HCV
cycle, most patients will have serologic evidence of
chronic active hepatitis with ,15% showing advanced
cirrhosis.
Left untreated, type 2 MC from HCV is a precursor sign
for the emergence of B cell lymphoma in 6% of patients and
an additional risk factor for cardiovascular death from
coronary vasculitis (18). Therefore, treatment of type 2 MC
and renal disease in HCV patients has a two-fold purpose:
reduce the risk of malignancy and decrease patient cardio-
vascular mortality.
Viral-Associated GN: Hepatitis C and HIV, Kupin 1339
Treatment
Ongoing HCV viremia is at the epicenter for the gener-
ation of nephritogenic immune complexes. The develop-
ment of DAAs against HCV has provided a revolutionary
opportunity for long-term successful eradication of HCV
and elimination of cryoglobulinemia (19). These oral agents
have virtually replaced the need for IFN. HCV carries an
innate ability to suppress natural IFNg production in the
host with a concomitant decrease in Treg cells that allow
for persistence of viremia and the development of autoim-
mune sequela. Exogenous IFN used to be the backbone of
therapy but was hampered by the need for prolonged ther-
apy (48 weeks), poor patient tolerance, and an unsatisfac-
tory sustained viral response (,65% on the basis of
genotype). More limiting was the inability to use IFN in
solid organ transplant recipients due to the risk of humoral
rejection (20).
DAAs target three groups of nonstructural proteins
called NS5A, NS5B, and NS3/4A. A variety of drugs in this
class have been developed that are used in combination
over a 12-week period without IFN and result in sustained
viral remissions of .95% for all genotypes. In the setting of
acute cryoglobulinemic vasculitis and GN, DAAs have re-
sulted in clinical remission and disappearance of cryogo-
bulinemia (21). Often, control of viremia alone will not
suffice due to the relative delay in viral clearance over
4–8 weeks, and in some circumstances plasmapheresis, ste-
roids, and rituximab are still needed to control the acute
inflammatory vasculitic symptoms. DAAs are now the rec-
ommended drugs of choice in an IFN-free regimen for pa-
tients with HCV-related MPGN or PAN.
HIV
The HIV pandemic has continued, with 37 million active
carriers in the world (1.1 million in the United States),
2 million newly infected cases per year, and another
15%–20% of patients still unaware of their HIV diagnosis.
The HIV population is significantly less than the 240 mil-
lion carriers of HBV and the 170 million carriers of HCV.
On the basis of the 2013 World Health Organization treat-
ment guidelines only 35%–40% of eligible patients globally
are receiving combined antiretroviral therapy (cART),
indicating that the majority of HIV patients are actively
viremic (22).
The differential diagnosis of glomerular disease in the
setting of HIV infection will be significantly influenced by
(1) the treatment status of the patient: cART-naïve or ac-
tively on cART, and (2) by their coinfection status with
other viruses such as with HBV (5%–10%) or with HCV
(25%–30%). As with all of the viral diseases previously
discussed the prerequisite need for ongoing active viremia
is essential for the development of the classic HIV-related
glomerular syndromes: HIV-associated nephropathy (HIVAN)
and HIV immune complex disease of the kidney (HIVICK)
(Figure 2).
HIVAN
HIVAN represents a unique manifestation of glomerular
injury that arises from direct viral infection of renal tis-
sue, particularly the visceral and parietal epithelial cells,
1340 Clinical Journal of the American Society of Nephrology
Figure 2. | Glomerular disease associated with chronic HIV in-
fection. Ag, antigen; DPGN, diffuse proliferative GN; HIVAN, HIV-
associated nephropathy; HIVICK, HIV immune complex disease of
the kidney; MC, mixed cryoglobulinemia; MN, membranous glo-
merulopathy; MPGN, membranoproliferative GN.
without the presence of immune complexes. HIVAN
comprises a constellation of four individual pathologic
findings in the renal biopsy that may not all be present
simultaneously: collapsing FSGS (cFSGS), microcystic di-
lation of the tubules, interstitial nephritis, and the presence
of intracytoplasmic tubulo-reticular inclusions (“TRI-IFN
footprints”). By definition, the only specific requirement
to fulfill the diagnosis of HIVAN is the presence of cFSGS
in the setting of HIV infection with the remaining lesions
found in variable frequencies (23).
HIVAN develops almost exclusively in patients of black
race origin who are homozygous or heterozygous for
APOL1 G1 or G2 variants. The lifetime risk of HIVAN in an
untreated HIV-infected black patient is 2%–10%, however,
this risk increases to 50% if that person is homozygous for
the APOL1 variants. APOLI variants, initially an evolution-
ary advantage for protection against trypanosomiasis in
Africa, now represent the single most important risk factor
for the development of HIVAN worldwide (24).
The histopathologic lesions of HIVAN in a susceptible
host require translation of the nine-gene HIV genome
which then leads to altered phenotype changes in the
podocytes with loss of maturation markers (synaptopodin.
podocalyxin) and upregulation of proliferation markers
(Ki-67). The main HIV genes responsible for these changes
are TAT (transactivator of transcription), NEF (negative fac-
tor), and Vpr (viral protein r) (25).
The one major question as yet unanswered is the method
for direct HIV entry into the podocytes, mesangium, and
tubular cells because they lack CD4 receptors and chemokine
receptors used by HIV for entry into nonrenal tissue. The use
of lipid rafts for freely circulating Tat and Vpr proteins or
binding of the whole HIV virion to DEC-205 (dendritic cell
receptor) or dendritic cell specific ICAM-3-grabbing non-
integrin may allow for direct tissue infection (26).
Although nephrotic range proteinuria is the expected
consequence of cFSGS in HIVAN, early collapsing lesions can
be seen in untreated HIV patients with only microalbumin-
uria (27). Therefore, HIVAN needs to be considered in any
cART-naïve HIV patient of black race ancestry with any de-
gree of abnormal albuminuria or proteinuria.
Because HIVAN is a direct consequence of viral repli-
cation, cART has been demonstrated to attenuate the rate
of decline of GFR and actually cause histologic regression
with a return of the normal podocyte phenotype within the
glomerular lesions (28). This favorable response is predi-
cated on achieving viral remission. Deterioration of renal
function in a patient successfully treated for HIVAN on
cART may be a reflection of the intrinsic nephrotoxicity
of either the protease inhibitors or the non-nucleotide(s)
reverse transcription inhibitors rather than due to HIV ne-
phropathy (29). Alternatively, a condition entitled immune
reconstitution syndrome with AKI from acute interstitial
nephritis or immune complex GN may occur shortly after
starting cART. Finally, because coinfection with HBV or
HCV is common, renal impairment after cART may also
reflect the glomerular injury from these ongoing untreated
and possibly unrecognized viral infections.
New emerging therapy for HIVAN includes renin-
angiotensin-aldosterone system inhibition, interruption
of the mTOR pathway, and retinoic acid derivatives
(30,31). Upregulation of angiotensin 2 with possible co-
stimulation of the mTOR pathway and involving the AT2
receptor lends support for the benefit of direct blockade of
these pathways. Experimentally, HIVAN lesions fail to de-
velop with the use of renin-angiotensin-aldosterone system
and mTOR inhibitors. The application of retinoids in HI-
VAN and other glomerular diseases is currently being in-
vestigated. HIV downregulates the retinoic acid receptor
supporting a potential clinical role for this therapy as an
adjunct to cART.
HIVICK
HIVICK represents a constellation of histopathologic dis-
eases rather than a specific glomerular syndrome of its own
such as HIVAN. This is why it is impossible to describe an
actual typical presentation or outcome for HIVICK because
it represents a pathophysiologic grouping of a wide variety
of glomerular diseases each with a different presentation and
prognosis. All glomerular diseases comprising HIVICK result
from the deposition of immune complexes in the glomerulus,
consisting of either HIV antigens or as a natural result of typi-
cal postinfectious immune complexes that occur due to the
increased risk of infections from a compromised immune
system found in HIV patients not on cART (32). Like HIVAN,
HIVICK is a complication of active HIV viremia in a cART-
naïve patient or a patient with cART resistance. Glomerular
lesions from coinfected HIV patients with HBV or HCV are
not considered HIVICK and are classified separately as second-
ary lesions due to their individual viruses.
Approximately 50% of glomerular histology within the
HIVICK category can be described as postinfectious GN,
with the remaining half resulting from immune complex
deposition consisting of HIV antigens in the form of
membranous, IgA, MPGN, and a “lupus-like” diffuse pro-
liferative GN (33). Some studies have excluded patients
with IgA from having HIVICK assuming it may be an id-
iopathic lesion, however, the colocalization of the HIVp24
and gp120 antigens with IgA in the presence of active HIV
disease and typical IgA histology on biopsy clearly
Clin J Am Soc Nephrol 12: 1337–1342, August, 2017
suggests that IgA can be and likely should be considered a
manifestation of HIVICK (34).
Each of these lesions has their own distinct prognosis, with
membranous and the “lupus- like” proliferative lesions pro-
gressing the fastest toward ESRD. In general, HIVICK prog-
resses at a slower pace toward ESRD than untreated HIVAN,
with 70% of HIVAN patients requiring dialysis within 2 years
of diagnosis compared with only 34% of HIVICK patients (35).
The majority of studies do not show a major effect of
cART on the progression of HIVICK. cART has been able to
induce histologic regression in HIVAN but this has only
been infrequently seen in HIVICK. This is likely due to the
permanent destructive injury to the glomerular basement
membrane from immune complex deposition in HIVICK
compared with the reversible intracellular phenotypic
changes of the podocyte characteristic of HIVAN.
The heterogeneous nature of HIVICK and the limited
number of published studies on outcomes makes it difficult
to make a recommendation on the benefit of cART. Because
50% of the lesions are postinfectious these would not be
expected to improve with cART, whereas the remaining
immune complex glomerular diseases should theoretically
show benefit depending on their degree of chronicity.
Idiopathic FSGS
The demographics of glomerular disease in HIV patients
have been changing on the basis of the specific demo-
graphics of the population being reported (36). Currently,
in Western Europe and in the United States, noncollapsing
FSGS is emerging as the most common glomerular lesion
seen. These results are self-fulfilling if the population is
predominantly cART-treated. Because APOL1 polymor-
phisms, which are restricted to black race origin, are vi-
tally important for the development of HIVAN, any study
dealing with European or largely white HIV patients will
clearly never show a significant percentage of HIVAN or
FSGS lesions and may show more HIVICK (37).
Summary
The pathogenic mechanisms of glomerular disease in HCV
and HIV patients exemplify the wide spectrum of immuno-
logic and microbiologic pathways utilized by viruses in
general to cause renal disease. Conclusive evidence exists both
for HIV and HCV for direct viral infection of renal tissue as
well as the development of immune complexes partially
consisting of viral antigens. These same principles can be
applied to other viral infections that will be discussed in part 2.
Although corticosteroids have been used in selected
patients with HIVAN and lymphocytotoxic immunosup-
pression has been advocated for patients with HCV-associated
cryoglobulinemia, invariably the ultimate control of active
viremia remains the key objective in the management of
both HIV- and HCV-associated GN.
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Viral-Associated GN
Hepatitis B and Other Viral Infections

Warren L. Kupin

Abstract
By definition, viral-associated GN indicates the direct pathogenic relationship between active viral replication and
the development of acute GN. This definition is in sharp contrast to the semantic label and pathophysiologic Division of
foundation behind postinfectious GN that uniquely develops only during a period of resolved and absent active Nephrology, Miami
infection. The primary example of postinfectious GN are the glomerular lesions described after a pharyngeal or Transplant Institute,
University of Miami
cutaneous streptococcal infection and do not represent the clinical or immunologic pattern seen with viral- Miller School of
associated GN. Hepatitis B (HBV) is the most common chronic viral infection in the world affecting >400 million Medicine, Miami,
people which is more than double the prevalence of chronic HIV and hepatitis C carriers combined. In addition, Florida
10%–20% of HBV patients may be coinfected with hepatitis C and 5%–10% will have coinfection with HIV. Being
able to distinguish the different types of GN seen with each viral infection is essential for the practicing clinician as Correspondence:
each virus requires its own specific antiviral therapy. HBV-induced immune complex disease with renal injury lies Dr. Warren Kupin,
University of Miami,
on one end of the spectrum of disorders that occurs after a prolonged chronic carrier state. On the opposite end of Miami Transplant
the spectrum are renal diseases that develop from acute or subacute viral infections. One important glomerular Institute, 1801 NW 9th
lesion in this category is the association of collapsing FSGS with acute active cytomegalovirus, Epstein–Barr virus, Ave, #568, Miami, FL
and parvovirus B19 infection. The data supporting or disproving this relationship for each of these viruses will be 33136. Email:
wkupin@med.miami.
discussed. A second renal manifestation of acute viral infections often occurs with many different sporadic or
edu
epidemic infections such as dengue and hantavirus and can lead to a transient proliferative GN that resolves upon
viral clearance. The complex interplay of HBV and all viruses with the immune system provides conceptual lessons
on the pathophysiology of immune complex GN that can be applied to all infection-related renal disease and plays
an integral role in developing an approach to therapeutic intervention.
Clin J Am Soc Nephrol 12: 1529–1533, 2017. doi: https://doi.org/10.2215/CJN.09180816

Introduction A new proposal for classification of the category,

This issue represents part 2 of the series on viral-
associated GN. Part 1 covered the pathophysiology,
histopathology, and clinical manifestations of the
unique glomerular syndromes seen in those patients
with actively replicating chronic hepatitis C (HCV) and
HIV infection. In this issue, the focus is on both the
glomerular manifestations seen in conjunction with a
chronic hepatitis B (HBV) carrier state as well as the
individual types of glomerular lesions seen with a
variety of acute and subacute viral infections including
cytomegalovirus (CMV), parvovirus, Epstein–Barr virus
(EBV), hantavirus, and dengue.
Many reviews have listed virus-associated GN syn-
dromes as a subset of the category called postinfec-
tious GN (PIGN) (1,2). This classification is not
mechanistically accurate because PIGN is associated
with the characteristic sequence of a latent time
period from a completely resolved infection followed
by an acute immune complex–mediated GN. This is
in distinct contrast to viral-associated GN which
occurs exclusively in the setting of an active replicat-
ing viral infection and resolves with eradication of the
viremic state. In this scenario, there is no onset of
renal disease that follows a latent period of absent or
resolved infection.
infection-related GN, centers on eliminating the term
PIGN because the only proven infection that causes
the clinical pattern of active infection – resolved
infection – latent period– acute GN is streptococcal
disease. Therefore, the term poststreptococcal GN
(PSGN) should replace the use of the general term
PIGN because no other infections fit into that category.
All other infection-related glomerular diseases are
considered separate and distinct from PSGN and the
term “associated” is used to delineate the coexistent
dependent relationship between active replicating
infection and renal disease whether the infection is
bacterial, fungal, protozoal, or viral (3,4).
Virus-associated GN syndromes do not share a final
common pathway of renal injury but do share the theme
of an acute, subacute, or chronically active viral infection
as the core foundation for their nephrotoxicity. By using
this new classification on the basis of pathophysiology it
is clear why antibiotic therapy is ineffective for PSGN
and the key therapy for infection/viral-associated GN.
HBV
A true global pandemic, chronic HBV antigenemia,
defined as persistent circulating hepatitis B surface

www.cjasn.org Vol 12 September, 2017 Copyright © 2017 by the American Society of Nephrology 1529
1530 Clinical Journal of the American Society of Nephrology
antigen (HBsAg), is present in 240 million people world-
wide, representing 5%–6% of the world population. Approx-
imately 2 million people in the United States are chronic HBV
carriers with 20,000–40,000 new cases of HBV exposure
occurring yearly (5).
Overall, renal disease may occur in 3%–5% of patients
with chronic HBV infection (6). The histologic manifesta-
tions of HBV-associated renal disease can be classified as
those that occur as a result of either (1) immune-complex
GN (membranous [membranoproliferative GN (MPGN)]
and IgA nephropathy) or (2) immune complex–related
vasculitis (polyarteritis nodosa [PAN]) (Figure 1). It is
important to note that many patients with chronic HBV
may also harbor coexistent HIV (5%–10%) and HCV (10%–
30%) that may dictate the glomerular pathology expressed
and further broaden the clinical differential diagnosis (7).
Checking for these other latent viruses in all HBV carriers is
essential during the evaluation process.
Membranous Nephropathy
The histologic appearance of HBV membranous ne-
phropathy (MN) is indistinguishable from idiopathic MN
with clearly defined subepithelial immune complex de-
posits on electron microscopy. The antigen within the
immune deposits in HBV-related MN may arise from three
potential viral particles: HBsAg, HBcAg, or the HBeAg (8).
In addition, from a mechanistic standpoint, the deposits
may form from either deposition of an IgG immune
complex with one or more of the stated antigens or with
the de novo formation of an immune complex after de-
position of the circulating antigen in the basement mem-
brane first followed afterward by deposition of the
circulating antibody. The size and charge of the antigens
are an important determinant of their pathogenicity and
ability to traverse across the glomerular basement mem-
brane. The HBeAg is the smallest of the three antigens at 17
kD, with HBsAg measuring 35–50 kD and HBcAg at 22 kD.
Approximately 90% of patients with chronic HBV and
biopsy-proven MN have detectable HBeAg isolated from
the glomerulus and .95% of these patients have measur-
able circulating HBeAg. IgG-HBeAg complexes tend to be
cationic enhancing their deposition in the subepithelial
Figure 1. | Glomerular syndromes associated with an HBV carrier
state. MC, mixed cryoglobulinemia; MN,membranousglomerulopathy;
MPGN, membranoproliferative GN; PAN, polyarteritis nodosa.
space compared with the anionic IgG-HBsAg complexes
which are more restricted to the subendothelial space (9).
In addition, acquired missense nucleotide mutations
of the HBV x gene in specific locations (C1653T, A1726C,
A1727T, C1730G, T1753C, A1762T, and G1764A) were found
in 84% of patients with MN and in only 8% of control patients,
which may explain the predisposition of certain HBV carriers
to develop renal disease (10). Of the eight genotypes of HBV,
genotype A appears to have the highest risk of MN or
MPGN.
It has been suggested that idiopathic MN can be differen-
tiated from HBV-associated MN by the presence of circulating
anti-phospholipase A2 receptor antibodies (anti-PLA2R) and
by the characterization of the IgG subtype in the glomerular
basement membrane as IgG4 (11). In HBV-associated MN the
IgG subtype tends to be predominantly of the IgG1 class.
Although initial reports showed ,5% of patients with HBV-
associated MN having a positive assay for anti-PLA2R (12), a
recent study indicated contradictory findings with 64% of
HBV patients showing anti-PLA2R (13). The study also
demonstrated the presence of HBV antigens colocalizing
with anti-PLA2R antibody confirming the possible association
of these two findings. Therefore, the utility of anti-PLA2R in
separating idiopathic MN from HBV-related MN is not
clearly substantiated at the present time.
Tubular reticular inclusions have been frequently reported
in Systemic Lupus Erythematosis and HIV renal disease but
have now also been described in MN associated with HBV
and even in HCV glomerular lesions (14). The renal presence
of tubular reticular inclusions then appears to confirm the
local upregulation of IFN which any significant viral illness
may stimulate and identifying their presence makes the
diagnosis of MN less likely idiopathic in origin and more
likely secondary to an autoimmune or infectious origin.
Progression of HBV-related MN toward ESRD occurs in
approximately 25%–35% of adults compared with a rate of
,5% in children (15). Spontaneous biopsy-proven histo-
logic resolution of MN has been shown in children which
has been associated with systemic HBeAg clearance by the
age of 4 years (16).
MPGN
MPGN represents the second most common renal glo-
merular syndrome in HBV carriers after MN in both adults
and children and is characterized by the typical lobular
appearance of the glomerulus with splitting of the base-
ment membrane and mesangial, subendothelial, and even
subepithelial deposits. The typical glomerular antigen
deposited is the HBsAg due to its size restriction with
IgG to the subendothelial space (17). Both type 1 and type 3
MPGN have been described in chronic HBV carriers. The
clinical presentation is similar to patients with idiopathic
MPGN and is characterized by the nephritic syndrome with
or without nephrotic range proteinuria and decreased levels
of serum C primarily in the classic pathway (low C3 and C4)
(8).
Recently reported as an additional cause of type 1 MPGN
in HBV carriers is mixed cryoglobulinemia. The majority
of these patients (75%) presented after .10 years of HBV
infection with predominantly type 3 cryoglobuline-
mia (polyclonal IgM – polyclonal IgG). This compares to a
Clin J Am Soc Nephrol 12: 1529–1533, September, 2017
greater propensity (80%) of type 2 cryoglobulinemia
(monoclonal IgM – polyclonal IgG) with type 1 MPGN
in chronic HCV infection of .10–15 years (18). HBV
patients with cryoglobulinemia may present with ne-
phrotic syndrome, AKI, and systemic vasculitis with low
C4 (92%) and low C3 (58%). Because HBV is not lympho-
tropic, it is not known how HBV induces B cell cryoglobulin
production. As a result of this new relationship of HBV and
cryoglobulinemia it is essential to exclude coinfection with
hepatitis C as a cause of MPGN in HBV carriers because up to
10% of patients worldwide carry both viral infections and the
treatment will be dictated by which infection is causing the
renal lesion.
Treatment
For HBV patients with MN, Kidney Disease Improving
Global Outcomes recommends the use of IFN or oral
antiviral agents which consist of either nucleotide (tenofo-
vir, adefovir) or nucleoside (lamivudine, entecavir, telbivu-
dine) reverse transcription inhibitors (19). In the treatment of
hepatitis B MN, lamivudine (a cytidine analog) has been the
most commonly used agent associated with an initial
remission of viremia and complete resolution of the MN
lesion in 75%–80% of patients. However, lamivudine is
associated with a 20% per year resistance rate as a conse-
quence of a somatic mutation of the HBV reverse transcrip-
tion gene at the YMDD motif (Y, tyrosine; M, methionine; D,
aspartic acid; D, aspartic acid) (20). For this reason, either
entecavir or tenofovir have now been recommended as first
line therapy as neither drug is associated with clinically
relevant acquired resistance (21).
A recent meta-analysis of 13 studies and 325 patients
confirmed the clinical safety and renal efficacy of these
agents in the treatment of HBV-associated MN. Cortico-
steroids may be given for a period of ,6 months without a
significant effect on liver disease, HBV viremia, or patient
morbidity or mortality as long as concomitant antiviral
therapy is used (22).
The treatment of HBV-related MPGN with type 3 cryo-
globulinemia is completely distinct from the treatment of
HCV type 2 cryoglobulinemia and focuses on the control of
HBV viremia rather than the use of direct-acting antivirals,
rituximab, plasmapheresis, and possible cytotoxic therapy as
systemic cryoglobulinemic vasculitis is unusual with HBV.
Universal HBV vaccination has been shown to success-
fully reduce those childhood cases of HBV MN related to
horizontal transmission of the virus but will have no effect
of HBV MN due to vertical acquisition of HBV which still
represents an important transmission vector in third world
countries (23).
Additional HBV-Associated Glomerular Lesions
The most common cause of PAN in the 1980s was HBV
(.80%) however with global efforts of HBV vaccination,
not only has the prevalence of HBV-associated MN in
children declined dramatically but so have the number of
cases of PAN from HBV (,20% of all cases). PAN in HBV
patients is a result of HBsAg antibody immune complexes
depositing in medium size blood vessels (24). Compared
with idiopathic PAN, HBV patients had a more severe
Viral-Associated GN, Kupin 1531
Birmingham Vasculitis Score on presentation, more fre-
quent mesenteric artery aneurysms compared with renal
artery involvement, a greater propensity for gastrointes-
tinal vasculitis, less severe skin manifestations, and a more
favorable response to therapy with fewer relapses. HBV-
associated PAN leads to AKI from renal ischemia and
infarction. Therefore, the presence of acute GN should
exclude PAN from the differential diagnosis.
HBV viral transcripts have also been noted in patients
with IgA nephropathy and are located in renal mesangial
cells of patients with FSGS suggesting HBV as a possible
etiology of both of these lesions (25). In anecdotal cases,
antiviral therapy led to resolution of the glomerular disease
substantiating the possible causative role of HBV in a select
group of IgA and FSGS patients. In addition, case reports of
minimal change (MC) disease in children with HBV who
entered into clinical remission strictly after antiviral ther-
apy proposes yet another renal lesion with possible links to
chronic HBV viremia (26).
Acute and Subacute Viral-Induced GN
Although any acute viral illness can lead to an immune
complex–proliferative GN, a select group of viral syndromes
deserve special consideration for the way in which they
induce glomerular injury: dengue, hantavirus, and the group
of non-HIV viruses that have been associated with collapsing
FSGS (cFSGS) (parvovirus, EBV, and cytomegalovirus).
Dengue is truly a worldwide infection with 40% of the
global population living in endemic areas especially Latin
America, Southeast Asia, and the Pacific Islands. An estimated
100 million new infections occur each year through the bite
primarily of the female mosquito Aedes aegyptii. Dengue is
classified into specific syndromes: dengue fever, dengue
hemorrhagic fever, and dengue shock syndrome. AKI is found
in approximately 10%–14% of patients and is primarily seen in
dengue hemorrhagic fever and dengue shock syndrome and
results from acute tubular necrosis (ATN) as a consequence of
hypovolemia (capillary leak) and/or rhabdomyolysis (27).
GN in dengue is now well described in animal models
and in human infection and results not only from immune
complex deposition but also from direct viral entry into
renal tissue (28). Predominant mesangial hypercellularity
with immune complexes and IgM deposition has been
reported with some patients showing diffuse proliferative
GN. The presence of hematuria and proteinuria (both non-
nephrotic and nephrotic) helps distinguish these cases from
typical ATN. Treatment remains supportive in all categories
of dengue but the sheer size of the population involved with
dengue makes it certain that nephrologists need to be aware
of the glomerular manifestations of this infection.
Hantaviruses are RNA viruses that belong to the Bunya-
viridae family and enter the population through exposure to
rodent urine, saliva, or feces. Consequently, public health
programs worldwide are challenged with the responsibility
to eliminate the rodent vector from urban and rural pop-
ulation areas (29). Two major syndromes can develop from
the 100,000 new cases of hantavirus exposure each year both
of which may have associated renal involvement: hanta
pulmonary syndrome and hemorrhagic fever with renal
syndrome. Hantavirus has recently been implicated as one
potential explanation for mesoamerican nephropathy (30).
1532 Clinical Journal of the American Society of Nephrology
Hemorrhagic fever with renal syndrome is characterized
by diffuse endothelial cell injury as a consequence of direct
viral infection (via integrin avb3 and CD55) of most cells
including renal tissue with resultant capillary leak and
intravascular volume depletion leading to ATN. Capillary
endothelial cells are similarly affected and podocyte ef-
facement has been demonstrated leading to both nephrotic
and nephritic syndromes (31). Complementing the podo-
cyte injury is an extensive interstitial CD81 T cell infiltrate
with a “cytokine storm” that may contribute further to the
degree of systemic hypotension and podocyte dysfunction
(32). Mesangial proliferative GN with deposits of C3 and
IgM and immune complex deposition have been reported.
Similar to dengue, no specific therapy is available for
hantavirus infection but preventive strategies with wide-
spread vaccination are undergoing clinical trials.
cFSGS
Viral-induced cFSGS has long been associated with
parvovirus B19 (33). This relationship has been repeatedly
emphasized in the differential diagnosis of cFSGS using in
situ hybridization techniques; parvovirus DNA has been
identified in renal endothelial and epithelial cells, both
visceral and parietal, from patients with a variety of renal
diseases including cFSGS (90%), idiopathic FSGS (80%),
membranous (50%), and MC disease (50%) (34). Addi-
tional investigators have confirmed the ability to identify
parvovirus within the podocyte and parietal cells of
patients with cFSGS lesions to a greater extent than other
renal diseases (35). Clearly, parvovirus proteins appear to
remain in the kidney but whether they have any replica-
tive properties that result in podocyte dysfunction is still a
matter of significant debate. The final assessment is that in
contrast to current accepted dogma the precise link
between parvovirus and cFSGS is still circumstantial (36).
CMV like parvovirus and EBV can cause acute immune
complex GN especially with vertical transmission and MN
has been the most common renal histology reported in this
setting (37). In addition, CMV causes a distinct tubuloin-
terstitial nephritis in transplant patients and may play a
role in the development of transplant glomerulopathy.
Acute CMV infection has also been associated with cFSGS.
It has been suggested that the acute local renal IFN
response could be responsible for the development of
the FSGS lesion as opposed to a direct effect of the virus on
the podocyte (38). Interestingly, the data supporting CMV
as a cause of cFSGS appears stronger than that of
parvovirus.
EBV has been linked to the development of MN in both the
acute and subacute setting and in rare circumstances cFSGS
(39). EBV viral DNA however has been consistently localized
to the renal tubules but rarely has glomerular deposition been
demonstrated. Anecdotal cases of MPGN and postinfectious
GN have been published but there are too few cases to draw
consistent conclusions regarding the pathogenesis. The cor-
relation of cFSGS is the weakest for EBV compared with
CMV and parvovirus (40).
Finally, the potential interaction of specific virus infec-
tions in a host with APOL1 variants and the long term risk
of developing FSGS are being studied (41). At present, the
unexpected association of the polyoma JC virus with the
development of FSGS has been demonstrated. This data
supports the importance of not just looking at the direct
influence of a virus itself on podocyte regulation but also on
host genetic susceptibility to FSGS that may be magnified
by the viral infection.
Viral-Induced De novo and Clinical Relapse of
MC Disease
In children there is strong data supporting the role of
many different types of viral diseases leading to a relapse
of previously diagnosed MC disease. In particular, upper
respiratory viral infections have been implicated such as
respiratory syncitial virus, influenza, and parainfluenza
(42). In addition, new onset varicella infection and the
actual mumps/measles/rubella vaccine have been linked
to a relapse of nephrotic syndrome from prior MC disease.
It is hypothesized that cytokine release as a consequence of
the acute viral syndrome may induce foot process effacement
and nephrotic proteinuria.
In contrast, a number of series have shown that acute
measles infection has led to a temporary remission of MC
disease (43). A variety of extrarenal autoimmune syndromes
have also been reported to be attenuated temporarily and go
into remission with acute measles, including immune throm-
bocytopenia and hyperimmune globulin E syndrome. An
alteration of T suppressor/helper cells during active measles
has been suggested as a cause of this downregulation of the
immune system and transient remission of MC disease. No
consistent effect of the mumps/measles/rubella vaccine has
been reported on childhood nephrotic syndrome.
Summary
In the evaluation of patients with GN, the presence of acute
or chronic viral infections must be an important part of the
differential diagnosis. Familiarity with the different renal
syndromes associated with viral diseases is paramount
which can then lead to specific diagnostic testing and
therapeutic interventions that would not normally have
been considered. The study of viral-associated GN has
led to a better understanding of the complex interactions
of the adaptive immune system, viral antigen–antibody
immune complexes, genetic risk factors, and host cytokine
responses that all lead to a unique array of renal pathology.
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 ANCA Glomerulonephritis and Vasculitis
J. Charles Jennette and Patrick H. Nachman

Abstract
ANCA vasculitis has an associated autoimmune response that produces ANCAs that induce distinct pathologic
lesions. Pauci-immune necrotizing and crescentic GN is a frequent component of ANCA vasculitis. ANCA vasculitis
is associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). A diagnosis of
ANCA vasculitis should always specify the serotype as MPO-ANCA positive, PR3-ANCA positive, or ANCA- Department of
negative. To fully characterize a patient, the serotype also should be accompanied by the clinicopathologic variant Pathology and
if this can be determined: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), eosinophilic Laboratory Medicine,
granulomatosis with polyangiitis (Churg–Strauss), or renal-limited vasculitis. ANCA vasculitis is most prevalent in Department of
Medicine, and Kidney
individuals >50 years old. There are racial/ethnic and geographic influences on the prevalence, serotype Center, School of
frequencies, and clinicopathologic phenotypes. There is clinical, in vitro, and animal model evidence that ANCAs Medicine, University
cause disease by activating neutrophils to attack small vessels. Immunomodulatory and immunosuppressive of North Carolina at
therapies are used to induce remission, maintain remission, and treat relapses. Over recent years, there have been Chapel Hill, Chapel
Hill, North Carolina
major advances in optimizing treatment by minimizing toxic therapy and utilizing more targeted therapy.
Clin J Am Soc Nephrol 12: 1680–1691, 2017. doi: https://doi.org/10.2215/CJN.02500317
Correspondence: Dr.
J. Charles Jennette,
Kenneth M. Brinkhous
Distinguished
Introduction necrotizing GN alone with no evidence for systemic Professor and Chair,
Department of
GN and vasculitis caused by ANCAs is the most com- vasculitis (1). Unlike MPA, GPA has extravascular Pathology and
mon form of new-onset GN in adults .50, although granulomatous inflammation, most often in the re- Laboratory Medicine,
it can occur at any age. Prompt diagnosis and initi- spiratory tract. EGPA has extravascular granuloma- School of Medicine,
ation of appropriate immunosuppressive therapy is tous inflammation as well as blood eosinophilia and Chief of Pathology and
essential for optimum patient and renal outcomes. Laboratory Medicine
asthma. Less than 10% of patients with clinical and
Services, UNC
Diagnosis and treatment of ANCA disease is compli- pathologic features of MPA, GPA, RLV, and EGPA Hospitals, Executive
cated by the marked differences in symptoms, signs, with necrotizing GN are negative for ANCA using Director, UNC
activity, chronicity, and severity among patients. This current clinical assays. To be most helpful for clinical Nephropathology
review will summarize the spectrum of clinicopath- management, an ANCA disease diagnosis in a given Division, University of
North Carolina at
ologic phenotypes and serotypes of ANCA disease, patient should include both the serotype and the Chapel Hill, 308
the related epidemiologic and demographic charac- clinicopathologic phenotype, if known. For example, Brinkhous-Bullitt
teristics, the underlying pathogenic mechanisms, and CHCC 2012 calls for adding a prefix to the clinico- Building, CB#7525,
the current approaches to treatment. pathologic phenotype indicating the ANCA specificity Chapel Hill, NC
27599-7525. Email:
in a given patient with ANCA-associated vasculitis (i.e.,
jcj@med.unc.edu
MPO-ANCA GPA, PR3-ANCA MPA, ANCA-negative
Diagnostic Classification MPA, etc.) (1).
ANCA GN and vasculitis are defined by distinct
pathologic lesions and an associated autoimmune re- Clinicopathologic Classification
sponse that produces ANCAs. The 2012 Chapel Hill Pauci-immune necrotizing and crescentic GN is the
Consensus Conference Nomenclature of Vasculitides typical pattern of glomerular injury in all forms of
(CHCC 2012) defines ANCA-associated vasculitis systemic ANCA-associated vasculitis (2). ANCA-
as necrotizing vasculitis, with few or no immune de- associated pauci-immune necrotizing and crescentic
posits, predominantly affecting small vessels (i.e., GN also occurs in the absence of systemic vasculitis as
capillaries, venules, arterioles, and small arteries) so-called RLV. The characteristic acute lesion in
(Table 1) (1). ANCA vasculitis is associated with glomeruli as well as other vessels in the kidney and
ANCA specific for myeloperoxidase (MPO-ANCA) throughout the body is localized vessel wall necrosis,
or proteinase 3 (PR3-ANCA). On the basis of path- which releases constituents of the plasma, includ-
ologic and clinical features, ANCA-associated vas- ing coagulation factors, into the necrotic zone where
culitis is subdivided into microscopic polyangiitis thrombogenic factors, such as tissue factor, activate
(MPA), granulomatosis with polyangiitis (Wegener) the coagulation cascade to produce fibrin. This ne-
(GPA), and eosinophilic granulomatosis with poly- crotic area filled with fibrin is called fibrinoid necrosis
angiitis (Churg–Strauss) (EGPA) (Table 1), as well as (Figure 1). Unlike immune complex GN and anti–
renal-limited vasculitis (RLV) with pauci-immune glomerular basement membrane (anti-GBM) crescentic

1680 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 October, 2017
Clin J Am Soc Nephrol 12: 1680–1691, October, 2017 ANCA GN and Vasculitis, Jennette et al. 1681

Table 1. CHCC 2012 categories of ANCA-associated vasculitis (modified from reference (1))

CHCC 2012 Name CHCC 2012 Definition

ANCA-associated vasculitis
Microscopic polyangiitis
Granulomatosis with polyangiitis
(Wegener)
Eosinophilic granulomatosis with
polyangiitis (Churg–Strauss)
Necrotizing vasculitis, with few or no immune deposits, predominantly affecting
small vessels (i.e., capillaries, venules, arterioles, and small arteries), associated
with myeloperoxidase (MPO) ANCA or proteinase 3 (PR3) ANCA. Not all
patients have ANCA. Add a prefix indicating ANCA reactivity, e.g., MPO-
ANCA, PR3-ANCA, ANCA-negative.
Necrotizing vasculitis, with few or no immune deposits, predominantly affecting
small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis
involving small and medium arteries may be present. Necrotizing GN is very
common. Pulmonary capillaritis often occurs. Granulomatous inflammation is
absent.
Necrotizing granulomatous inflammation usually involving the upper and
lower respiratory tract, and necrotizing vasculitis affecting predominantly
small-to-medium vessels (e.g., capillaries, venules, arterioles, arteries, and
veins). Necrotizing GN is common.
Eosinophil-rich and necrotizing granulomatous inflammation often involving
the respiratory tract, and necrotizing vasculitis predominantly affecting small-
to-medium vessels, and associated with asthma and eosinophilia. ANCA is
more frequent when GN is present.

CHCC 2012, 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides.

GN that have extensive localization of immunoglobulin in Serologic Classification

glomeruli detected by immunofluorescence microscopy,
ANCA GN has a paucity of staining for immunoglobulin
in glomeruli (2).
The pathologic activity and chronicity of ANCA GN can
be classified by Berden et al. (3) on the basis of the extent of
glomerular crescents and sclerosis, and the proportion of
glomeruli with no lesion by light microscopy. Focal class
with $50% normal glomeruli has the least progression to
ESRD, sclerotic class with $50% globally sclerotic glo-
meruli has the worst progression, and crescentic class
with $50% glomerular crescents and mixed class with no
predominance of a lesion type have intermediate pro-
gression (3). A caveat is that in patients with eGFR,15
ml/min per 1.73 m2, the Berden class does not predict
renal outcome (4). In this setting, normal glomeruli #10%
(P50.04) and higher overall chronicity score (P50.02) are
risk factors for ESRD.
Figure 1. | Photomicrographs of a kidney biopsy specimen from a
patient with ANCA vasculitis showing segmental fibrinoid necrosis.
In a glomerulus (A) and an interlobular artery (B) (short arrows). The
glomerulus has a small cellular crescent (long arrow), and a break in
Bowman’s capsule in the upper left corner. (Masson trichrome stain.)
Serologic classification of ANCA-associated vasculitis
(e.g., MPO-ANCA, PR3-ANCA, ANCA-negative) as well as
clinicopathologic classification (e.g., MPA, GPA, EGPA,
RLV), and combinations of both, are useful for character-
izing the nature and outcome of the disease in a given
patient, and for predicting the prognosis and response to
treatment (5,6). When used in patient management, ANCA
testing should be performed by a clinical laboratory that
can determine ANCA specificity for PR3 and MPO (7).
Accurate assays for ANCA are valuable for diagnosis and
prognostication (8); however, ANCA titers are more pre-
dictive of renal disease activity than nonrenal disease
activity (9). Patients with ANCA GN who become ANCA
negative during follow-up have low risk for relapse, and a
rise in ANCA titer increases the likelihood of relapse .11
times (9).
Classifying patients on the basis of PR3-ANCA versus
MPO-ANCA correlates with a number of disease charac-
teristics (10). PR3-ANCA vasculitis is more common in
northern Europe, northern North America, and Australia;
whereas MPO-ANCA vasculitis is more common in south-
ern Europe, southern United States, and Asia. PR3-ANCA
has an HLA-DP genetic association whereas MPO-ANCA
vasculitis has an HLA-DQ association. PR3-ANCA vascu-
litis has more upper respiratory tract disease whereas
MPO-ANCA vasculitis has more renal disease. PR3-ANCA
vasculitis has more granulomatous inflammation and MPO-
ANCA vasculitis less granulomatous inflammation. At the
time of biopsy, PR3-ANCA GN has more necrosis and
MPO-ANCA GN has more sclerosis.
Our data from the University of North Carolina (UNC)
indicate that ANCA specificity independently predicts
relapse among patients with ANCA vasculitis more effec-
tively than classification systems that use only the clinico-
pathologic phenotype, with PR3-ANCA–positive patients
1682 Clinical Journal of the American Society of Nephrology

approximately twice as likely to relapse compared with
MPO-ANCA–positive patients (hazard ratio, 1.89; 95%
confidence interval, 1.33 to 2.69; P,0.001) (5). ANCA spec-
ificity has the best predictive model fit compared with
classification on the basis of the CHCC 2012 definitions
(1), or the European Medicines Agency classification (11).
Tables 2 and 3 show demographic and selected clinical
data from an inception cohort of ANCA vasculitis patients
primarily from the southeastern United States seen at
UNC between 1985 and 2007 (5). This cohort came from
a nephrology-based clinical setting, and thus is skewed
toward patients encountered by nephrologists. This co-
hort included 502 ANCA-positive patients diagnosed with
biopsy-confirmed ANCA vasculitis (including MPA, GPA,
and RLV, but excluding EGPA) followed by the Glomerular
Disease Collaborative Network. Patients with EGPA are rarely
seen by nephrologists at UNC. Patients received conventional
therapies (5). Figure 2, which shows organ system involve-
ment in this cohort, demonstrates that the MPO-ANCA and
PR3-ANCA serotypes correlate with different predilections for
organ involvement (5). At one extreme are RLV patients with
GN as the only expression of vasculitis, with approximately
80% of patients MPO-ANCA positive. At the other extreme
are patients with destructive lesions in the nasal septum with
.90% positivity for PR3-ANCA. Patients with pulmonary
capillaritis and no nodules or cavities have a similar frequency
of MPO-ANCA and PR3-ANCA, whereas patients with lung
nodules or cavities more often have PR3-ANCA.
Epidemiology, Demographics, and Genetics
MPA, GPA, and EGPA have a peak incidence of 65–75,
but may occur at any age, with a slight male predominance
(12). Figure 3 shows data derived from 21,374 patients
with any form of glomerular disease identified in renal
biopsy specimens evaluated by the University of North
Carolina Nephropathology Laboratory from 1986 to 2015
(13). Only a subset of the most common glomerular disease
categories that cause GN are shown on these graphs. In
patients with GN ,60 years old, lupus nephritis and IgA
nephropathy are diagnosed most often, whereas ANCA GN is
diagnosed most often after 60 years old (13). As a percentage
of all biopsies performed in different age groups (panel on
the right in Figure 3), IgA nephropathy declines with age,
lupus nephritis peaks in early adulthood, and ANCA GN
increases with age, with a dramatic surge after 50 years old.
ANCA vasculitis has geographic and race/ethnic differences
in prevalence (12). In the United Kingdom, GPA is more
prevalent than MPA (148 versus 65 per million), and EGPA is
least prevalent (46 per million). ANCA vasculitis prevalence in
France is higher in people with European lineage compared
with non-European lineage (105 per million versus 53 per
million). In North America, ANCA vasculitis incidence is
greater in whites than in blacks, which may be caused by HLA
differences (14). ANCA vasculitis is less common in blacks,
occurs at a younger age (mean 52 versus 57 years), and is more
often MPO-ANCA positive compared with whites (71% versus
54%) (15). There are no differences compared with whites in
treatment response, ESRD, renal relapse, or death.
In the United Kingdom and northern Europe, PR3-ANCA
and GPA are more common than MPO-ANCA; however, in
southern Europe, Asia, and India, MPO ANCA and MPA are
more common than PR3-ANCA and GPA (12). In the United
States, there is a similar trend with more PR3-ANCA and
GPA in northern states and more MPO-ANCA-and MPA in
southern states. In China, GPA patients more often have MPO-
ANCA than PR3-ANCA. Geographic and racial differences in
serotypes and clinicopathologic phenotypes may be deter-
mined by HLA differences (14,16,17).
Although only approximately 50% of patients with EGPA
have ANCA, which is usually MPO-ANCA, the presence
of ANCA correlates with phenotypic features of vasculitis
including GN, alveolar capillaritis, and peripheral neu-
ropathy (12). The GN in MPA, GPA, EGPA, and RLV is
histologically indistinguishable (2).

Table 2. Patient characteristics on the basis of clinicopathologic phenotype (RLV, MPA, GPA) of an inception cohort of patients with
ANCA vasculitis with high-frequency renal involvement evaluated at the University of North Carolina Kidney Center (excluding patients
with eosinophilic granulomatosis with polyangiitis). The proportion of patients with each characteristic (other than age) is expressed as a
percent of RLV patients, MPA patients and GPA patients.

P Valuea RLV P Valuea P Valuea

Characteristic RLV n5121 MPA n5264 GPA n5117 versus MPA RLV versus MPA versus
versus GPA MPA/GPA GPA

Diagnosis age ,0.001 ,0.01 ,0.001

Mean6SD 59.8618.4 57.5618.1 47.9619.8
Median (IQR) 66 (50, 73) 61 (49, 71) 50 (32, 64)
MPO/PR3 ,0.001 ,0.001 ,0.001
MPO 98 (81.0%) 155 (58.7%) 30 (25.6%)
PR3 23 (19.0%) 109 (41.3%) 87 (74.4%)
Kidney involvement 121 (100%) 262 (99.2%) 105 (89.7%) ,0.001 ,0.03 ,0.001
Lung involvement 0 (0%) 157 (59.5%) 95 (81.2%) ,0.001 NA ,0.001
ENT involvement 0 (0%) 97 (36.7%) 88 (75.2%) ,0.001 NA ,0.001

The proportion of patients with each characteristic (other than age) is expressed as a percent of RLV patients, MPA patients and GPA patients.
Other characteristics of this cohort were published by Lionaki et al. (5). (MPA/GPA 5 all patients with MPA and with GPA combined.) RLV,
renal-limited vasculitis; MPA, microscopic polyangiitis; GPA, granulomatosis with polyangiitis; IQR, interquartile range; PR3, proteinase 3;
NA, not aplicable becuase by definition RLV patients do not have lung or ENT involvement.; ENT, ear, nose and throat.
a
P values are calculated using Fisher’s exact test for categoric variables and Wilcoxon two-sample test for continuous variables.
Clin J Am Soc Nephrol 12: 1680–1691, October, 2017 ANCA GN and Vasculitis, Jennette et al. 1683

Table 3. Patient characteristics on the basis of ANCA specificity (MPO-ANCA, PR3-ANCA) of an inception cohort of patients with
ANCA vasculitis with high-frequency renal involvement evaluated at the University of North Carolina Kidney Center (excluding patients
with eosinophilic granulomatosis with polyangiitis). The proportion of patients with each characteristic (other than age) is expressed as a
percent of all ANCA disease patients, MPO-ANCA disease patients and PR3-ANCA disease patients.

Characteristic All n5502 MPO-ANCA n5283 PR3-ANCA n5219 Pa Value MPO versus PR3

Age at diagnosis ,0.001

Mean6SD 55.8619.1 59.2617.6 51.5620.0
Median (IQR) 60 (46, 71) 64 (50, 72) 56 (38, 67)
CHCC ,0.001
RLV 121 (24.1%) 98 (34.6%) 23 (10.5%)
MPA 264 (52.6%) 155 (54.8%) 109 (49.8%)
GPA 117 (23.3%) 30 (10.6%) 87 (39.7%)
Kidney involvement 488 (97%) 282 (99.7%) 206 (94.1%) 0.001
Lung involvement 252 (50%) 117 (41.3%) 135 (61.6%) ,0.001
ENT involvement 185 (37%) 67 (23.7%) 118 (53.9%) ,0.001

The proportion of patients with each characteristic (other than age) is expressed as a percent of all ANCA disease patients, MPO-ANCA
disease patients and PR3-ANCA disease patients. Other characteristics of this cohort were published by Lionaki et al. (5). MPO-ANCA,
ANCA specific for myeloperoxidase; PR3-ANCA, ANCA specific for proteinase 3; MPO, myeloperoxidase; PR3, proteinase 3; IQR, interquartile
range; CHCC, 2012 Chapel Hill Consensus Conference Vasculitis Nomenclature; RLV, renal-limited vasculitis; MPA, microscopic polyangiitis;
GPA, granulomatosis with polyangiitis; ENT, ear nose and throat.
a
P values are calculated using Fisher’s exact test for categoric variables and Wilcoxon two-sample test for continuous variables.

The demographic data in Tables 2 and 3 are representative
of ANCA-positive patients with ANCA vasculitis in the south-
eastern United States (5). Among these patients, approxi-
mately a quarter have RLV, a quarter have GPA, and half
have MPA. MPO-ANCA occurred in 81% of RLV, 59% of
MPA, and 26% of patients with GPA. Conversely, PR3-ANCA
occurred in 19% of RLV, 41% of MPA, and 74% of patients
with GPA. During the time when this cohort of patients was
identified, ,5% of patients at UNC with clinical and pathologic
features of ANCA vasculitis were ANCA-negative. These
patients are not included in Tables 2–4. Patients with concur-
rent ANCA and anti-GBM disease also were not included.

Figure 2. | Frequency of PR3-ANCA and MPO-ANCA positivity in ANCA-positive patients with a particular organ system involvement in an
inception cohort of 502 ANCA vasculitis patients with MPA, GPA, or RLV evaluated at the University of North Carolina Kidney Center
(excluding patients with EGPA) (Modified from Lionaki et al. [5]). Organ groupings are not mutually exclusive. ‘No lung and no ENT’ has
vasculitis in some other organs. Plus means there is vasculitis in an additional organ. EGPA, eosinophilic granulomatosis with polyangiitis; ENT,
ear, nose and throat; GI, gastrointestinal tract; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO-ANCA, ANCA
specific for myeloperoxidase; PR3-ANCA, PR3-ANCA, ANCA specific for proteinase 3; RLV, renal-limited vasculitis.
1684 Clinical Journal of the American Society of Nephrology

Figure 3. | These data are derived from 21,374 patients with any form of glomerular disease identified in renal biopsy specimens evaluated by the
University of North Carolina Nephropathology Laboratory from 1986 to 2015. Only a subset of the most common glomerular disease categories that
cause GN are shown on these graphs (modified from reference 13, with permission). Anti-GBM GN, anti–glomerular basement membrane GN.

Approximately 5% of patients with ANCA vasculitis also
have anti-GBM antibodies, and approximately 35% of patients
with anti-GBM disease have ANCA (usually MPO-ANCA)
(18). These patients have kidney disease that more closely
resembles anti-GBM disease, i.e., it is more severe patholog-
ically and clinically, and the risk of progression to ESRD is
greater than for ANCA GN in the absence of anti-GBM.
Table 4 demonstrates responses to treatment of a large
ANCA vasculitis cohort managed by nephrologists in the
southeastern United States from 1985 to 2007 (5). The out-
come data represent blended results derived from different
conventional treatment approaches among different ne-
phrologists over several decades. Nevertheless, we believe
that these data provide an informative overview of the
spectrum of patients with ANCA vasculitis encountered
by nephrologists. Note that classification by both ANCA
serotype and clinicopathologic phenotype have statisti-
cally significant correlations with demographic and clinical

Table 4. Outcomes for patients with ANCA vasculitis on the basis of different classification systems evaluated in the same cohort
characterized in Tables 2 and 3

Treatment Resistance Relapse ESRD Death

Classification System
(n5109 of 483) (n5147 of 374) (n5161 of 502) (n5139 of 502)

Classification on the basis of CHCC 2012 definitions

GPA (n5117) 20 of 117 (17%) 58 of 97 (60%) 24 of 117 (21%) 20 of 117 (17%)
MPA (n5264) 56 of 255 (22%) 74 of 199 (37%) 80 of 264 (30%) 79 of 264 (30%)
RLV (n5121) 33 of 111 (30%) 15 of 78 (19%) 57 of 121 (47%) 40 of 121 (33%)
P value 0.07 ,0.001 ,0.001 ,0.01
European Medicines Agency classification
GPA (n5324) 68 of 317 (22%) 110 of 249 (44%) 92 of 324 (28%) 84 of 324 (26%)
MPA (n5178) 41 of 166 (25%) 37 of 125 (30%) 69 of 178 (39%) 55 of 178 (31%)
P value 0.42 ,0.01 ,0.02 0.25
Classification on the basis of ANCA specificity
PR3-ANCA (n5219) 37 of 213 (17%) 90 of 176 (51%) 56 of 219 (26%) 50 of 219 (23%)
MPO-ANCA (n5283) 72 of 270 (27%) 57 of 198 (29%) 105 of 283 (37%) 89 of 283 (31%)
P value ,0.02 ,0.001 ,0.01 0.03

(Modified from Lionaki, et al. [5]). Treatment resistance 5 persistence or new appearance of extrarenal manifestations and/or progressive decline
in renal function with active urine sediment in spite of immunosuppressive therapy. Relapse 5 reactivation of vasculitis in any organ after initial
response to treatment. ESRD 5 chronic need for dialysis or transplantation. Death 5 death from any cause. CHCC 2012, 2012 International
Chapel HillConsensusConferenceonthe NomenclatureofVasculitides;GPA,granulomatosiswithpolyangiitis;MPA,microscopicpolyangiitis;
RLV, renal-limited vasculitis; PR3-ANCA, ANCA specific for proteinase 3; MPO-ANCA, ANCA specific for myeloperoxidase.
Clin J Am Soc Nephrol 12: 1680–1691, October, 2017
parameters (Tables 2–4). For example, in this cohort, 81%
of patients with RLV have MPO-ANCA compared with
59% of patients with MPA and 26% of patients with GPA
(Table 2). From another perspective, 35% of patients with
MPO-ANCA have RLV compared with 10% of patients
with PR3-ANCA (Table 3). Table 4 shows that both
serotype and phenotype correlate with outcomes. For
example, relapse rates are 19% for RLV, 37% for MPA, and
60% for GPA using CHCC 2012 definitions; and 51%
for patients with PR3-ANCA and 29% for patients with
MPO-ANCA.
Pathogenesis
Clinical Support
There is clinical, animal model, and in vitro experi-
mental evidence that ANCAs are pathogenic (19). The
presence of ANCAs in .90% of patients with MPA, GPA,
and RLV raises the possibility that ANCAs are causing
the disease. The efficacy of immunosuppressive and
immunomodulatory therapy in ANCA vasculitis, and
the rough correlation of ANCA titers with response to
therapy and relapse, also support an immune pathogen-
esis. The utility of plasmapheresis and targeted B cell
therapy (e.g., rituximab) suggests a primary pathogenic
role for autoantibodies.
ANCA pathogenicity also is supported by the obser-
vation in one neonate that transplacental transfer of
maternal MPO-ANCA to the child was associated with
development of nephritis and pulmonary hemorrhage
(20). Some drugs, such as hydralazine, propylthiouracil,
penicillamine, and illicit cocaine adulterated with leva-
misole can induce ANCA vasculitis (21). This induction of
ANCAs followed by onset of ANCA vasculitis supports a
causal relationship. However, these associations do not
prove causality, and the presence of an ANCA vasculitis
disease phenotype in patients who are ANCA-negative
by current clinical assays, and the persistence of ANCA
positivity in some patients in remission, raises doubts
about the pathogenic link between ANCAs and ANCA
vasculitis.
One possible explanation for these inconsistent serologic
correlations is that some ANCA epitope specificities are
not pathogenic and thus ANCAs with these specificities
can be present in the absence of active disease, and that
some ANCA are specific for autoantigen epitopes that are
not detected in current serologic assays for ANCA.
Experimental evidence for both possibilities was reported
by Roth et al. (22) who observed that MPO-ANCAs with
certain epitope specificities only occur in patients with
active disease, whereas other MPO-ANCA epitope spec-
ificities occur not only in patients with active disease, but
also in patients in remission and even in very low titers in
healthy controls as natural autoantibodies. Roth et al. (22)
also observed that an MPO epitope recognized by some
pathogenic MPO-ANCAs could not be detected in usual
serologic assays but only in assays that eliminated a serum
blocking factor by using isolated IgG.
In Vitro Evidence
The most compelling evidence for induction of ANCA
vasculitis by ANCAs comes from in vitro and in vivo
ANCA GN and Vasculitis, Jennette et al. 1685
experiments (19,23). Figure 4 depicts a putative sequence
of pathogenic events that is consistent with in vitro and in
vivo animal model experiments, and supported by clinical
observations. Each localized vascular lesion resulting from
this process progresses from an acute to a chronic phase
within 1 or 2 weeks; however, multiple new acute lesions
in multiple vessels continue to develop until patients enter
remission. Thus, patients with active disease have accrued
chronic lesions as well as newly developing acute lesions.
This is observed in most ANCA GN renal biopsy speci-
mens as varying numbers of glomeruli with acute necro-
tizing lesions (usually accompanied by crescents), sclerotic
lesions, or both (2).
Both MPO-ANCA and PR3-ANCA IgG can activate primed
normal human neutrophils in vitro causing respiratory
burst with release of toxic oxygen radicals, degranulation
with release of lytic and proinflammatory enzymes, re-
lease of complement alternative pathway–activating fac-
tors, and release of neutrophil extracellular traps (NETS),
which contain extruded DNA with adherent cytoplasmic
proteins that can cause tissue injury and augment the
autoimmune response (19,23,24). Priming of neutrophils,
for example by cytokines, is required for optimum acti-
vation by ANCA IgG. Priming causes a minor degree to
ANCA autoantigens translocation from the cytoplasm to
the cell surface where the autoantigens can interact with
ANCAs. In in vitro and in vivo animal models, tumor ne-
crosis factor suffices as a priming factor. In patients, neu-
trophil priming for activation by circulating ANCA could
be caused by a concurrent synergistic infection, for example a
respiratory tract viral infection. Priming causes neutrophils to
increase the availability of ANCA antigens on their surfaces,
where they are accessible to interact with ANCAs. Neutro-
phils are activated when ANCA IgG bound to ANCA
antigens engages Fc g receptors on the surface of neutro-
phils. ANCA-activated neutrophils adhere to endothelial
cells and release mediators of inflammation and cell injury,
including NETS (19,24) (Figure 4).
Animal Model Evidence
Multiple animal models have been used to demonstrate
the pathogenicity of MPO-ANCAs and also to incriminate
a role for T cells (23,25–27). Interestingly, no convincing
animal model of ANCA vasculitis caused by PR3-ANCA
has been developed. This is probably because of the dif-
ference in the biology of PR3, including the amount pro-
duced, between humans and the experimental animals that
have been used to attempt to cause disease with anti-PR3
antibodies (28).
One animal model that has been reproduced in multiple
labs was first reported by Xiao et al. (25) and entails injection
of mouse anti-MPO antibodies into susceptible strains of
mice resulting, within one week, in pauci-immune necro-
tizing and crescentic GN, and small vessel vasculitis in
other organs. In this model, there is no difference in disease
induction in wild-type mice compared with mice with no
functioning T cells (25). Thus, T cells are not required to
induce acute necrotizing vascular injury. Of course, T cells
are undoubtedly critically important in initiating and
regulating the autoimmune ANCA response in patients,
and in the inflammatory response to injury, even if they are
not involved in causing the acute lesions.
1686 Clinical Journal of the American Society of Nephrology

Figure 4. | Diagram depicting the pathogenesis of vascular lesions in ANCA vasculitis and GN. The events from left to right occur sequentially at
each site of injury, and are repeatedly initiated at multiple sites until induction of remission. Neutrophil priming, for example by cytokines generated
by a synergistic infection, primes neutrophils and presents ANCA antigens at the surface and in the microenvironment of neutrophils. ANCA-
activated neutrophils adhere to and penetrate vessel walls, and release destructive inflammatory mediators and undergo NETosis. ANCA-activated
neutrophils release factors that activate the alternative complement pathway, which generates C5a and amplifies the inflammation by attracting and
priming moreneutrophils. At sites ofvessel wall disruption, plasma spills intothe necrotic zone and coagulationfactors are activated to produce fibrin,
resulting in a fibrinoid necrosis in vessels in tissue and crescents in glomeruli. Leukocytes undergo apoptosis and necrosis producing leukocytoclasia.
Within a few days, the acute inflammation and necrosis is replaced by infiltrating macrophages and lymphocytes, and scarring begins as activated
fibroblasts and myofibroblasts lay down collagen. (Shown only at the right side of the acute lesion is monocyte activation by ANCA, which is oc-
curring in parallel with neutrophil activation at all sites of acute injury.) NET, neutrophil extracellular trap.

Multiple studies using the mouse model induced by
anti-MPO IgG have shown that disease is mediated by neu-
trophil activation, prevented by neutrophil depletion,
influenced by genetic background, modulated by Fc g re-
ceptor repertoire, and requires inflammatory amplification
by the alternative complement pathway (23) Unexpectedly,
activation of the alternative complement pathway was
found to play an important role in amplifying ANCA-
induced inflammation (29,30). ANCA-activated neutrophils
release factors that activate the alternative complement
pathway, resulting in the generation of C5a that is strongly
chemotactic for neutrophils and primes neutrophils to
facilitate further activation by ANCAs (29,30).
Observations in patients with ANCA disease support a
role for complement in pathogenesis. Gou et al. (31) observed
changes in the levels of complement components, includ-
ing activation fragments, in the circulation of patients with
ANCA vasculitis that substantiate alternative complement
pathway activation in patients with ANCA vasculitis. They
observed that patients with ANCA vasculitis have increased
plasma levels of alternative pathway activation markers
C3a, C5a, soluble C5b-9, and Bb during active disease but
not remission. The plasma level of Bb correlated with
severity of glomerular injury on the basis of percentage of
cellular crescents in renal biopsy specimens and with
Birmingham Vasculitis Activity Scores (31). Clinical trials are
currently underway to evaluate the value of complement
activation blockade in the treatment of ANCA vasculitis.
Careful studies of renal biopsy specimens from patients
with ANCA GN confirm the presence of many of the
Clin J Am Soc Nephrol 12: 1680–1691, October, 2017
mediators incriminated in animal studies, and illustrated
in Figure 4. For example, in one study of MPO-ANCA GN
biopsy specimens, active lesions contained neutrophils,
monocytes, macrophages, T cells, NETS, and cellular and
extracellular MPO, including MPO decorating NETS (32).
Genesis of ANCA Autoimmunity
There is a general understanding of the likely pathogenic
events that cause vascular injury. However, there is less
understanding of the initial cause for the autoimmune res-
ponse that results in ANCA production. Adaptive immune
responses begin with presentation of antigens to the im-
mune system in the antigen-presenting pocket of HLA
molecules, which will present the antigen to the T cell re-
ceptor, which in turn influences the specificity of the B cell
receptor (i.e., the immunoglobulin molecule). This predicts
that different HLA molecules would be involved in initi-
ating the MPO-ANCA autoimmune response versus the
PR3-ANCA autoimmune response. This was in fact ob-
served in patients with ANCA vasculitis by genome-wide
association studies that showed specific, and different, HLA
associations with MPO-ANCA and PR3-ANCA vasculitis
(16,17). Not surprisingly given their lineal role in immune
responses, the HLA associations correlated better with
ANCA specificity than with clinicopathologic phenotypes.
Another genetic influence that may affect the genesis of
an immune response, or the intensity of pathogenic event,
is epigenetically controlled increased expression of ANCA
autoantigens. The MPO and PRTN3 genes in peripheral
blood neutrophils and monocytes, that produce MPO and
PR3, respectively, are overexpressed in patients with ac-
tive ANCA vasculitis compared with patients in remission
and healthy controls, as a result of epigenetic dysregula-
tion (33). Increased expression of MPO and PR3 genes
may influence disease pathogenesis either by augmenting
ANCA-induced neutrophil activation, or stimulating the
pathogenic autoimmune response, or both.
ANCA-induced neutrophil activation causes NETosis.
NETosis is a form of neutrophil activation and cell death
that results in the release of NETS that contain a frame-
work of extruded DNA from decondensed chromatin
decorated with multiple adherent cytoplasmic proteins,
including MPO and PR3, many of which have antimicro-
bial properties. NETosis could contribute to the pathoge-
nies of ANCA disease, both by presenting PR3 and MPO
proteins to the immune system in a way that facilitates
the autoimmune ANCA response, and by mediating in-
flammatory injury at sites of ANCA-induced activation
through destructive enzymes and complement-activating
factors (24).
Another hypothetic mechanism for initiating an ANCA
autoimmune response entails an initial response to com-
plementary (antisense) peptides that induces anti-idiotypic
antibodies that react with sense peptides (autoantigen
epitopes) (34). Both antibodies (34) and T cells (35) specific
for complementary PR3 have been detected in patients with
ANCA vasculitis. Evaluation of the functional significance
of ANCA vasculitis genome-wide association study data
also suggested a role for immune recognition of comple-
mentary peptides by T cells (17).
Although the mechanisms are not fully elucidated,
both the adaptive and innate immune systems clearly are
ANCA GN and Vasculitis, Jennette et al. 1687
responsible for causing ANCA vasculitis. Thus, appropri-
ate immunosuppression and immunomodulation therapy
are likely to ameliorate ANCA vasculitis injury.
Treatment
For decades, conventional treatment of ANCA disease
with major organ involvement has been with high-dose
cyclophosphamide and glucocorticoids, which has induced
remission in approximately 75% of patients at 3 months
and up to 90% at 6 months, although relapses and adverse
side effects were frequent. More recently, new treatment
regimens have been developed to limit cyclophosphamide
and glucocorticoid exposure during both the induction and
maintenance phases. Biologic therapies that target specific
cellular and molecular components of the autoimmune
response and the mediators of inflammatory injury may be
more effective and less toxic.
Timely diagnosis and institution of appropriate immu-
nomodulatory therapy is critically important for optimum
renal outcome in patients with ANCA GN; however, pa-
tients often have delay in diagnosis and treatment because
of delay in referral to a nephrologist by a primary care
physician, and by patients not going to physicians at the
onset of symptoms. In a study of 127 patients with ANCA
GN by Poulton et al. (36), 71% had a delay in primary care
physician referral to a nephrologist, and 57% of patients
who delayed seeking care had a delay in diagnosis and
appropriate treatment. Patients with initial flu-like or upper
respiratory tract symptoms were more likely to have a delay
in diagnosis, perhaps because these symptoms suggested
common nonprogressive infections to the patient and the
primary care physician.
Induction of Remission
The most widely used current induction therapy com-
prises cyclophosphamide combined with glucocorticoids
(Figure 5). The optimum dose, duration, and route of admin-
istration of cyclophosphamide and rituximab therapy have
been studied in multiple clinical trials (e.g., 37–40). There is no
randomized trial to guide dosage of glucocorticoids. There is
no universal consensus on optimum treatment regimens. A
major issue has been the relative efficacy of daily oral versus
pulse intravenous (iv) cyclophosphamide, and comparative
toxicity of each. The Cyclophosphamide Oral versus Pulse
Trial (CYCLOPS) evaluated 149 patients with GPA or MPA
who received either oral (2 mg/kg per day; maximum oral
dose 200 mg) or iv pulse cyclophosphamide (15 mg/kg;
maximum pulse dose 1.2 g), initially every 2 weeks for the
first three pulses then every 3 weeks for the next three to six
pulses. The two treatment groups had no difference in time to
remission, renal survival, mortality, or adverse events (37,38).
Although the rate of relapse was approximately twice as
high in the iv group after long-term follow-up, there were
no differences between the groups with respect to renal
and patient outcomes. This may favor the use of iv pulses
because of the reduced cumulative dose of cyclophospha-
mide. Vigilance for leukopenia and infections is prudent
with cyclophosphamide therapy. High cumulative dose of
cyclophosphamide should be avoided by using alternative
therapies for induction of remission, maintenance of re-
mission, and treatment of relapses.
1688 Clinical Journal of the American Society of Nephrology
Figure 5. | ANCA vasculitis treatments algorithm in accord with current practice at the University of North Carolina Kidney Center. IV, intravenous.
Initial high-dose iv or oral glucocorticoid administration is
followed by tapering does of oral prednisone. The dose and
duration of prednisone therapy varies, and may be influenced
by the rate and extent of disease remission. A meta-analysis
concluded that longer courses of glucocorticoids are associated
with fewer relapses (41). Our goal is to discontinue prednisone
after 4–5 months if remission has been induced. Continuing
prednisone beyond 6 months is associated with increased risk of
infection, and may not provide significant benefit (42).
Targeted B cell therapy to eliminate pathogenic ANCA is
conceptually attractive because this could selectively re-
duce antibody production while preserving other adaptive
and innate immune cells. Rituximab, which is an mAb that
targets CD20 on B cells, is an alternative to cyclophospha-
mide. Two controlled prospective clinical trials, Rituximab
versus Cyclophosphamide for ANCA-associated Vasculitis
(RAVE), and Rituximab versus Cyclophosphamide in ANCA-
associated Renal Vasculitis (RITUXIVAS), have demonstrated
the value of targeted B cell therapy with rituximab in induction
therapy for ANCA disease (39,40), which led to Food and
Drug Administration approval for induction therapy. In the
RITUXIVAS trial, patients in the rituximab group also
received iv cyclophosphamide, whereas in the RAVE trial,
patients in the rituximab group did not receive cyclophos-
phamide. All patients in both trials received iv and oral
glucocorticoid therapy. Patients in the RITUXIVAS trial had
more severe kidney disease. Both trials showed that ritux-
imab was noninferior for inducing remission compared with
iv cyclophosphamide (RITUXIVAS trial) or oral cyclophos-
phamide (RAVE trial). Adverse events were not reduced
in the patients treated with rituximab in either trial.
A biomarker that can guide rituximab therapy would be
valuable. Bunch et al. (43) have observed that the percent-
age of peripheral blood CD5-positive regulatory B cells is
a useful indicator of disease activity, remission, and future
relapse after rituximab therapy, and thus may help mea-
sure the effectiveness of induction therapy and guide
maintenance therapy vigilance for relapse. To our knowl-
edge, assays for CD5-positive B cells are not routinely
available in clinical laboratories, although this test could
be added to current flow cytometry lymphocyte phenotyping
assays as a locally validated laboratory-developed test.
Plasmapheresis is another strategy to remove patho-
genic ANCA, as well as inflammatory mediators, from the cir-
culation. Plasmapheresis has been shown to have a
therapeutic effect in patients with ANCA disease (includ-
ing ANCA plus anti-GBM disease) who have severe renal
impairment (serum creatinine .6 mg/dl or requiring di-
alysis), and those with alveolar hemorrhage (44,45). The
MEPEX (Methylprednisolone versus Plasma Exchange Trial)
evaluated patients with severe renal disease (serum creati-
nine .5.8 mg/dl) treated with oral cyclophosphamide and
glucocorticoids, and either plasmapheresis or pulse iv meth-
ylprednisolone (46). Plasmapheresis was associated with
increased rate of renal recovery compared with methylpred-
nisolone at both 3 and 12 months of follow-up. Severe adverse
event rates and patient survival were similar in both groups.
The Plasma Exchange and Glucocorticoids for Treatment
of ANCA-Associated Vasculitis trial (PEXIVAS) is under-
way to evaluate plasma exchange in patients with GPA or
MPA with pulmonary hemorrhage and/or severe renal
disease (47). All patients will receive standard induction
therapy with cyclophosphamide or rituximab. Patients will
be randomized to receive seven plasma exchanges and
either standard or low-dose glucocorticoids, or no plasma
exchange and either standard or low-dose glucocorticoids
(47). The goal is to determine whether plasma exchange
combined with immunosuppressive therapy is effective in
Clin J Am Soc Nephrol 12: 1680–1691, October, 2017
reducing death and ESRD. The trial will also study whether
low-dose glucocorticoid therapy is as effective as standard
glucocorticoid therapy.
Maintenance of Remission
Once remission has been induced, continued lower-level
immune suppression is needed for most patients to prevent
relapse, which usually entails low-dose glucocorticoids
plus an additional immunomodulatory therapy such as
azathioprine, rituximab, or mycophenolate mofetil (MMF)
for 12–18 months. Patients with PR3-ANCA or GPA are
more likely to relapse than patients with MPO-ANCA,
MPA, or RLV (Table 4). Maintenance therapy may be for
a shorter interval or not required for patients at low risk
for relapse, such as patients with MPO-ANCA who have
complete remission and are MPO-ANCA negative. More
prolonged maintenance may be appropriate for patients
with increased risk for relapse, such as PR3-ANCA posi-
tivity, prior recurrence, and pulmonary involvement. Sus-
tained use of cyclophosphamide is not recommended
because of toxicity. A randomized controlled trial compar-
ing cyclophosphamide for 12 months with maintenance
therapy with azathioprine once complete remission is
attained demonstrated no difference in outcome including
relapse rate (48,49). Compared with azathioprine, mainte-
nance therapy with MMF was associated with a signifi-
cantly higher rate of relapse (50,51). Nevertheless, MMF
remains an option for maintenance therapy in patients who
are intolerant or allergic to azathioprine. Methotrexate may
be useful in maintaining remission in patients with mild
disease and no renal impairment.
Rituximab is another option for maintenance of remis-
sion. The Maintenance of Remission using Rituximab in
Systemic ANCA-associated vasculitis trial (MAINRITSAN)
compared rituximab (500 mg iv every 6 months) to aza-
thioprine for remission maintenance in patients with MPA,
RLV, and GPA in complete remission after induction treat-
ment with a cyclophosphamide and glucocorticoid reg-
imen (50). Rituximab was better than azathioprine for
preventing relapse, including renal relapse.
The optimum duration of maintenance therapy depends on
multiple factors. Ending too soon increases the risk of relapse.
Patients with PR3-ANCA (versus MPO-ANCA), lung, or
upper respiratory tract vasculitis have a higher risk for
relapse that warrants longer maintenance therapy (52,53).
However, in a randomized controlled trial of patients with
PR3-ANCA disease who remained ANCA-positive at the time
of stable remission, extending the duration of maintenance
therapy with azathioprine from 1 year (followed by taper) to 4
years (followed by taper) was not associated with a significant
difference in relapse-free survival at 4 years (54). The result of
this study should not be extrapolated to other agents, and the
optimal duration of maintenance therapy with rituximab has
not been formally evaluated. Conversely, patients with none
of the risk factors of relapse may not need an extended
duration of maintenance therapy.
Relapse Treatment and Other Challenges
Some patients with ANCA disease are refractory to in-
duction of remission. In some studies, patients with PR3-
ANCA are more likely to have refractory disease (53). Options
for the treatment of refractory disease include the addition of
ANCA GN and Vasculitis, Jennette et al. 1689
plasmapheresis, or the addition of rituximab to a cyclophos-
phamide-based regime, or vice versa.
In patients with very severe disease at the time of diag-
nosis, such as dialysis-dependent kidney disease with
extensive glomerular scaring on renal biopsy, a decision
to treat with toxic immunosuppressive therapy can be dif-
ficult. However, patients with ANCA GN with severe
kidney failure at the initiation of therapy have a low but not
negligible response to treatment. In a study of 155 patients
with ANCA GN with eGFR,15 ml/min per 1.73 m 2 at
presentation, within 4 months after biopsy, 51% attained
treatment response, 35% remained on dialysis, and 14% died
(4). However, only 5% of patients who remained on dialy-
sis after 4 months subsequently recovered renal function,
indicating that continued immunosuppressive therapy is un-
likely to benefit patients who are dialysis dependent for .4
months provided there are no extrarenal manifestations.
Throughout the treatment of ANCA disease with immu-
nosuppressive agents, the onset of adverse events must be
monitored carefully, especially infections and cancer. In a
retrospective study of 489 patients with ANCA disease
receiving standard therapies, McGregor at al. observed 1-,
2-, and 5-year cumulative incidence of infection of 51%,
58%, and 65%, and severe infection was 22%, 23%, and 26%.
Pulmonary and upper respiratory infections were most com-
mon, and Staphylococcus aureus was the pathogen identified
most often in positive cultures (41%) (42). Prophylactic therapy
that could decrease infection-associated morbidity and mor-
tality should be considered in at-risk patients.
Risk for developing cancer after treatment for MPA and
GPA was 1.6–2.4 times higher than the general population
in patients with MPA and GPA who received immuno-
suppressive therapy in the 1970s and 1980s, especially for
bladder cancer and leukemia (55). In an analysis of .500
patients with ANCA vasculitis enrolled between 1995 and 2002
in four European clinical trials, cancer rates for immunosup-
pressed patients with MPA and GPA exceeded rates for the
general population (1.58 for cancers at all sites, 1.30 for cancers
at all sites excluding nonmelanoma skin cancer), but were
less than the rates reported from earlier studies. The authors
hypothesized that the smaller risk might reflect less extensive
use of cyclophosphamide in recent treatment protocols.
Conclusion
Prompt diagnosis and rapid initiation of effective treat-
ment are the most important factors for optimum outcome
in patients with ANCA disease. Prompt diagnosis requires
an appropriate index of suspicion, familiarity with the
broad range of presenting symptoms and signs, and the
knowledge required to accurately distinguish ANCA vas-
culitis and GN from other forms of small vessel vasculitis
and GN with similar presentations. Optimum treatment
requires an understanding of the implications on treatment
regimens of different serotypes, different clinicopathologic
phenotypes, and different degrees of activity, chronicity,
and severity. Current management strategies are superior
to those in earlier decades because of more effective and
more targeted drugs, and treatment regimens that are more
personalized to the nature of the disease in individual
patients. Ongoing advances in understanding ANCA dis-
ease mechanisms, and development of more effective, less
1690 Clinical Journal of the American Society of Nephrology
toxic, and more targeted therapies, undoubtedly will lead
to even better outcomes in the future.
Acknowledgments
We thank Susan L. Hogan, Associate Professor, University of
North Carolina (UNC) Division of Nephrology and Hypertension
and the UNC Kidney Center, and Yichun Hu, Statistician, UNC
Division of Nephrology and Hypertension and the UNC Kidney
Center for the compilation and analysis of the data presented in
Tables 2 and 3.
Disclosures
J.C.J. is on the unbranded speaker bureau for Genentech. Some
of this work was supported by federal grant P01 DK058335-06
from the National Institutes of Health/National Institute of
Diabetes and Digestive and Kidney Diseases.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Pregnancy and Glomerular Disease
A Systematic Review of the Literature with Management Guidelines

Kimberly Blom,* Ayodele Odutayo,* Kate Bramham,† and Michelle A. Hladunewich*

Abstract
During pregnancy, CKD increases both maternal and fetal risk. Adverse maternal outcomes include progression of
underlying renal dysfunction, worsening of urine protein, and hypertension, whereas adverse fetal outcomes
*Division of
include fetal loss, intrauterine growth restriction, and preterm delivery. As such, pregnancy in young women with Nephrology,
CKD is anxiety provoking for both the patient and the clinician providing care, and because the heterogeneous Department of
group of glomerular diseases often affects young women, this is an area of heightened concern. In this invited Medicine,
review, we discuss pregnancy outcomes in young women with glomerular diseases. We have performed a Sunnybrook Health
Sciences Centre,
systematic review in attempt to better understand these outcomes among young women with primary GN, we University of Toronto,
review the studies of pregnancy outcomes in lupus nephritis, and finally, we provide a potential construct for Toronto, Ontario,
management. Although it is safe to say that the vast majority of young women with glomerular disease will have a live Canada; and
†
birth, the counseling that we can provide with respect to individualized risk remains imprecise in primary GN Department of Renal
Medicine, Division of
because the existing literature is extremely dated, and all management principles are extrapolated primarily from
Transplantation
studies in lupus nephritis and diabetes. As such, the study of pregnancy outcomes and management strategies in these Immunology and
rare diseases requires a renewed interest and a dedicated collaborative effort. Mucosal Biology,
King’s College,
Clin J Am Soc Nephrol 12: 1862–1872, 2017. doi: https://doi.org/10.2215/CJN.00130117 London, United
Kingdom

Introduction in young women with glomerular diseases. We have Correspondence:

Pregnancy is a physiologic stress, wherein failure to
adapt can result in adverse pregnancy outcomes.
Systemic and renal vasodilation results in a drop in BP
along with a decrease in renal vascular resistance
leading to increased renal plasma flow, and conse-
quently, nearly a 50% increase in glomerular filtration.
Inadequate adaptation occurs in women with under-
lying hypertension and CKD, and is a poor prognostic
indicator. In general, more resistant hypertension and
advanced CKD are associated with greater risks of
renal disease progression, prematurity, and growth
restriction. Data from Italy estimate the risks for
deterioration of kidney function are 7.6%, 12.6%,
16.2%, and 20% at stages 1–4, respectively (1). Fur-
thermore, fetal outcomes deteriorate along this same
continuum with preterm delivery before 37 weeks
gestation increasing from 24% in stage 1 CKD to 89%
in stages 4 and 5 CKD and neonatal birth weight
dropping by approximately 1300 g between the two
groups (mean birth weight 29666659 and 16396870 g
in stage 1 and stages 4 and 5 CKD, respectively) (1). It
is important to note that only 16% of the patients in this
study had glomerular disease, and of those with
advanced CKD (stages 3–5), only 11 of 45 had in
excess of 1 g urine protein.
As such, pregnancy in young women with CKD
is anxiety provoking for both the patient and the
clinician providing care, and because the heteroge-
neous group of glomerular diseases often affects
young women, this is an area of heightened concern.
In this invited review, we discuss pregnancy outcomes
performed a systematic review in attempt to better Dr. Michelle A.
understand these outcomes among young women Hladunewich,
Sunnybrook Health
with primary GN, we review the studies of pregnancy Sciences Centre, 3rd
outcomes in lupus nephritis, and finally, we discuss a Floor, Canadian
potential construct for management. National Institute for
the Blind Kidney
Centre, 1929 Bayview
Avenue, Toronto, ON,
Systematic Review of Primary Glomerular Canada M4G 3E8.
Diseases Email: michelle.
A comprehensive review of pregnancy outcomes hladunewich@
has been conducted in lupus nephritis (2), but there sunnybrook.ca
are limited data assessing pregnancy risk associated
with other forms of primary GN. Accordingly, we
conducted a systematic review of the literature on
pregnancy outcomes in women with biopsy-proven
primary glomerular-based diseases. The outcome of
interest was the frequency of live births according to
primary GN etiology and the influence of baseline
characteristics on pregnancy outcomes. Full study
methods are in Supplemental Material. In summary,
results from 18 studies, including 887 women and
1414 pregnancies, were abstracted from studies pub-
lished after 1980 (Supplemental Figure 1, Supplemental
Table 1). Study heterogeneity was significant, preclud-
ing any pooling of data, and baseline characteristics
were often not reported or inadequately described,
precluding determination of the potential influence of
hypertension, renal insufficiency, or proteinuria on
pregnancy outcomes (Supplemental Table 2). Over
time, the pathologic descriptions of some glomerular
diseases have also evolved, and the definitions of

1862 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 November, 2017
Clin J Am Soc Nephrol 12: 1862–1872, November, 2017
important pregnancy complications, such as preeclampsia,
have changed. As such, the review is narrative, and urgent
contemporary data are required. Table 1 below summarizes
pregnancy outcomes.
The most commonly reported GN was IgA nephropathy,
with 12 studies including 10–136 patients (one study
included two IgA cohorts) (3–13). The proportion of
women with hypertension at baseline was reported in
eight studies and ranged from 9% to 40%. The proportion
of women with increased creatinine at study entry was
rarely reported, and definitions of renal insufficiency
varied. Across all 12 studies, live birth rate ranged from
70% to 100%. Live birth rates seemed to be lower before
2000 (6,7), but were variable, likely reflecting small study
sizes and reporting biases in addition to improvements in
neonatal care over the decades. Only five studies reported
the mean birth weight, which ranged from 2911 to 3200 g,
and few studies (n55) reported the rate of superimposed
preeclampsia, which ranged from 0% to 25%. A minority
of studies provided long-term follow-up data. One study
reported both sclerosis and vascular disease to be associated
with adverse events, but no others attempted to assess the
relationship between histologic features and outcome (14).
As expected, general themes that emerged included the
association of adverse pregnancy outcomes, including
perinatal death, preterm delivery, and small birth weight,
with hypertension and renal insufficiency (3–5). In the
second largest study of 118 pregnant women (9), women
with hypertension at baseline (BP$140/90 mmHg) or
impaired renal function (eGFR,70 ml/min per 1.73 m2)
were more likely to have an unsuccessful pregnancy.
Perinatal mortality was 33% in women with hyperten-
sion compared with 1% in normotensive women and 14%
in women with renal dysfunction compared with 3% in
women with normal renal function. The largest study to
date, published in 2010, reported outcomes for 229 preg-
nancies and compared renal outcomes of 136 pregnant
women with 87 nonpregnant women, all with serum
creatinine levels #1.2 mg/dl at diagnosis (10). Although
pregnancy did not affect renal disease progression in this
study, a second much smaller group studied with impaired
renal function (n510 with baseline serum creatinine levels
.1.2 mg/dl, averaging 1.6560.39 mg/dl) showed hastened
progression, suggesting an imminent need for more data in
women with IgA at more advanced stages of CKD. Finally,
the most recently published study noted an association
between proteinuria and adverse pregnancy outcomes (13).
Time-averaged proteinuria, the arithmetic average of pro-
teinuria during pregnancy and follow-up, was inversely as-
sociated with infant birth weight (correlation coefficient 5
20.61; P,0.001) and also associated with adverse preg-
nancy outcomes, including severe preeclampsia and intra-
uterine death (13). The strategy for managing worsening
proteinuria during pregnancy in women with IgA is
presently unclear.
Data to support prepregnancy counseling for the other
forms of primary glomerular disease are very sparse.
Only four studies reported outcomes for women with
FSGS (3,4,6,15), all were published before 1990, and all were
small (17–31 pregnancies), with limited reporting of dis-
ease severity or hypertension. The proportion of live births
ranged from 55% to 94% with high rates of complications
Glomerular Disease in Pregnancy, Blom et al. 1863
(e.g., spontaneous abortion, 8%; preterm delivery, 24%;
small for gestational age, 4%; perinatal death, 16% [3]),
with hypertension, impaired renal function, and nephrotic-
range proteinuria identified to be associated with the
greatest risk (3,4). Only two studies included women with
minimal change disease (5,16) or membranous nephropa-
thy (5,17), and similarly, nephrotic-range proteinuria and
hypertension in the early stages of pregnancy were asso-
ciated with worse pregnancy outcomes. In 33 pregnancies in
24 women with membranous nephropathy (17), only 20%
(two of 10) of women with .5 g/24 h proteinuria had a live
infant born after 32 weeks gestation compared with 91%
(21 of 23) with #5 g/24 h (P,0.001), suggesting man-
agement of nephrotic syndrome with pregnancy-safe im-
munosuppression is likely critical and highlighting the
urgent need for contemporary, collaborative studies to
provide informed prepregnancy counseling.
Overview of Pregnancy Outcomes in Lupus Nephritis
The onset of lupus most frequently occurs in women of
child-bearing age (18), and therefore, it is imperative that
nephrologists are comfortable with reproductive counsel-
ing in this subpopulation. Unlike the other primary
glomerular diseases, there are now robust data to inform
pregnancy outcomes and guide a management approach,
including a systematic review (2) and two large multicenter
prospective studies (19,20) as well as numerous smaller
retrospective analyses. The take-home message from all of
these studies is that women with active disease should be
strongly discouraged from conceiving until their lupus is
controlled.
Evidence from meta-analysis data, 37 studies of 2751
pregnancies in 1842 women, showed a higher risk of
adverse outcomes, including fetal loss, preeclampsia,
preterm delivery, and small for gestational age infants,
in those with active disease in early pregnancy (2).
Furthermore, any maternal disease flare and renal flare
were estimated to occur in 26% and 16% of pregnan-
cies, respectively. A recent prospective multicenter cohort
study of 71 pregnancies in 61 women with lupus nephri-
tis reported an increased odds for preterm delivery by 15%
for each increase of proteinuria by 1 g/d every trimester
(20). Even low C3 and C4, without systemic manifestations,
have been reported to be associated with increased risk
in a prospective cohort (21). Other factors that adversely
affect pregnancy outcomes, including fetal or neonatal
death, birth before 36 weeks due to placental insufficiency,
hypertension or preeclampsia, small for gestational age
neonate (below the fifth percentile), and maternal renal
flares in women with lupus nephritis, include severity of
preexisting disease, nonwhite ethnicity, presence of anti-
cardiolipin antibody or lupus anticoagulant, and hyperten-
sion (19,21,22). One cohort study suggested that women
with classes 3 and 4 lupus nephritis are more likely to have
pregnancies complicated by preeclampsia and lower-birth
weight babies than those with class 2 or 5 lupus nephritis
(23), but histologic class was not associated with different
outcomes in the aforementioned meta-analysis (2). As such,
women with normal renal function and quiescent disease
can expect to have excellent pregnancy outcomes. A recent
large prospective cohort study of 385 women with inactive
 1864

Table 1. Pregnancy outcomes by primary glomerular disease type

No. of Infants
Women (No. Average Age at Prepregnancy Prepregnancy ↑ Pregnancies with ↑ BP ↑ Creatinine
Study, yr [Survived BW, g GA, wk
of Pregnancies) Pregnancy, yr Hypertension (%) Creatinine (%) Preeclampsia (%) Postpregnancy Postpregnancy
Infants (%)]

IgA nephropathy
Surian et al. (3) 21 (29) NA NA NA NA NA 0 (0) 29 [26 (90)] NA NA
Barceló et al. (4) 10 (15) NA NA NA 0(0) NA 0 (0) 15 [14 (93)] NA NA
Jungers et al. (5) 34 (69) NA 10 (14) 3 (4) NA NA 3 (4) 70 [57 (81)] 3200 NA
Kincaid-Smith 65 (102) NA NA NA NA 16 (16) NA 102 [74 (73)] NA NA
and Fairley (6)
Packham et al. (7) 70 (116) NA 18 (16) 1 (1) NA 15 (13)a NA 118 [83 (70)] NA NA
Nagai et al. (8) 17 (19) 29 5 (26) 0 (0) NA 9 (47) 1 (5) 19[19 (100)] 2937 39
Abe (9) 118 (168) NA 15 (9) NA NA 9 (11)b NA 168 [146 (87)] NA NA
Limardo et al. (10) 136 (229) 27 27 (20)c 0 (0) 17 (9) 34 (31) 13 (9.6) 229 [195 (85)] 3039 NA
Limardo et al. (10) 10 (10) 29 4 (40) 10 (100) NA NA NA 10 [8 (80)] NA NA
Shimizu et al. (11) 29 (29) 31 NA NA 0 (0) NA NA 29 [29 (100)] 2911 38
Clinical Journal of the American Society of Nephrology

Waness et al. (12) 12 (12) 29 2 (17) 0 (0) 3 (25) NA NA 12 [12 (100)] 3100 NA
Liu et al. (13) 62 (69) 27 7 (11) NA 6 (9) 8 (12) NA 69 [59 (86)] 2972 NA
FSGS
Surian et al. (3) 19 (25) NA NA NA NA NA 0 (0) 25 [19 (76)] NA NA
Barceló et al. (4) 13 (17) NA NA NA 1 (6) 1 (6) 0 (0) 17 [16 (94)] NA NA
Kincaid-Smith 15 (28) NA NA NA NA 5 (18) NA 28 [23 (81)] NA NA
and Fairley (6)
Packham et al. (15) 21 (31) NA 5 (24) NA NA NA 4 (13) 31 [17 (55)] NA 31
MCD
Abe et al. (16) 10 (17) NA NA NA NA NA 0 (0) 17 [12 (71)] NA NA
Jungers et al. (5) 19 (31) NA 0 (0) 0 (0) NA 0 (0) 0 (0) 34 [26 (76)] 3300 NA
MN
Jungers et al. (5) 18 (37) NA 7 (19) 0 (0) NA NA 1 (3) 37 [25 (67)] 2900 NA
Packham et al. (17) 24 (33) NA 0 (0) NA NA 3 (9) 2 (8) 33 [25 (76)] NA NA
GN, disease type
not specified
Malik et al. (90) 17 (85) 36 NA NA 14 (16) NA NA 85 [81 (95)] NA NA
Abe (91) 12 (15) 28 NA NA 7 (58) NA NA 15 [11 (73)] 2115 NA
Packham et al. (92) 91 (168) NA 20 (12) 0 (0) NA 11 of 80 without 0 (0) 169 [136 (80)] NA NA
hypertension
at baseline
Abe et al. (16) 32 (50) NA NA NA NA NA 4 (8) 50 [43 (86)] NA NA
Hou et al. (93) 12 (12) NA 6 (50) 12 (100) NA 3 (25) 9 (75) 12 [11 (92)] NA 33

Studies are arranged in order of date of publication and then alphabetically by first author. BW, birth weight; GA, gestational age; NA, not available; MCD, minimal change disease; MN,
membranous nephropathy.
a
Postpartum defined as maternal outcomes—exact postpartum timeframe unclear.
b
Data collected from 85 subjects who remained in follow-up for at least 3 years.
c
Number of subjects with hypertension (rather than number of pregnancies).
Clin J Am Soc Nephrol 12: 1862–1872, November, 2017
lupus, excluding those with creatinine concentration
.1.2 mg/dl and/or a urinary protein-to-creatinine ratio
.1000 mg/g, reported that 81% did not experience any
adverse events (19). Severe maternal flares were rare,
occurring in the second trimester in only 2.5% and third
trimester in 3.0% of women (19). However, those with
previous lupus nephritis, despite preserved GFR, have
been reported to have higher rates of preterm delivery and
earlier-onset preeclampsia than women with lupus with-
out renal involvement (24). Estimates of pregnancy out-
comes in women with more severe renal impairment and
controlled lupus require extrapolation from literature that
includes different etiologies of renal disease, and the risk
of renal progression is related to severity of renal impair-
ment and the potential for reactivation or flare of the
disease.
Women with anti-Ro/Anti-Sjögren’s-syndrome–related
antigen A (SSA) antibody should be informed of the po-
tential risk of development of fetal heart block due to
placental transfer of Ig leading to endocardial fibroelasto-
sis. In a retrospective cohort study of 186 pregnancies,
5% of offspring were affected; however, this was only
in women with titers $50 U/ml (25). Similarly, neonatal
cutaneous lupus was reported to be more common in
women with high-titer anti-La/Anti-Sjögren’s-syndrome–
related antigen B (SSB) ($100 U/ml), occurring in 57%
of infants (25). The European League against Rheumatism
guidelines recommend that all women with suspected fetal
dysrhythmia or myocarditis, especially those with anti-Ro/
SSA and/or anti-La/SSB antibody, should have fetal echo-
cardiography (26).
In addition to pregnancy-safe immunosuppression (in
Immunosuppression below), hydroxychloroquine is now
recognized as a critical component of disease management
in women with lupus nephritis. Hydroxychloroquine is rec-
ommended to be commenced or continued for all women
with lupus nephritis because prospective cohort studies have
shown maternal and fetal benefits (20,21). Those who dis-
continue hydroxychloroquine have been reported to
have higher incidence of lupus flares, leading to greater use
of antenatal steroids (27). No increased risk of congenital
abnormalities is confirmed from a recent meta-analysis (28),
although a higher rate of spontaneous abortion in exposed
pregnancies than controls was noted with disease activity
as a potential confounder. As such, there are no reported
adverse effects on the fetus or neonate. Furthermore, there
are limited data to suggest up to an 85% reduction in the
risk of fetal growth restriction (20) and recurrence of fetal
heart block (29).
Management Recommendations
Despite lack of data in the primary glomerular diseases,
recent evidence from the Predictors of Pregnancy Out-
come in Systemic Lupus Erythematosus and Antiphospho-
lipid Syndrome (PROMISSE) Study (19) and other smaller
studies in systemic lupus (20) and even vasculitis (30) that
show much better outcomes in women with adequately
controlled disease before pregnancy have indirectly in-
formed care in other glomerular diseases (Figure 1).
Prepregnancy optimization is defined as stabilization of
rapid progression where possible, minimization of urine
Glomerular Disease in Pregnancy, Blom et al. 1865
protein with pregnancy-compatible immunosuppression,
and control of hypertension with pregnancy-safe antihy-
pertensive agents, while actively delaying pregnancy
when these conditions cannot be met. During pregnancy,
careful surveillance to detect the first signs of maternal
or fetal compromise is critical, whereas postpartum care
must include ongoing vigilant care of the underlying
GN along with emotional support to assist young mothers
to cope with a chronic disease while raising a child. Table 2
includes acceptable therapeutic agents that can be used in
pregnancy.
Prepregnancy Care
Contraception. Given the risks associated with preg-
nancy in women with CKD, an unplanned pregnancy
should be vigorously avoided to ensure that conception
does not occur before disease quiescence or while confir-
mation of disease stability after adjustment to pregnancy-
safe medications. As such, questions about sexual activity
and contraception should be part of routine nephrology care
in young women, but are often overlooked. Estrogen-
containing contraception is contraindicated in all women
with vascular disease, and should be used with caution
in young women with hypertension and CKD due to the
increased risk of thrombosis and exacerbation of hyperten-
sion (31). Furthermore, there is limited evidence from
studies in women with diabetic nephropathy that estrogen
may exacerbate preexisting proteinuria (32), possibly
secondary to stimulation of the renin angiotensin system
(RAS) (33,34). As such, progesterone-only preparations are
generally recommended and include the progesterone-only
pill, which is now available with a wider dosing window in
some countries, intramuscular depot injections, and the
intrauterine coil (preferably in multiparous women due to
difficulties with insertion in nulliparous women). Barrier
contraception is less reliable, and therefore, is not recom-
mended as a sole method of birth control.
Fertility. The desire to have a child is innate; therefore,
many women will want to conceive at some time during
their journey with CKD, but both their underlying disease
as well as treatment choices can affect fertility. Along with
advancing renal dysfunction are increased rates of infer-
tility due to hormonal aberrations and progressive sexual
dysfunction due to medication side effects, fatigue, symp-
toms of depression, and altered body image, which can be
significant due to the cosmetic side effects of commonly
used immunosuppressive agents in patients with glomer-
ular diseases (35). Assisted conception is, therefore, likely
to be used more widely in women with various forms of
GN due to increased availability; however, to date, there
are no data to guide this practice.
It is recognized that there is a reduction in the number
of pregnancies reported with advancing severity of renal
disease, and many women with advanced CKD report
amenorrhea or erratic cycles. A small cohort study of
17 women with CKD reported an increase in luteinizing
hormone in women with CKD and reduced cyclic changes
in hypothalamic-pituitary-ovarian hormones (36), whereas
others have confirmed an increase in both prolactin
production and clearance with reducing GFR (37). Self-
reporting of menopause suggests that it occurs early in
women with CKD (38), but these data are confounded by the
1866 Clinical Journal of the American Society of Nephrology
Figure 1. | Management of glomerular disease before, during, and after pregnancy. BMI, body mass index; BPP, biophysical profile; VTE,
venous thromboembolism.
lack of biochemical evidence of menopause and may reflect
misreporting of anovulatory cycles secondary to renal disease.
The choice to use cyclophosphamide must also be made
with care because there is a direct association between
ovarian damage and the prescribed dose, duration,
and route of administration of this medication, with oral
cyclophosphamide inducing a more sustained amenor-
rhea than intravenous administration as noted in a Chi-
nese study of 212 women (39). Furthermore, advancing
age significantly increases the risk for irreversible ovarian
damage in young women. A controlled retrospective
cohort study of 39 women age ,40 years old reported
sustained amenorrhea after cyclophosphamide therapy in
12% of women ,25 years of age, 27% of women 26–31 years
of age, and 62% of women .30 years old (40). The use of
leuprolide acetate, a synthetic gonadotropin-releasing hor-
mone analog, to limit ovarian damage has not been studied
in women with GN, and its use is not routine in this patient
population. Of three recent meta-analyses conducted in
women with malignancies and rheumatologic diseases, two
found a significant benefit with regard to resumption of
menses and ovulation (41,42), whereas another found no
benefit of gonadotropin-releasing hormone analog cotreat-
ment (43). It is, therefore, best to attempt to avoid cyclo-
phosphamide in women of child-bearing age and use other
agents where possible and appropriate (e.g., mycophenolate
mofetil for lupus nephritis and rituximab for vasculitis).
Disease Optimization. As mentioned, a sustained clin-
ical remission before conception has been noted to signif-
icantly improve maternal and fetal outcomes in women
with both lupus nephritis (19,20) and vasculitis (30), and
active nephritis is associated with higher rates of pre-
eclampsia, increased premature delivery, small for gesta-
tional age births, and accelerated loss of renal function
(2,44). From this, we deduce that any active GN will
potentially contribute to adverse pregnancy outcomes,
and control of the glomerular disease with pregnancy-safe
immunosuppression is desirable, whereas all potentially
teratogenic medications must be discontinued. A reasonable
approach includes treatment with pregnancy-safe immuno-
suppression (Immunosuppression below) to attain remission
for at least 3–6 months before a pregnancy attempt (45). In
patients without immunologic treatment options, control of
urine protein with agents that block the RAS is the mainstay of
therapy. Although clearly teratogenic in the second and third
trimesters of pregnancy (BP Therapy below), data for terato-
genicity with only early pregnancy exposure are no longer
supported (46). Unfortunately, the potential use of these agents
in pregnancy planning is not derived from data published in
the management of GN, but comes from small, uncontrolled
studies in patients with diabetic nephropathy, wherein in-
tensive treatment with angiotensin-converting enzyme inhibi-
tion in addition to optimization of glucose control before
conception have been shown to stabilize proteinuria during
pregnancy (47,48), and compared with older preexisting
literature, prolong gestation and improve birth weights (49).
Data in other primary glomerular diseases are urgently
required, especially IgA nephropathy, which is a common
entity with management outside of pregnancy that is debated.
Antenatal Care
Immunosuppression. Women with GN often receive
conflicting information from health care professionals re-
garding medication safety during pregnancy. Reassurance re-
garding balance of risk versus benefit is frequently needed,
while cautioning women that the recommendation from
pharmaceutical companies and information that they glean
from online sources may conflict with current expert opinion.
Clin J Am Soc Nephrol 12: 1862–1872, November, 2017 Glomerular Disease in Pregnancy, Blom et al. 1867

Table 2. Acceptable therapeutic agents in pregnancy and breastfeeding

Purpose Therapeutic Options

Management of Methyldopa
hypertension Labetalol
Long-acting nifedipine
Hydralazine
Amlodipine (used in Europe, but presently limited published safety data)
Thiazide diuretics (typically avoided, but can be considered in difficult to
control hypertension)
RAS blockade strictly contraindicated in pregnancy, but enalapril, captopril,
and quinalapril do not pass into breast milk and can be used postpartum
to manage hypertension and proteinuria
Immunosuppression Prednisone
iv Methylprednisolone
Azathioprine
Calcineurin inhibitors
Rituximab (can be considered early in pregnancy, but no long-term safety
data on exposed infants)
Plasmapheresis
Preeclampsia prevention Low-dose aspirin (75–81 mg daily)
Calcium and vitamin D supplementation (in women who may be deficient)
Nephrotic syndrome Low molecular weight heparin
Furosemide

RAS, renin angiotensin system.

Safety data for immunosuppressive agents come from large
registry and population studies of women with transplants,
but can be used to inform treatment for women with GN.
Prednisone is considered to be relatively safe in preg-
nancy, and benefits of continuation usually considerably
outweigh any risk. Early case-control studies suggested an
increased incidence of cleft lip and palate with first trimester
exposure (50), but subsequent well conducted population
studies did not confirm an association (51). Prednisone is
metabolized by placental 11-b-hydroxysteroid dehydroge-
nase type 2 to inactive cortisone; therefore, the fetal dose is
minimal. However, dexamethasone, administered for fetal
lung maturation, is not inactivated, and the fetus is exposed
to approximately 30% of the maternal dose. High doses of
prednisone have been associated with premature rupture
of membranes (52); however, the simultaneous influence of
preexisting disease activity contributing to preterm deliv-
ery is unknown. Other reported complications are simi-
lar to those in nonpregnant patients, including high rates
of gestational diabetes, weight gain, hypertension, osteo-
porosis, cataracts, infection, and mood changes. Stress
doses of glucocorticoids (typically hydrocortisone) are rec-
ommended during labor for women taking the equivalent
of prednisone 20 mg or more for .3 weeks (53).
Azathioprine is frequently the drug of choice to maintain
disease quiescence during pregnancy. A Danish population
study compared the outcomes of 11 infants exposed in utero
to azathioprine with those of 19,418 pregnancies without
exposure and reported an increase in malformations, pre-
maturity, and perinatal mortality (54). However, several
hundreds of pregnancy outcomes in transplant recipients
prescribed azathioprine during pregnancy have been re-
ported with rates of congenital malformations comparable
with those in the general population (55). Azathioprine
requires activation by inosinate pyrophosphorylase to me-
tabolite 6-mercaptopurine, which is absent in the fetal liver.
Studies of transplant recipients also support safety of calci-
neurin inhibitors, with no evidence of increased risk of
teratogenicity with cyclosporin or tacrolimus (55–57). Fre-
quently, calcineurin inhibitor concentrations fall during preg-
nancy, assumed due to increased hepatic metabolism, and may
require an increase in dose up to 20%–25% compared with
prepregnancy doses (58). A small study of ten women suggested
that free tacrolimus concentrations may be greater in pregnancy
relative to postpartum (59); hence, low therapeutic ranges
should be targeted because high concentrations may cause
nephrotoxicity and hypertension. Some experts do not monitor
concentrations during pregnancy given the uncertainty of the
relevance of recommended targets in pregnancy, and instead,
titrate doses as dictated by changes in the clinical condition.
Cyclophosphamide and mycophenolate mofetil are
teratogenic and should be avoided during pregnancy.
Cyclophosphamide is associated with calvaria, ear and
craniofacial structure, limb and visceral organ abnormal-
ities, and developmental delay with first trimester expo-
sure and growth restriction, suppression of hematopoiesis,
and neurologic impairment with exposure in later trimes-
ters (60). Up to 15% of infants exposed to mycophenlate
mofetil in the first trimester develop major congenital
defects, including cleft lip and palate, microtia with atresia
of the external auditory canals, micrognathia, and hyper-
telorism, and high rates of miscarriage are reported (61).
Experience with rituximab before and during pregnancy is
expanding due to studies from hematologic malignancies.
Transplacental transfer occurs, and B cell depletion was
reported in 11 of 90 exposed infants, with increasing
incidence and severity from second trimester adminis-
tration to term (62); hence, if required in pregnancy, early
1868 Clinical Journal of the American Society of Nephrology
treatment is preferable. In our practice, we currently consider
rituximab only as a last resort in early pregnancy pending
further data. Neonatal monitoring is recommended before
routine vaccination, with delay if necessary. There are no long-
term follow-up studies of infants with in utero exposure to
rituximab, and therefore, its potential deleterious effects on the
developing immune system remain unknown.
BP Therapy. To date, there have been no studies con-
ducted to establish BP treatment goals in young women with
any form of CKD, but it is well accepted that poorly
controlled hypertension during pregnancy significantly wor-
sens both maternal and fetal outcomes, and experts agree
that maintaining BP,140/90 mmHg is prudent in this
patient population (63); the safety of which has been recently
confirmed in an unblinded, multicenter, randomized, con-
trolled study in pregnant women with either chronic or ges-
tational nonproteinuric hypertension (64). The Control of
Hypertension in Pregnancy Study (CHIPS) randomized 987
women to either less tight (target diastolic BP 5100 mmHg)
or tight (target diastolic BP 585 mmHg) BP control. The
achieved BP difference was 85.3 compared with 89.9 mmHg
in the tight versus less tight group, respectively. No signifi-
cant difference between the groups was noted in the primary
outcome, a composite of pregnancy loss or high-level neo-
natal care for .48 hours, which was 31.4% in the less tight
versus 30.7% in the tight control group. Of note, there was
also no difference in low birth babies or perinatal mortality.
The most significant trial finding was that women receiving
less tight (versus tight) control more commonly developed
severe hypertension (.160/110 mmHg) at 40.6% versus
27.5% (P,0.001), which would be a particularly concerning
deterioration in a woman with underlying kidney disease.
There are a number of drug options for the management
of hypertension in pregnancy, including methyldopa, labe-
talol, hydralazine, and long-acting nifedipine. Although
labetalol is frequently considered the first-line agent, a
secondary analysis of the CHIPS cohort noted that women
treated with methyldopa (versus labetalol) had fewer ad-
verse perinatal and maternal outcomes, including fewer
babies who were small for gestational age, fewer deliver-
ies ,34 and ,37 weeks, less severe hypertension, and pre-
eclampsia (65). The use of methyldopa seemed to be
especially beneficial for women with preexisting hyper-
tension. Another study showed higher rates of respiratory
distress syndrome, sepsis, and seizures in infants of mothers
with chronic hypertension dispensed only labetalol com-
pared with those dispensed only methyldopa (adjusted odds
ratio, 1.51; 95% confidence interval [95% CI], 1.02 to 2.22) (66),
suggesting that this is an area that requires further research in
women with CKD. Although diuretics are often avoided due
to the theoretical concern of intravascular contraction, they
can be used in select women. Similarly, other b-blockers (e.g.,
metoprolol) and calcium channel blockers (e.g., amlodipine
and diltiazem) have been used, but again, only in women in
whom the aforementioned safer alternatives are not tolerated
pending further studies. Inhibitors of the RAS are strictly
contraindicated beyond the first trimester due to their
potential to cause cardiac and renal defects, including atrial
septal defects, ventricular septal defects, pulmonary stenosis,
patent ductus arteriosus, renal dysgenesis, and the associated
complications of oligohydramnios (limb contractures, pul-
monary hypoplasia, and hypocalvaria) (67).
Management of Worsening Proteinuria. Worsening
proteinuria in pregnancy poses a significant diagnostic
and therapeutic challenge to the practicing clinician. Al-
though lupus nephritis and vasculitis may flare during
pregnancy, the effect of pregnancy on the other primary
glomerular diseases is unclear. Certainly, GN can present or
flare during pregnancy, and at least early on in pregnancy,
the diagnostic approach is similar to the nonpregnant state,
including a careful urinalysis and the relevant serologic assess-
ment. With the exception of serology and complement levels,
there are presently no other established biomarkers for use in
pregnancy. Although M-type phospholipase A2 receptor in
membranous nephropathy (68) and soluble urokinase plas-
minogen activator receptor in FSGS (69) have been described
in case reports, their use in pregnancy requires further study.
Of note, pregnancy is essentially a state of acute-phase
response, and therefore, complement levels should be normal
or high. Falling complement, even within the normal range,
suggests that lupus is becoming more active.
Kidney biopsy is not contraindicated in pregnancy, but
should be considered only when the information garnered
is likely to affect the treatment approach. In lupus and
vasculitis, serology can often assist with diagnosis, ren-
dering biopsy less necessary. However, the presentation of
de novo significant proteinuria or nephrotic syndrome early
in pregnancy (during the first or second trimester) typically
does necessitate a renal biopsy to establish a diagnosis and
guide immunosuppressive therapy, and it is considered safe as
long as BP is adequately controlled. A recent meta-analysis of 39
studies that compared the associated complications of 243
antepartum with 1236 postpartum kidney biopsies showed a
significantly higher complication rate with antepartum com-
pared with postpartum biopsies (7% versus 1%; P50.001), but
fortunately, most complications were minor, such as loin pain
and macroscopic hematuria early in gestation, with all signif-
icant complications occurring between 23 and 26 weeks (70). Of
note, the aim of 23 of the studies was to study the morphology
of preeclampsia, the potential presence of which should be
considered a contraindication to biopsy given the associ-
ated hypertension and the potential to develop coagulopa-
thies (hemolysis, elevated liver enzymes and low platelets).
Furthermore, biopsy becomes more technically difficult as
the gravid uterus grows, often precluding prone positioning.
As such, the risks often outweigh the benefits of
establishing a diagnosis after approximately 30 weeks of
gestation, but each patient requires careful individual-
ized consideration. In patients in whom renal biopsy has
been delayed to the postpartum period, it is ideal to wait
approximately 4–6 weeks for complete resolution of poten-
tial coexisting endotheliosis (71), but again, the clinical
condition will dictate the most appropriate timing.
After a diagnosis is established, immunosuppressive
treatment should begin promptly, because the symptoms
of nephrotic syndrome can be severe in pregnant women.
In addition to the already reviewed immunosuppressive
options (Immunosuppression above), pulse methylpred-
nisolone and plasmapheresis are options that can be
applied for a more rapid effect where appropriate. How-
ever, supportive therapy is often required while awaiting
a response to definitive treatment or when definitive
diagnosis or treatment is delayed. Peripheral edema is
common in healthy pregnancies and can be severe in
Clin J Am Soc Nephrol 12: 1862–1872, November, 2017
pregnant women with the nephrotic syndrome. Serum
albumin levels also decrease in normal pregnancy (72), and
therefore, hypoalbuminemia can also be severe. Conserva-
tive treatments include compression stockings and avoid-
ance of prolonged standing. Loop diuretics are appropriate
for severe edema, and supportive albumin infusions have
been reported in case reports of women with severe
nephrosis (73,74). Severe hypoalbuinemia (albumin ,25 g/L)
is also associated with an increased risk of venous throm-
boembolic events (75), and pregnancy itself is a prothrom-
botic state. Unfortunately, there are no available data to
guide the use of anticoagulation in this patient population,
and practice varies significantly. Expert opinion suggests
that women with severe proteinuria and serum albumin
,20 g/L should receive thromboprophylaxis throughout
pregnancy, but anticoagulation should also be considered
in those with less severe nephrotic syndrome with addi-
tional risk factors for, for example, obesity, immobility,
membranous nephropathy, or vasculitis. Subcutaneous low
molecular weight heparin is the anticoagulant of choice.
Although thromboprophylaxis is typically held before
anticipated delivery, it should be resumed as soon as
possible and continued for at least 6 weeks, because the
postpartum period carries a particularly high risk of
thrombosis (76).
Preeclampsia Prevention, Diagnosis, and Manage-
ment. Women with CKD are at a substantially increased
risk for the development of placental disease, and hence,
preeclampsia. A recent systematic review and meta-
analysis reported a tenfold increased risk of preeclampsia
among women with CKD compared with the general
population, with effect modifiers including prepregnancy
proteinuria and the type of underlying disease (77). Rates
of preeclampsia were higher in women with nondiabetic
nephropathy, suggesting that glomerular disease might
be particularly hazardous (77). As such, all women with
GN are candidates for preventative strategies. Low-dose
aspirin is now considered part of standard care. In a
meta-analysis of 34 randomized, controlled trials, low-
dose aspirin started at or before 16 weeks of gestation was
associated with a significant reduction in preeclampsia
(relative risk [RR], 0.47; 95% CI, 0.34 to 0.65) and in-
trauterine growth restriction (RR, 0.44; 95% CI, 0.30 to 0.65) (78).
Early administration of low-dose aspirin also resulted in a
significant reduction of severe preeclampsia and preterm de-
livery. Similarly, calcium supplementation has been shown
to reduce the incidence of preeclampsia. In a Cochrane
review of 12 randomized, controlled trials of over 15,000
women, wherein at least 1 g calcium supplementation was
compared with placebo, there was a significant reduction in
the risk of preeclampsia (RR, 0.48; 95% CI, 0.33 to 0.69)
that was even more pronounced in high-risk woman and
those with a low calcium intake (79). As such, calcium
intake should be assessed and supplemented as needed.
An understanding of the pathophysiology facilitates the
diagnosis of preeclampsia. The cascade that results in pre-
eclampsia begins with insufficient placentation character-
ized by inadequate trophoblast invasion and impaired
spiral artery remodeling, which ultimately results in
placental ischemia and the release of antiangiogenic fac-
tors, soluble fms-like tyrosine kinase-1 (sFlt1) and endog-
lin, that induce widespread maternal vascular endothelial
Glomerular Disease in Pregnancy, Blom et al. 1869
dysfunction by binding to proangiogenic factors, including
vascular endothelial factor and placental growth factor
(PlGF), neutralizing their effects (80,81). Both sFlt and
endoglin have been shown to increase before onset of
preeclampsia and correlate with disease severity, whereas
circulating levels of vascular endothelial factor and PlGF
have been noted to significantly decrease. As such, circu-
lating levels of sFlt1 and PlGF are promising potential
biomarkers that can predict risk as well as assist diagnos-
tically in women with GN, in whom the diagnosis is
especially complex. In women with CKD and chronic
hypertension, low maternal PlGF concentrations had high
diagnostic accuracy for superimposed preeclampsia re-
quiring delivery within 14 days (82). Unfortunately, these
biomarkers are not as yet widely available, and pres-
ently, the diagnosis must be made clinically (Table 3). In
women with GN and worsening BP or proteinuria, a care-
ful assessment of the placenta along with fetal growth can
substantially aid in the diagnosis of preeclampsia because
poor or decreasing fetal growth in conjunction with
abnormal placental examinations have been showed to
be diagnostically useful in patients with CKD (83). The
need to assess the mother in conjunction with placental and
fetal parameters speaks to the importance of collaborative
care between nephrology and obstetrics.
To date, the cornerstone of safe management is expedit-
ed delivery, but in a small, open label study, removal of sFlt1
by dextran apheresis seemed safe and prolonged pregnancy
Table 3. Diagnosing preeclampsia: Placental and fetal clues
First trimester screen—11–13 wk gestation
↓ Pregnancy-associated plasma protein A
Activate inulin-like growth factors that facilitate
placental growth
Maternal serum screen—15–20 wk gestation
↑ a-Fetoprotein
Source is fetal liver; therefore, presence suggests
breach in the placental villi
↑ Human chorionic gonadotropin
Excessive secretion by an abnormal
syncytiotrophoblast (beware as cleared by kidneys;
therefore, less use in more advanced CKD)
↑ Dimeric inhibin assay
Excessive secretion by an abnormal trophoblast
Abnormal placental appearance
Length ,10 cm, thickness .4 cm, heterogeneous
appearance, echogenic cystic areas
Abnormal uterine artery Doppler examination
Presence of bilateral notching or pulsatility index
.1.45
Abnormal umbilical artery Doppler
Absent or reverse end diastolic flow
Poor fetal growth
Decreasing growth percentile
Intrauterine growth restriction or growth below the
tenth percentile for gestational age
Abdominal circumference below the 2.5th percentile.
Modified from data presented at http://www.mountsinai.on.
ca/care/placenta-clinic, with permission.
1870 Clinical Journal of the American Society of Nephrology
in women with early-onset preeclampsia (84). Controlled
studies are needed to further investigate dextran apheresis
as a therapeutic option. Magnesium sulfate will be prescribed
to prevent escalation to eclampsia and must be used with
caution in women with renal dysfunction. Close collabora-
tion between high-risk obstetrics and nephrology is essential
to establish the diagnosis and safely manage these vulner-
able women and babies because the false diagnosis of
preeclampsia will result in unnecessary urgent delivery and
iatrogenic prematurity, whereas the failure to detect super-
imposed preeclampsia may have severe maternal and fetal
consequences. Mode of delivery should be dictated by
standard obstetric practice and should not be influenced by
the presence or severity of GN.
Postpartum Care
Both immunosuppressive medications and antihyperten-
sive treatments deemed safe during pregnancy are also
typically of acceptable risk during breastfeeding, and
breastfeeding should be encouraged in women with all
forms of CKD due to the established fetal and maternal
benefits, despite manufacturer recommendations, which
invariably suggest that lactation be avoided. Minimal
prednisone and azathioprine are excreted in breast milk
(85). Levels of both the calcineurin inhibitors have been
assayed in breast milk and assessed in neonates, with most
frequently undetectable levels for cyclosporin (86) and
at most, 0.23% of the maternal weight–adjusted dose for
tacrolimus (87). However, the change in maternal physiology
mandates early reassessment of trough levels and readjustment
of dose to avoid nephrotoxicity in both the mother and
potentially, the baby. At times, significant disease activity
necessitates the use of either mycophenolate mofetil or cyclo-
phosphamide, precluding breastfeeding. The large monoclonal
antibodies do not pass into breast milk, and rituximab may
prove a viable alternative for some forms of active nephritis
in the postpartum. With respect to antihypertensive agents,
methyldopa, labetalol, and long-acting nifedipine are most
used. Diuretics again may theoretically hamper milk supply
due to dehydration and are typically avoided. A number of
inhibitors of the RAS have been assessed in breast milk and
have been deemed absent, including enalapril, captopril (88),
and quinalapril (89). As such, targeting of proteinuria with
RAS inhibition can be initiated early in the postpartum
period. Because these pregnancies are high risk, the emo-
tional toll that they can have on a young woman cannot be
understated. Careful screening for postpartum depression
and lack of coping is mandatory, and ongoing multidisci-
plinary support is critical for maternal wellbeing.
Summary
Although it is safe to say that the vast majority of young
women with glomerular disease will have a live birth, the
counseling that we can provide with respect to individu-
alized risk remains imprecise. In the primary glomerular
diseases, the existing literature is extremely dated, and all
management principles are extrapolated primarily from
studies in lupus nephritis. As such, the study of pregnancy
outcomes and management strategies in these rare dis-
eases requires a renewed interest and a dedicated collab-
orative effort to answer the many unanswered questions.
Fortunately, such studies are underway within existing GN
collaborative groups, including Cure Glomerulonephrop-
athy, which will hopefully provide important data to help
guide young women making this life-altering decision.
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
This article contains supplemental material online at http://cjasn.
asnjournals.org/lookup/suppl/doi:10.2215/CJN.00130117/-/
DCSupplemental.
 Diabetic Kidney Disease
Challenges, Progress, and Possibilities

Radica Z. Alicic,*† Michele T. Rooney,* and Katherine R. Tuttle*†‡§|

Abstract
Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause
of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the *Providence Health
majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement Care, Spokane,
therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive Washington;
†
albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular University of
Washington School
hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there
of Medicine, Seattle,
is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently Washington; ‡Division
needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require of Nephrology,
characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and University of
development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, Washington School of
Medicine, Seattle,
inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices Washington; §Institute
is needed in both clinical and community settings.Introduction of Translational Health
Sciences, Seattle,
Washington;
Clin J Am Soc Nephrol 12: 2032–2045, 2017. doi: https://doi.org/10.2215/CJN.11491116 and |Kidney Research
Institute, Seattle,
Washington
It took more than three millennia from the first de- for patients with diabetes is related to the presence
scription of diabetes in 1552 BC to the recognition of an of DKD (12). Correspondence:
association between diabetes and kidney disease, but it Dr. Radica Z. Alicic,
104 West 8th Avenue,
took only several decades for diabetic kidney disease
6050, Spokane, WA
(DKD) to become the leading cause of ESRD in the Risk Factors 99204. Email: radica.
United States (1,2). This microvascular complication DKD risk factors can conceptually be classified as alicic@providence.
develops in approximately 30% of patients with type susceptibility factors (e.g., age, sex, race/ethnicity, and org
1 diabetes mellitus (DM1) and approximately 40% of family history), initiation factors (e.g., hyperglycemia
patients with type 2 diabetes mellitus (DM2) (2,3). and AKI), and progression factors (e.g., hypertension,
The increasing prevalence of DKD parallels the dietary factors, and obesity) (Table 1) (13). Two of the
dramatic worldwide rise in prevalence of diabetes most prominent established risk factors are hypergly-
(4,5). In the United States, the prevalence of diabetes cemia and hypertension.
among adults increased from 9.8% in the 1988–1994 time
period to 12.3% in the 2011–2012 time period (6). Hyperglycemia
Worldwide, in the year 2015, 415 million people were In normoalbuminuric patients with DM1, poor gly-
estimated to have diabetes; by 2040, prevalence is cemic control is an independent predictor of pro-
projected to increase to 642 million, with dispropor- gression to development of proteinuria (albuminuria)
tionate growth in low- to middle-income countries (7). and/or ESRD (14). Two landmark trials conducted with
The driving force behind the escalating prevalence of patients with early-stage DM1 or DM2 showed that
diabetes is the global pandemic of obesity (4). Between intensive blood glucose control early in the course of
the years 1980 and 2000, the overall prevalence of disease exhibits a long-lasting favorable effect on the
obesity in adults snowballed from 15% to 31% in the risk of DKD development (15,16). This “legacy effect,”
United States (8). By 2013–2014, the adjusted prevalence also named “metabolic memory,” suggests that early
of obesity was up to 35% among men and 40% among intensive glycemic control can prevent irreversible
women (9). damage, such as epigenetic alterations, associated
Kidney disease attributed to diabetes is a major but with hyperglycemia (17). In patients with DM1, an
under-recognized contributor to the global burden of intensive glucose control intervention targeting a he-
disease. Between 1990 and 2012, the number of deaths moglobin A1C (HbA1C) level #7% reduced the 9-year
attributed to DKD rose by 94% (10). This dramatic rise risks of developing microalbuminuria and macroalbu-
is one of the highest observed for all reported chronic minuria by 34% and 56%, respectively, compared with
diseases (11). Notably, most of the excess risk of all- standard care (18). After a median follow-up of 22 years,
cause and cardiovascular disease (CVD) mortality the intensive therapy group had approximately 50%

2032 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 December, 2017
Clin J Am Soc Nephrol 12: 2032–2045, December, 2017
Table 1. Risk factors for diabetic kidney disease
Risk Factor Susceptibility
Demographic
Older age
Sex (men)
Race/ethnicity (black, American Indian,
Hispanic, Asian/Pacific Islanders)
Hereditary
Family history of DKD
Genetic kidney disease
Systemic conditions
Hyperglycemia
Obesity
Hypertension
Kidney injuries
AKI
Toxins
Smoking
Dietary factors
High protein intake
DKD, diabetic kidney disease.
lower risk of a low eGFR (,60 ml/min per 1.73 m2), and the
average rate of eGFR loss was significantly reduced from
1.56 ml/min per 1.73 m2 per year with standard therapy to
1.27 ml/min per 1.73 m2 per year with intensive therapy (19).
Similarly, in patients with newly diagnosed DM2, 10 years of
an intensive glycemic control intervention targeting an
HbA1C of 7% produced a 24% reduction in development
of microvascular complications, including DKD, compared
with conventional therapy (20,21). After 12 years, intensive
glycemic control resulted in a 33% reduction in the risk of
development of microproteinuria or “clinical grade” pro-
teinuria and a significant reduction in the proportion of
patients with a doubling of the blood creatinine level (0.9%
versus 3.5%) relative to the conventional therapy group
(20,21).
Hypertension
In patients with newly diagnosed DM2, treating to a
target BP of ,150/85 mmHg over a median of 15 years
resulted in a significant 37% risk reduction of microvas-
cular complications compared with that in patients treated
to a target of ,180/105 mmHg. Each 10-mmHg increase in
mean systolic BP was associated with a 15% increase in the
hazard ratio for development of both micro- and macro-
albuminuria and impaired kidney function defined as
eGFR,60 ml/min per 1.73 m2 or doubling of the blood cre-
atinine level (22). Broadly, a baseline systolic BP .140 mmHg
in patients with DM2 has been associated with higher risk of
ESRD and death (23,24).
Structural Changes
Development of DKD is associated with many alter-
ations in the structure of multiple kidney compartments.
The earliest consistent change is thickening of glomerular
basement membrane, which is apparent within 1.5–2 years
of DM1 diagnosis. It is paralleled by capillary and tubular
Diabetic Kidney Disease, Alicic et al. 2033
Initiation Progression
1
1
1 1
1
1
1 1 1
1 1 1
1 1
1 1
1 1
1 1
1 1
1 1
basement membrane thickening (14,25,26) (Figure 1). Other
glomerular changes include loss of endothelial fenestra-
tions, mesangial matrix expansion, and loss of podocytes
with effacement of foot processes (Figure 2). Mesangial
volume expansion is detectable within 5–7 years after DM1
diagnosis (14,25,27,28). Segmental mesangiolysis is ob-
served with progression of diabetes and thought to be
associated with development of Kimmelstiel–Wilson nod-
ules and microaneurysms, which often present together
(29,30) (Figure 3). The exudative lesions result from sub-
endothelial deposits of plasma proteins, which form peri-
odic acid–Schiff-positive and electron-dense deposits and
accumulate in small arterial branches, arterioles, and
glomerular capillaries as well as microaneurysms. These
deposits can result in luminal compromise (e.g., hyaline
arteriosclerosis). Similar subepithelial deposits are seen in
Bowman’s capsule (capsular drop lesion) and proximal
renal tubules. In later stages of diabetes, interstitial changes
and glomerulopathy coalesce into segmental and global
sclerosis (31). In patients with DM1, GFR, albuminuria, and
hypertension are strongly correlated with mesangial ex-
pansion and somewhat less strongly associated with glo-
merular basement membrane width (31) (Figure 4).
Renal structure changes in patients with DM2 are similar
to those seen in DM1, but they are more heterogeneous and
less predictably associated with clinical presentations (32).
Early renal pathology studies described a high prevalence
of nondiabetic glomerular disease in the patients with DM2
population, probably because of selection bias: patients
who were diabetic and underwent biopsies tended to have
atypical presentations of DKD. Conclusions from more re-
cent biopsy studies are more conservative, estimating ,10%
prevalence of non-DKD in patients with diabetes and
albuminuria (24).
Factors underlying the different presentation of DKD in
DM2 may include the unreliable timing of DM2 onset
compared with DM1, with potentially longer exposure to
2034 Clinical Journal of the American Society of Nephrology

Figure 1. | Electron microscope images of structural changes in diabetic kidney disease. Structural changes in diabetic glomerulopathy found
with electron microscopy. A indicates marked expansion of the mesangium. B indicates marked diffuse thickening of capillary basement
membranes (to three times the normal thickness in this case). C indicates segmental effacement of the visceral epithelial foot processes.
Original magnification, 33500.

hyperglycemia before diagnosis; an older patient popu-
lation; and a higher burden of atherosclerosis. Additionally,
many patients with DM2 are treated with renin-angiotensin
system inhibitors before diagnosis of diabetes. An in-
ternational consensus working group has provided a
pathologic classification system to address the hetero-
geneity of DKD presentation, which includes scoring of
glomerular, interstitial, and vascular lesions (Tables 2
and 3) (33).
Natural History
The paradigm of the natural history of DKD continues to
evolve. In many patients, DKD clearly does not follow the

Figure 2. | Normal kidney morphology and structural changes in diabetes mellitus. Diabetic kidney disease induces structural changes,
including thickening of the glomerular basement membrane, fusion of foot processes, loss of podocytes with denuding of the glomerular
basement membrane, and mesangial matrix expansion.
Clin J Am Soc Nephrol 12: 2032–2045, December, 2017 Diabetic Kidney Disease, Alicic et al. 2035

Figure 3. | Diabetic glomerulopathy. Changes in glomerular histology in diabetic glomerulopathy (A) Normal glomerulus. (B) Diffuse mesangial
expansion with mesangial cell proliferation. (C) Prominent mesangial expansion with early nodularity and mesangiolysis. (D) Accumulation of
mesangial matrix forming Kimmelstiel–Wilson nodules. (E) Dilation of capillaries forming microaneurysms, with subintimal hyaline (plasmatic
insudation). (F) Obsolescent glomerulus. A–D and F were stained with period acid–Schiff stain, and E was stained with Jones stain. Original
magnification, 3400.

classic pattern of glomerular hyperfiltration progressing to
persistent albuminuria associated with hypertension and
declining GFR (34) (Figure 5). The United Kingdom Pro-
spective Diabetes Study (UKPDS) offered a unique oppor-
tunity to observe the natural history of DKD in patients
with DM2 from early in the course of diabetes. Of enrolled
patients, approximately 2% per year progressed from
normo- to microalbuminuria and from micro- to macro-
albuminuria. At a median of 15 years after diagnosis, 40%
of participants developed albuminuria, and 30% developed
eGFR,60 ml/min per 1.73 m2 or doubling of the blood
creatinine level (22,35). It is noteworthy that 60% of those
developing kidney functional impairment did not have
preceding albuminuria, and 40% never developed albu-
minuria during the study (22). This finding underscores the
fact that albuminuria is a dynamic, fluctuating condition
rather than a linearly progressive process. For example, in
the Multifactorial Intervention for Patients with Type 2
Diabetes Study, 31% of participants with microalbuminuria
progressed to macroalbuminuria, whereas 31% regressed
to normoalbuminuria during 7.8 years of follow-up. An-
other 38% remained microalbuminuric during this time
period (36). Recent clinical data from over 20,000 patients
with DM1 show lower frequencies of low eGFR (,60
ml/min per 1.73 m2) and albuminuria in this population;
19613 years after diagnosis, frequencies of low eGFR and
albuminuria were 8% and 19%, respectively (37).
In step with the changing paradigm of the natural history
of DKD, emerging evidence suggests that the clinical
presentation of DKD is altering. A comparison of DKD
presentation in adults with diabetes during the time
periods between 1988 and 1994 and between 2009 and
2014 shows that the prevalence of albuminuria as a
manifestation of DKD decreased from 21% to 16%, that
low eGFR (,60 ml/min per 1.73 m2) increased from 9% to
14%, and that severely reduced eGFR (,30 ml/min per
1.73 m2) increased from 1% to 3% (38). Furthermore, lack of
albuminuria or low eGFR may not necessarily preclude
structural DKD. A recent autopsy study found a consid-
erably higher prevalence of DKD diagnosed histologically
compared with that indicated by clinical laboratory testing.
Of 168 patients with DM1 or DM2, 106 exhibited histo-
pathologic changes characteristic of DKD. Albuminuria or
low eGFR was absent in 20% (20 of 106) of patients through-
out life. Moreover, structural changes were highly vari-
able and encompassed almost all histopathologic classes of
DKD (39).
In later stages of DKD, as GFR declines, both kidney- and
nonkidney-related DKD complications develop. Anemia
and bone and mineral metabolism disorders often develop
earlier in DKD than in other types of CKD. Predominant
tubulointerstitial disease is associated with damage to the
peritubular interstitial cells that produce erythropoietin. As a
result, patients with diabetes may be prone to erythropoietin
deficiency and are nearly twice as likely to have anemia
compared with patients with nondiabetic CKD and com-
parable eGFR (40). Insulin is a cofactor for parathyroid
hormone release; therefore, insulin deficiency and/or re-
sistance may be associated with lower parathyroid hormone
levels than in other types of CKD (41), which may pre-
dispose patients with DKD to adynamic bone disease.
Deaths due to CVDs and infections are highly prevalent
and compete with progression to ESRD. In the UKPDS,
the overall death rate after onset of DKD in those with
blood creatinine levels .2 mg/dl or those receiving kid-
ney replacement therapy was nearly 20% per year (35).
2036 Clinical Journal of the American Society of Nephrology

Figure 4. | Tubulointerstitial changes and arteriolar hyalinosis in diabetic kidney disease. Tubulointerstitial changes in diabetic kidney disease.
(A) Normal renal cortex. (B) Thickened tubular basement membranes and interstitial widening. (C) Arteriole with an intimal accumulation of
hyaline material with significant luminal compromise. (D) Renal tubules and interstitium in advancing diabetic kidney disease, with thickening
and wrinkled tubular basement membranes (solid arrows), atrophic tubules (dashed arrow), some containing casts, and interstitial widening with
fibrosis and inflammatory cells (dotted arrow). All sections were stained with period acid–Schiff stain. Original magnification, 3200.

Follow-up data from 2003 showed crude 1-year mortality of
patients on dialysis ranging from 6.6% in Japan to 21.5% in
the United States (42). Patients on dialysis over age 75 years
old are 3.9 times more likely to die than their counterparts in
the general population (43).
Pathophysiology of DKD
Critical metabolic changes that alter kidney hemodynam-
ics and promote inflammation and fibrosis in early diabe-
tes include hyperaminoacidemia, a promoter of glomerular
hyperfiltration and hyperperfusion, and hyperglycemia

Table 2. International pathologic classification of glomerular changes in diabetic kidney disease

Class Description Inclusion Criteria

1 Mild or nonspecific light microscopy GBM.395 nm in women and .430 nm in men 9 yr

changes and electron microscopy– of age and older; biopsy does not meet any of
proven GBM thickening the criteria mentioned below for classes 2–4
2a Mesangial expansion, mild Mild mesangial expansion in .25% of the
observed mesangium; biopsy does not meet
criteria for class 3 or 4
2b Mesangial expansion, severe Severe mesangial expansion in .25% of the
observed mesangium; biopsy does not meet
criteria for class 3 or 4
3 Nodular sclerosis (Kimmelstiel–Wilson At least one convincing Kimmelstiel–Wilson
lesion) lesion; biopsy does not meet criteria for class 4
4 Advanced diabetic glomerulosclerosis Global glomerular sclerosis in .50% of glomeruli;
lesions from classes 1–3

Degree of mesangial expansion: mild mesangial expansion occupies an area smaller than the area of the capillary lumen. Severe
mesangial expansion occupies an area greater than the area of the capillary lumen (33). GBM, glomerular basement membrane.
Clin J Am Soc Nephrol 12: 2032–2045, December, 2017
Table 3. International classification of interstitial and vascular
lesions in diabetic kidney disease
Type of Lesion and Criteria
IFTA, %
Absent
,25
25–50
.50
Interstitial inflammation
Absent
Infiltration only in relation to IFTA
Infiltration in areas without IFTA
Vascular lesions arteriolar hyalinosis
Absent
At least one area of arteriolar hyalinosis
More than one area of arteriolar hyalinosis
Presence of large vessels arteriosclerosis
No intimal thickening
Intimal thickening less than thickness
of media
Intimal thickening greater that thickness
of media
IFTA, interstitial fibrosis and tubular atrophy.
(44–47) (Figure 6). In DM2, systemic hypertension and
obesity also contribute to glomerular hyperfiltration via
mechanisms, such as high transmitted systemic BP and
glomerular enlargement (47). Glomerular hyperfiltration
is a well characterized consequence of early diabetes.
Overall, it is observed in 10%–40% or up to 75% of patients
with DM1 and up to 40% of patients with DM2 (48).
Mechanisms underlying glomerular hyperfiltration in di-
abetes are incompletely understood (48); however, one
plausible mechanism is increased proximal tubular reab-
sorption of glucose via sodium–glucose cotransporter 2,
which decreases distal delivery of solutes, particularly
sodium chloride, to the macula densa (49,50). The resulting
decrease in tubuloglomerular feedback may dilate the
afferent arteriole to increase glomerular perfusion, while
Figure 5. | Conceptual model of the natural history of diabetic kidney disease. Duration of diabetes, in years, is presented on the horizontal axis.
Timeline is well characterized for type 1 diabetes mellitus; for type 2 diabetes mellitus, timeline may depart from the illustration due to the
variable timing of the onset of hyperglycemia. *Kidney complications: anemia, bone and mineral metabolism, retinopathy, and neuropathy.
Diabetic Kidney Disease, Alicic et al. 2037
concurrently, high local production of angiotensin II at the
efferent arteriole produces vasoconstriction. The overall
effect is high intraglomerular pressure and glomerular
hyperfiltration (47,49) (Figure 7).
Score
0 Diagnosis of DKD
1 The clinical diagnosis of DKD is on the basis of mea-
2 surement of eGFR and albuminuria along with clinical
3 features, such as diabetes duration and presence of diabetic
retinopathy (51,52). DKD is identified clinically by persis-
0 tently high urinary albumin-to-creatinine ratio $30 mg/g
1 and/or sustained reduction in eGFR below 60 ml/min per
2 1.73 m2 (53). Screening for DKD should be performed
annually for patients with DM1 beginning 5 years after
0
1 diagnosis and annually for all patients with DM2 begin-
2 ning at the time of diagnosis. In patients with albuminuria,
the presence of diabetic retinopathy is strongly suggestive
0 of DKD. The preferred test for albuminuria is a urinary
1 albumin-to-creatinine ratio performed on a spot sample,
preferably in the morning (51,52). The eGFR is calculated
2 from the serum creatinine concentration. Although the
Chronic Kidney Disease-Epidemiologic Prognosis Initia-
tive equation is more accurate, particularly at eGFR levels
in the normal or near-normal range, the Modification of
Diet in Renal Disease equation is typically reported by
clinical laboratories (52). Confirmation of albuminuria or
low eGFR requires two abnormal measurements at least 3
months apart. If features atypical of DKD are present, then
other causes of kidney disease should be considered.
Atypical features include sudden onset of low eGFR or rap-
idly decreasing eGFR, abrupt increase in albuminuria or
development of nephrotic or nephritic syndrome, refrac-
tory hypertension, signs or symptoms of another systemic
disease, and .30% eGFR decline within 2–3 months of
initiation of a renin-angiotensin system inhibitor (53).
Treatment of DKD
Prevention of diabetic complications, particularly DKD,
by long-term intensive glycemic control from early in the
course of diabetes is well established for DM1 and DM2
2038 Clinical Journal of the American Society of Nephrology
Figure 6. | Different pathways and networks involved in the initia-
tion and progression of diabetic kidney disease. AGE, advanced
glycation end product; CTGF, connective tissue growth factor; JAK-
STAT, Janus kinase/signal transducer and activator of transcription;
PKC, protein kinase C; RAAS, renin-angiotensin-aldosterone system;
ROS, reactive oxygen species; SAA, serum amyloid A; VEGF-A,
vascular endothelial growth factor A. *JAK/STAT signaling can be
unchanged (↔) or upregulated (↑) in early and later stages of diabetes,
respectively.
(19,22). However, intensive glucose control after onset of
complications or in longstanding diabetes has not been
shown to reduce risk of DKD progression or improve
overall clinical outcomes. Targeting low HbA1C (6%–6.9%)
compared with standard therapy in this population did not
reduce risk of cardiovascular (CV) or microvascular com-
plications but increased the risk of severe hypoglycemia
(54–56). Furthermore, an analysis of patients with DM2 and
early-stage CKD showed 30% and 40% higher risks for all-
cause mortality and CV mortality, respectively, with in-
tensive glycemic control compared with standard therapy
(57). The finding that intensive glycemic control incurs
great risk of hypoglycemia and does not benefit the risk
of CVD or all-cause mortality has been sustained over
the long term (8–10 years). A small benefit of inten-
sive glycemic control on the risk of ESRD was observed,
but the absolute number of patients was minute
(58). A stratified analysis showed that the greatest bene-
fit of intensive glycemic control for preventing ESRD was
seen in participants without kidney disease at study
entry, further supporting the concept that intensive glyce-
mic control initiated during early diabetes can prevent
DKD (59).
The American Diabetes Association recommends that
targets for glycemia should be tailored to age, comorbid-
ities, and life expectancy of individual patients. More strin-
gent goals, such as HbA1C,6.5%, may be reasonable for
patients with shorter duration of diabetes, younger age,
absence of complications, and a longer life expectancy.
To the contrary, less stringent goals of HbA1C,8% are
recommended for patients with longstanding diabetes,
older age, micro- and macrovascular complications, and
limited life expectancy (51). Similarly, the National Kidney
Foundation–Kidney Disease Outcomes Quality Initiative
and the Kidney Disease Improving Global Outcomes
(KDIGO) guidelines recommend a target HbA1c of about
7.0% to prevent or delay progression of the microvascular
complications of diabetes. However, patients at risk for
hypoglycemia, such as those with diabetes and CKD,
should not be treated to an HbA1c target of ,7.0% (53).
For management of hypertension, the Eighth Joint
National Committee (JNC-8) recommended initiation of
pharmacologic treatment at a systolic BP $140 mmHg
or diastolic BP $90 mmHg, with treatment goals less
than these levels. In the general hypertensive population,
including those with diabetes, initial antihypertensive
treatment may include a thiazide-type diuretic, a calcium
channel blocker, an angiotensin-converting enzyme (ACE)
inhibitor, or an angiotensin receptor blocker (ARB). In
black patients with diabetes, the JNC-8 recommends initial
treatment with a thiazide diuretic or calcium channel blocker.
The same BP targets are recommended for those with
CKD irrespective of diabetes status. In patients who are
diabetic with high levels of albuminuria, the medication
regimen should include an ACE inhibitor or an ARB alone
or in combination with medication from another drug
class (60). The KDIGO guidelines recommend use of an
ACE or an ARB and a BP goal ,130/80 mmHg in all
patients with CKD and albuminuria irrespective of di-
abetes status (52). There is unambiguous evidence that
renin-angiotensin system blockade with either an ACE
inhibitor or an ARB reduces the progression of DKD in
patients with macroalbuminuria (61). However, combi-
nation therapy (an ACE inhibitor and an ARB adminis-
tered together) increases the risk of serious side effects,
primarily hyperkalemia and AKI, and offers no clinical
benefits (62,63).
Following the liberalized JNC-8 recommendations, tar-
get BP goals have been challenged by results of the Systolic
BP Intervention Trial (SPRINT). The SPRINT included 9361
nondiabetic participants with hypertension and high CV
risk. Participants were randomized to either an intensive
(,120 mmHg) or standard (,140 mmHg) systolic BP goal.
The trial was terminated early after a median of 3.26 years,
because rates of the primary outcome (myocardial infarc-
tion, acute coronary syndrome, stroke, heart failure, or
death from CV causes) and all-cause mortality were re-
duced by 25% and 27%, respectively, in the intensively
treated group compared with the standard regimen group.
These results held across prespecified subgroups defined
according to CKD stage, age .75 years old, sex, race, pre-
vious CVD, and baseline levels of systolic BP (64,65).
In contrast to the SPRINT, the Action to Control
Cardiovascular Risk in Diabetes (ACCORD) Trial, which
included 4733 patients with diabetes at high risk for CV
events, showed that achieving the same systolic BP targets
(,120 versus ,140 mmHg) did not have a statistically
significant effect on the risk of nonfatal myocardial in-
farction, nonfatal stroke, death from CV cause, or death
from any causes (66). One of the possible explanations for
this incongruent finding is that the ACCORD Trial was
underpowered to show between-group differences,
Clin J Am Soc Nephrol 12: 2032–2045, December, 2017
Figure 7. | Normal and diabetic nephron with altered renal hemodynamics.
because CV morbidity and mortality occurred at substan-
tially lower rates than predicted. However, in the SPRINT
participants who had CKD at study entry, intensive BP
treatment did not reduce incidence of ESRD, cause a 50%
decline in eGFR, or cause $30% decline in eGFR to a value
of ,60 ml/min per 1.73 m2. Furthermore, hospitalizations
or emergency room visits for AKI occurred more frequently
in the intensive treatment group than the standard regimen
group (4.4% versus 2.6%; hazard ratio, 1.71) (64,67). Sim-
ilarly, the ACCORD Trial detected a signal suggestive of a
possible negative effect of intensive BP control on kidney
function. Even among participants who had normal kidney
function at baseline, instances of eGFR#30 ml/min per
1.73 m2 were almost doubled in the intensive treatment
group (99 in the intensive treatment group versus 52 in the
standard treatment group; P,0.001) (66).
Novel Therapies and Approaches
Despite current approaches to management of diabetes
and hypertension and use of ACE inhibitors and ARB,
there is still large residual risk in DKD. Novel agents
targeting mechanisms, such as glomerular hyperfiltration,
inflammation, and fibrosis, have been a major focus for
development of new treatments. Agents that have shown
promise include ruboxistaurin, a protein kinase C-b in-
hibitor (68); baricitinib, a selective Janus kinase 1 and Janus
kinase 2 inhibitor (69); pentoxifylline, an anti-inflammatory
and antifibrotic agent (70); atrasentan, a selective endothe-
lin A receptor antagonist (71,72); and finerenone, a highly
Diabetic Kidney Disease, Alicic et al. 2039
selective nonsteroidal mineralocorticoid receptor antago-
nist (Table 4) (73). However, thus far, there are no available
phase 3 clinical trial data for these agents, and none are
approved for use in DKD.
Since the year 2008, the US Food and Drug Administra-
tion has mandated that new antihyperglycemic therapies
seeking approval for the treatment of DM2 must show CV
safety. Three agents within the glucagon-like peptide-1
receptor agonist class of medications, lixisenatide, liraglu-
tide, and semaglutide, currently have CV outcome trial
data available. The Evaluation of Lixisenatide in Acute
Coronary Syndrome Trial showed that the addition of
lixisenatide to standard care did not significantly alter the
rate of major CV events (74). In contrast, in the Liraglutide
Effect and Action in Diabetes: Evaluation of Cardiovascular
Outcome Results (LEADER) Study and the Trial to Eval-
uate Cardiovascular and Other Long-Term Outcomes with
Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-
6), fewer participants reached the primary composite CV
end point in the liraglutide and semaglutide groups
compared with those receiving placebo (hazard ratio,
0.87; P50.01 for superiority and hazard ratio, 0.74;
P,0.001 for noninferiority, respectively) (75,76). Notably,
similar benefits on CV outcomes were observed in the
LEADER Study and the SUSTAIN-6 subsets with moderate
to severe CKD. Studies in patients with DKD have
additionally shown that liraglutide lowered albuminuria
levels in patients with normal kidney function or early-
stage CKD and showed improved glycemic control in CKD
 2040

Table 4. Studies of novel treatments for diabetic kidney disease

Name of the Study Tested Intervention/Drugs Study Population Outcomes

Tuttle et al., 2005 (68) Ruboxistaurin (PKC inhibitor)
PIONEER (81) PYR-311 (anti-AGE treatment)
PREDIAN (70) Pentoxifylline (anti-inflammatory,
antifibrotic action)
Study to Test Safety and Efficacy of Baricitinib, JAK1/2 inhibitor
DM2, macroalbuminuria
DM2, HTN, 1.3#SCr#3.0 mg/dl,
protein-to-creatinine ratio $1200
mg/g
DM2, eGFR515–60 ml/min per
1.73, UAE.300 mg/24 h
DM2, eGFR520–75 ml/min per
Decreased albuminuria, stabilized kidney
function
Halted
Pentoxifylline group: eGFR decline 4.3 ml/
min per 1.73 m2 less than control group;
mean difference in albuminuria of 21%
Albuminuria reduction by 40% in the
Clinical Journal of the American Society of Nephrology

Baricitinib in Participants with 1.73 m2, macroalbuminuria highest treatment group; no effect on
Diabetic Kidney Disease (69) eGFR
RADAR and RADAR/JAPAN (71) Atrasentan (ETA) DM2, eGFR530–75 ml/min per 35% Reduction of albuminuria
1.73 m2, UACR5300–3500 mg/g
SONAR, ongoing (72) Atrasentan (ETA) HTN, eGFR515–90 ml/min per Ongoing
1.73 m2, UACR.30,5000 mg/g
PERL, ongoing (82) Allopurinol (xanthine oxidase) DM1, eGFR540–99 ml/min per Ongoing
1.73 m2, UAE518–5000 mg/d
ARTS-DN, 2015 (83) Finerenone (steroid mineralocorticoid DM2, UACR$30 mg/g, eGFR.30 No difference in eGFR, 17%–40%
receptor antagonist) ml/min per 1.73 m2 albuminuria reduction dose dependent

SCr is in milligrams per deciliter. Protein to creatinine ratio is in milligrams per gram. eGFR is in milliliters per minute per 1.73 m2. UAE is in milligrams per day. UACR is in milligrams per
gram. PKC, protein kinase C; DM2, diabetes mellitus type 2; PIONEER, A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of
Pyridorin (Pyridoxamine Dihydrochloride) in Subjects With Nephropathy Due to Type 2 Diabetes; PYR-311, pyridoxamine-311; AGE, advance glycation end product; HTN, hypertension;
SCr, serum creatinine; PREDIAN, Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease; UAE, urine albumin excretion; JAK1/2, Janus
kinases 1/2; RADAR, Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan—A Phase 2b, Prospective, Randomized, Double-Blind, Placebo-Controlled
Trial to Evaluate Safety and Efficacy; RADAR/JAPAN, RADAR in Japan; ETA, endothelin A; UACR, urinary albumin-to-creatinine ratio; SONAR, A Randomized, Multicountry, Multicenter,
Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Atrasentan on Renal Outcomes in Subjects With Type 2 Diabetes and Nephropathy; PERL, A Pilot Study of Allopurinol to Prevent
GFR Loss in Type 1 Diabetes; DM1, diabetes mellitus type 1; ARTS-DN, A Randomized, Double-blind, Placebo-controlled, Multi-Center Study to Assess the Safety and Efficacy of Different Oral
Doses of BAY94-8862 in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Nephropathy.
Table 5. Kidney outcomes in clinical trials of newer antihyperglycemic therapies

Name of the Study Tested Intervention/Drugs Study Population Outcomes

SAVOR-TIMI (84) Saxagliptin (DPP-4 inhibitor) DM2, HbA1c$6.5%, high risk for CV
events
CARMELINA (85) Linagliptin (DPP-4 inhibitor) DM2, 6.5%$HbA1c#10%,
albuminuria, macrovascualar
complications, eGFR.15 ml/min per
1.73 m2
LEADER (75) Liraglutide (GLP-1 receptor agonist) DM2, HbA1c.7%, eGFR,60 ml/min
Improvement in and/or less deterioration in
ACR categories from baseline to end of
trial (P50.02, P,0.001, and P50.05 for
normoalbuminuria, microalbuminuria,
and macroalbuminuria, respectively); no
changes in eGFR
In progress, estimated completion in January
of 2018
Lower incidence of nephropathy (new-
Clin J Am Soc Nephrol 12: 2032–2045, December, 2017

per 1.73 m2, CV coexisting disease
AWARD-7, (86) Dulaglutide (GLP-1 receptor agonist) DM2, 7.5%$HbA1c#10.5%,
15$eGFR#60 ml/min per 1.73 m2
EMPA-REG OUTCOME (78) Empaglifozin (SGLT-2 inhibitor) DM2, eGFR$30 ml/min per 1.73 m2,
high CV risk
CREDENCE (87) Canaglifozin (SGLT-2 inhibitor) DM2, 6.5%$HbA1c#12%, high CV risk,
300 mg/g$UACR#5000 mg/g,
30$eGFR#90 ml/min per 1.73 m2
onset albuminuria, doubling of SCr and
CrCl,45 ml/min per 1.73 m2; need for RRT,
death to renal causes [1.5 number of events
per 100 patients per year versus 1.9 number of
events per 100 patients per year; P50.003])
In progress, estimated completion in July of
2018
44% Relative risk reduction of doubling of
SCr (1.5% versus 2.6%); 38% relative risk
reduction of progression to
macroalbuminuria (11.2% versus 16.2%);
55% relative risk reduction of initiation of
RRT (0.3% versus 0.6%); slowing GFR
decline (annual decrease 0.1960.11 versus
1.6760.13 ml/min per 1.73 m2; P,0.001)
In progress, estimated completion in June
of 2019

eGFR is in milliliters per minute per 1.73 m2 . UACR is in milligrams per gram. SAVOR-TIMI, Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to
Other Diabetes Medications; DPP-4, dipeptidyl peptidase-4 inhibitor; DM2, diabetes mellitus type 2; HbA1c, hemoglobin A1c; CV, cardiovascular; ACR, albumin-to-creatinine ratio;
CARMELINA, Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus; LEADER, Liraglutide Effect and Action in Diabetes:
Evaluation of Cardiovascular Outcome Results; GLP-1, glucagon-like peptide-1; SCr, serum creatinine; CrCl, creatinine clearance; AWARD-7, A Study Comparing Dulaglutide With
Insulin Glargine on Glycemic Control in Participants With Type 2 Diabetes (T2D) and Moderate or Severe Chronic Kidney Disease (CKD); EMPA-REG OUTCOME, Empagliflozin Cardiovascular
Outcome Event Trial in Type 2 Diabetes Mellitus Patients; SGLT-2, sodium-glucose cotransporter 2; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in
Participants with Diabetic Nephropathy; UACR, urine albumin-to-creatinine ratio.
Diabetic Kidney Disease, Alicic et al.
2041
2042 Clinical Journal of the American Society of Nephrology
stage 3 (75). Recently released data from clinical trials of
semaglutide and dulaglutide consistently show reduced
risk of albuminuria onset and progression (75,76). The
consistency of these data across glucagon-like peptide-1
receptor agonists persuasively suggests a class effect of
protection from DKD. The mechanisms of action may be
multifactorial and include glycemic control, weight control,
and direct effects on the kidney.
In the Empagliflozin Cardiovascular Outcome Event Trial
in Type 2 Diabetes Mellitus Patients, an sodium-glucose
cotransporter 2 inhibitor, empaglifozin, also showed signif-
icantly lowered rates of death from CVD causes (38% relative
risk reduction), hospitalization for heart failure (35% relative
risk reduction), and death from any cause (32% relative risk
reduction) compared with placebo (77,78). Analysis of pre-
specified secondary outcomes showed that empaglifozin also
slowed progression of DKD and lowered rates of clinically
relevant kidney outcomes among patients with CKD stages
2–4 (78) (Table 5).
Population-Based Approaches
Success of this strategy has been shown by recently
available data from the Centers for Disease Control. A 54%
decrease in diabetes-related kidney failure occurred be-
tween the years 1996 and 2013 among American Indians, a
group with a historically high prevalence of diabetes and
DKD. Interventions leading to this change included sys-
tematic implementation of guidelines for treatment of
hypertension and diabetes, regular albuminuria testing,
use of ACE inhibitors and ARBs, services to support nutri-
tion, physical activity, and diabetes education (79).
Conclusion
Since the discovery of insulin in the 1920s, research has
made significant strides toward understanding and im-
proving the clinical management of diabetes. Although
these advances have meaningfully improved outcomes for
diabetes complications, such as CVD, these improvements
have not translated nearly as well to DKD or ESRD (80). In
response, the International Society of Nephrology has
convened a Global Kidney Health Initiative to call attention
to kidney diseases overall. Key collaborative stakeholders
in the quest to fight DKD should include patients, health
care providers and payers, advocacy groups, scientists, and
governmental agencies. Advocacy and a call to action are
essential to effective dissemination and implementation of
current best practices. Using public health and population
approaches in clinical practice and promoting meaningful
and strategic research will be key to improving health
outcomes for people with diabetes and DKD.
Disclosures
K.R.T. has received consulting fees from Eli Lilly and Company,
Amgen, Noxxon Pharma, and Boehringer Ingelheim. The other
authors have no disclosures.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Dysproteinemias and Glomerular Disease
Nelson Leung,1,2 Maria E. Drosou,1 and Samih H. Nasr 3

Abstract
Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage.
The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are
increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including
the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is Divisions of
deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomer- 1
Nephrology and
ulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Hypertension and
2
Ig deposition include the activation of the complement system, which causes complement deposition in C3 Hematology and
3
Department of
glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is Laboratory Medicine
involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be and Pathology, Mayo
produced by clones from any of the B cell lineages and that a malignant state is not required for the development of Clinic, Rochester,
kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called Minnesota
monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal
significance, preservation of renal function requires substantial reduction of the monoclonal protein. With Correspondence:
Dr. Nelson Leung, 200
better understanding of the pathogenesis, clone-directed strategies, such as rituximab against CD20 expressing First Street SW,
B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These Rochester, MN 55905.
clone-directed therapies been found to be more effective than immunosuppressive regimens used in non- Email: Leung.nelson@
monoclonal protein–related kidney diseases. mayo.edu
Clin J Am Soc Nephrol 13: 128–139, 2018. doi: https://doi.org/10.2215/CJN.00560117

Introduction
Dysproteinemia results from the overproduction of
a monoclonal Ig (1). All B cell clones can produce
monoclonal gammopathy, but the incidence varies. They
include CD201CD382 B cell clones involved in non-
Hodgkin lymphoma, CD51CD191 clones in chronic
lymphocytic leukemia, CD191CD381 clones in lym-
phoplasmacytic lymphoma that produce Waldenström
macroglobulinemia, and CD192 CD381 plasma cell
clones in multiple myeloma (2). Monoclonal gammop-
athy is nearly universal with the latter two clones but
less common in chronic lymphocytic leukemia and
CD201 CD382 B cell clones. Only one Ig light chain
can be produced by a clone. In rare circumstances, the
Ig heavy chain is truncated and circulates as a mono-
clonal heavy chain.
Because the size of the monoclonal protein often
reflects the clonal burden, it can be used as a bio-
marker for diagnostic and prognostic purposes. Mono-
clonal gammopathy of undetermined significance
(MGUS) is distinguished from multiple myeloma and
Waldenström macroglobulinemia by the size of the
monoclonal protein (M protein) or serum free light
chain (sFLC) (2,3). Conversely, response to therapy is
determined by the reduction of M protein and/or sFLC
concentration (4). The concentration of sFLC at diagnosis
is also prognostic in Ig light chain (AL) amyloidosis (5).
Some M proteins however are toxic and cause organ
dysfunction. Such is the case in AL amyloidosis. The
misfolded monoclonal free light chain (FLC) forms
amyloid that is deposited in the soft tissues (6). The organ
is damaged by the monoclonal FLC rather than the clonal
mass (7). This explains why most patients have ,10%
bone marrow plasma cells. In those with .10% bone
marrow plasma cells, most do not have any myeloma-
defining events known as hypercalcemia, AKI as a result
of light-chain cast nephropathy, anemia, or lytic bone
lesions (CRAB). In fact, over 80% of the patients would be
best classified as having monoclonal gammopathy of
renal significance (MGRS). Animal studies have shown
that only the M protein is necessary for reproduction of
the renal lesion (8). Unfortunately, efforts to identify
properties that predict nephrotoxicity have been unsuc-
cessful so far. The toxicity is not limited to the kidney,
because these proteins can also cause neuropathies,
dermopathies, ocular disorders, and other multisystemic
diseases (9).
Pathogenesis
The kidney is the organ most affected by M proteins.
A number of factors may contribute to this (10). The
kidneys are exposed to more cardiac output than any
other organ, except the lungs. This increased exposure is
paired with the unique environment, where the pH and
electrolyte concentrations are present in no other tissues.
These changes can alter the chemical characteristics of
the M protein, making it more toxic (11). Finally, recep-
tors and proteins are present in the kidney that can in-
teract with Igs. The megalin-cubilin receptor actively

128 Copyright © 2018 by the American Society of Nephrology www.cjasn.org Vol 13 January, 2018
Clin J Am Soc Nephrol 13: 128–139, January, 2018
endocytoses FLC for degradation in proximal tubular cells (12).
The inability to degrade certain Ig light chains is the pathogenic
basis in light-chain proximal tubulopathy. On the other hand,
formation of obstructive casts by the binding and precipitation
of monoclonal FLCs and Tamm Horsfall protein is the char-
acteristic of light chain cast nephropathy. (13).
Several mechanisms of nephrotoxicity have been de-
scribed, which include deposition, complement activation,
cytokine activation, and precipitation (Figure 1) (14,15).
Deposition is the most common and seen in Ig-related (AIg)
amyloidosis, monoclonal Ig deposition disease, prolifera-
tive GN with monoclonal Ig deposits, immunotactoid GN,
and fibrillary GN (FGN) (16). The deposits can be orga-
nized (as in AL, immunotactoid GN, and FGN) or un-
organized (e.g. proliferative GN with monoclonal Ig
deposits and monoclonal Ig deposition disease). Extrarenal
deposition can occur especially in AIg amyloidosis and
monoclonal Ig deposition disease (17–21). Extrarenal in-
volvement is rare with immunotactoid GN and FGN and
has not been described in proliferative GN with monoclonal
Ig deposits (22–25).
Precipitation is the mechanism of injury in cast nephropa-
thy, cryoglobulinemia, and (cryo)crystalglobulinemia. This oc-
curs predominately in the distal tubules in cast nephropathy
(10). In contrast, the precipitation occurs intravascularly in
cryoglobulinemic GN (26). Cryoglobulins are most charac-
teristically found in the glomerular capillaries, often result-
ing in pseudothrombi formation described as cryoplugs.
Complement activation and cytokine activation are also
associated with M proteins. The incidence of monoclonal
gammopathy in patients with C3 glomerulopathy has been
found to far exceed that of the normal population, especially in
people .50 years of age (27–30). Although C3 nephritic factor
and autoantibody against factor H have been reported in some
patients and while others have complement gene polymor-
phisms, the mechanism of complement activation remains
undetermined in the majority of patients (27,29–31). Comple-
ment is also activated in monoclonal gammopathy–associated
membranous nephropathy, proliferative GN with monoclonal
Ig deposits, immunotactoid GN, FGN, and cryoglobulinemic
GN. Cytokine activation is involved in the renal lesion of
patients with polyneuropathy, endocrinopathy, orga-
nomegaly, monoclonal gammopathy, and skin changes
(POEMS) syndrome (32). The cytokines activation results in
Figure 1. | Mechanisms of glomerular toxicity by monoclonal gammopathy. AIg amyloidosis, immunoglobulin-derived amyloidosis.; C3G, C3
glomerulopathy; MIDD, monoclonal Ig deposition disease; PGNMID, proliferative GN with monoclonal Ig deposits; POEMS, polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.
Dysproteinemias and Glomerular Disease, Leung et al. 129
a glomerulopathy that resembles thrombotic microangiopa-
thy but without the microangiopathic hemolytic anemia.
Interestingly, the M protein is not identifiable in the kidney in
either of these entities, and a direct link to either mechanism
has not been identified.
Glomerular Lesions
AIg Amyloidosis
AIg amyloidosis is the most common glomerular lesion
associated with monoclonal gammopathy (33). AL amy-
loidosis is the most common subtype, but AH amyloidosis
and Ig heavy and light chain (AHL) amyloidosis also exist
(Table 1). Clinically, the entire group behaves similarly,
with a median age of presentation in the low 60 years of
age and a slight dominance of men (approximately 60%).
Patients present with mild renal impairment (median
serum creatinine [Scr] of 1.2 mg/dl) and nephrotic-range
proteinuria (6 g/d). Nephrotic syndrome is present in more
than two thirds of patients. ESRD predominantly occurs in
patients who present with renal manifestation (34). Recur-
rence after kidney transplant has been reported but can
take years to occur (35). AIg amyloid is systemic and can be
deposited in any visceral organ (17). The heart is the most
common extrarenal organ involved followed by nerves. Heart
involvement may be less common in AH and AHL amyloid-
osis versus AL amyloidosis (36). Patients with severe heart
involvement have the poorest prognosis, even with modern
therapies (37). Although 40% of patients have .10% clonal
plasma cells on bone marrow biopsy, ,20% actually have
symptomatic multiple myeloma. The lethality of this disease
stems from the progressive organ dysfunction, which is not
dependent on clonal expansion as in multiple myeloma.
Amyloid deposits can be found in all three compart-
ments of the kidney (33). Amyloid deposits are best seen
along the glomerular basement membranes (GBMs) and
mesangium, causing mesangial expansion (Figure 2A). The
mesangial deposits can appear nodular. Deposits are typi-
cally periodic acid–Schiff (PAS) and silver negative (Figure
2A). However, amyloid spicules, which are a parallel align-
ment of subepithelial fibrils perpendicular to the GBM,
appear silver positive. Amyloid fibrils are congophilic and
display an apple green birefringence under a polarized light
(Figure 2, B and C). Immunofluorescence studies show a
 130

Table 1. Monoclonal gammopathy of renal significance glomerular lesions: Clinical features, pathologic characteristics, and outcomes

Renal Lesion Clinical Features Pathologic Characteristics Outcomes and Post-Transplant Course

Ig-related amyloidosis Proteinuria, NS, CKD LM: PAS (2), Ag (2) acellular deposits PRD and ESRD common; worse outcomes
(AL, AHL, AH) if concurrent cardiac involvement
HTN and hematuria uncommon IF: LC and/or HC restricted Recurrence in transplant uncommon
EM: random, nonbranching fibrils (7–12
nm)
Congo red (1)
Fibrillary GN Proteinuria, HTN, hematuria, CKD, NS LM: MesGN, mesangial expansion, PRD and ESRD common
MGN, MPGN, PAS (1), Ag (2)
IF: polyclonal IgG .80% Recurrence in transplant common if
monoclonal gammopathy is present
EM: random fibrils (9–26 nm)
Congo red (2)
Immunotactoid GN/ Proteinuria, NS, CKD, hematuria LM: MPGN, MGN, ECPGN, PAS (weak), PR common, PRD, ESRD
GOMMID Ag (2)
Clinical Journal of the American Society of Nephrology

Hypocomplementemia IF: IgG, C3, LC restricted Recurrence in transplant

Type 1 cryoglobulinemic
GN
Monoclonal Ig deposition
disease (LCDD,
LHCDD, HCDD)
Proliferative GN with
monoclonal Ig deposits
C3 glomerulopathy
C3 GN
DDD
EM: parallel, hollow microtubules (8–60
nm)
Congo red (2), cryoglobulin (2)
Proteinuria, hematuria LM: MPGN, ECPGN, subendothelial CR common, frequent relapse,
and intracapillary, PAS (1) CKD, ESRD, recurrence in
Nephritic/nephrotic syndrome, AKI, CKD, HTN, IF: monoclonal IgG/IgM and C3, C4, and transplant
purpura, arthralgias, hypocomplementemia C1q deposits
EM: curvilinear microtubules, 10–50 nm
Proteinuria, NS, CKD, AKI LM: PAS (1), Ag (1), mesangial PR common, ESRD
expansion, nodular GS, thickened
TBM
HTN and hematuria uncommon IF: linear LC- and/or HC-restricted Recurrence in transplant common
deposits in TBM, GBM, and vascular wall
EM: punctate, powdery electron dense
deposits
Proteinuria, hematuria, NS, CKD, AKI LM: MPGN, ECPGN, MesGN, MGN, PRD, PR, ESRD
crescents (occasionally)
IF: IgG (rarely IgM and IgA), LC and HC Recurrence in transplant common
restricted (mostly IgG3)
EM: mesangial, subendothelial, and
intramembranous deposits
Hematuria, proteinuria, CKD LM: MPGN, ECPGN, MesGN, MGN PRD and ESRD common
Low C3 level and normal C4 level common IF: granular C3 deposits, little or no Ig or C3GN: recurrence in transplant most
C1q deposits common
EM: DDD, intramembranous “sausage- DDD: recurrence in transplant
shaped deposits”; C3 GN, mesangial,
subendothelial, and subepithelial
deposits
Clin J Am Soc Nephrol 13: 128–139, January, 2018 Dysproteinemias and Glomerular Disease, Leung et al. 131

light-chain restriction with AL and AHL (Figure 2F).

Most common symptoms: The findings are sorted on the basis of order of frequency. AL, Ig light chain amyloidosis; AHL, Ig heavy and light chain amyloidosis; AH, Ig heavy chain amyloidosis;

endocapillary proliferative GN; PR, partial response: reduction in proteinuria by at least 50% and to ,2 g/d with stable renal function (#20% increase in serum creatinine); CR, complete remission:
microscopy; PRD, progressive renal disease: failure to meet criteria for either complete response or partial response but not reaching ESRD, including patients with unremitting proteinuria or

remission of proteinuria to ,500 mg/d with normal renal function; LCDD, light-chain deposition disease; LHCDD, light- and heavy-chain deposition disease; HCDD, heavy-chain deposition
disease; GS, glomerulosclerosis; TBM, tubular basement membrane; GBM, glomerular basement membrane; C3G, C3 glomerulopathy; DDD, dense deposits disease; ATN, acute tubular necrosis;
Monoclonal Ig heavy chain is seen in both AHL and
Outcomes and Post-Transplant Course

progressive CKD; MesGN, mesangial proliferative GN; MGN, membranous GN; MPGN, membranoproliferative GN; GOMMID, GN with organized microtubular Ig deposits; ECPGN,
AH, but monoclonal Ig light chain is absent in AH. Amyloid

NS, nephrotic syndrome; HTN, hypertension; LM, light microscopy; PAS, periodic acid–Schiff; Ag, silver stain; IF, immunofluorescence; LC, light chain; HC, heavy chain; EM, electron
deposits are typically identified in the vessels (.80%) and the
Course in transplant: insufficient

interstitium (53%–63% of patients). On electron microscopy

(EM), amyloid appears as solid randomly arranged fibrils
with a diameter of 7–12 nm irrespective of the precursor
protein (Figure 2, D and E). Typing of some amyloid can be
ESRD common, PRD

done by immunohistochemistry/immunofluorescence (38).

However, mass spectrometry with proteomic analysis has be-
come the gold standard for amyloid typing (39). Most recently,
urinary exosomes have been investigated as a potential tool in
evidence

diagnosis and response assessment in AIg amyloidosis (40).

Monoclonal Ig Deposition Disease

Monoclonal Ig deposition disease is also represented by
three subtypes (19). Light-chain deposition disease is the most
IF: fibrinogen material in GC lumen and
mesangiolysis, ATN, thrombi in GC

common followed by light- and heavy-chain deposition disease,

whereas heavy-chain deposition disease (HCDD) is the rarest.
Pathologic Characteristics

The subtypes are indistinguishable by light microscopy. They

can only be separated by immunofluorescence. The Ig heavy
LM: double contour of GBM,

EM: double contour of GBM,

chain in HCDD is typically truncated (41). Patients with HCDD

subendothelial “fluff”

have heavier proteinuria, but otherwise, all patients with mono-

clonal Ig deposition disease behave similarly (19). The median
age of these patients is between 56 and 64 years old. Nearly two
thirds are men (19,21,42). Median Scr ranges from 2.2 to 3.8
mg/dl. Proteinuria averages between 1.5 and 4.1 g/d.
Extrarenal manifestations mainly involve the heart and
liver but are much less common than in AL amyloidosis.
wall

Most patients with monoclonal Ig deposition disease have

MGRS instead of multiple myeloma. A series from Italy
found multiple myeloma in 65% of patients and chronic
lymphocytic leukemia in 3% of patients (20). However,
when myeloma was defined by CRAB, the rate dropped to
20%–22%, suggesting that most of the patients had
smoldering multiple myeloma rather than multiple mye-
Anemia, thrombocytopenia, schistocytes

loma (19,43). Mortality of these patients is largely de-

pendent on the presence of multiple myeloma. Recurrence
Clinical Features

in the renal allograft is quite common and rapid (44).

The most common renal histologic finding is nodular
Proteinuria, hematuria, CKD

mesangial sclerosis (19,42) (Figure 3A). The nodules are PAS

and silver positive and can mimic those of diabetic nephrop-
athy (Figure 3A). Membranoproliferative features, such as GBM
duplication and mesangial hypercellularity, may be present.
Cellular crescents can be seen focally in patients with rare cases
(particularly in aHCDD) (45). Linear staining of the GBM and
even more consistently, the tubular basement membranes
(TBMs) by a single Ig light chain is characteristic of light-chain
deposition disease and light- and heavy-chain deposition
disease on immunofluorescence (Figure 3, C and D). Nearly
90% of patients have a k-isotype. These deposits are electron
dense and have an amorphous or powdery appearance on
EM (Figure 3B).
GC, glomerular capillary.
Table 1. (Continued)

Renal Lesion

microangiopathy

Proliferative GN with Monoclonal Ig Deposits

Proliferative GN with monoclonal Ig deposits is another
Thrombotic

renal disease with nonorganized monoclonal Ig deposits.

The deposits are composed of the entire Ig and usually an
IgG, although IgA and IgM have rarely been described (46).
Patients present with renal impairment (median Scr of 2.8
mg/dl), proteinuria (median of 5.7 g/d), and hematuria
132 Clinical Journal of the American Society of Nephrology

Figure 2. | Renal biopsy in a 72-year-old woman showing lambda light chain amyloidosis. (A) Glomerular mesangial areas and glomer-
ular capillary walls are markedly and globally expanded by cellular silver-negative amyloid deposits (3200). (B) Amyloid deposits by definition are
Congo red positive (3200). (C) Under polarized light, they show anomalous colors (yellow, green, and red; 3200). (D) The deposits exhibit
randomly oriented, straight fibrils on transmission electron microscopy (49,000). (E) Amyloid spicules, resulting from parallel alignment of amyloid
fibrils perpendicular to the glomerular basement membrane, are seen (electron microscopy, 313,000). Amyloid spicules are more common in Ig
light chain amyloidosis than serum amyloid A amyloidosis and are not usually seen in other types of renal amyloidosis. (F) On immunofluo-
rescence, glomerular amyloid deposits stain brightly for l-light chain (3200). Staining for k-light chain was negative (not shown).

(22). Multiple myeloma is rare, with approximately 80% of
patients having no circulating M protein detectable at the
time of diagnosis. Clonal identification is difficult if an M
protein is not detected (46).
The renal lesion is characterized by proliferative GN (47).
Predominantly membranoproliferative GN and endocapil-
lary proliferative GN are the two most common patterns of
injury (Figure 4A). Segmental membranous nephropathy
features can coexist, and a pure mesangial proliferative GN
pattern has been reported. Crescents are seen in one third of
patients, and crescentic transformation has been reported
after upper respiratory tract infection and treatment with
filgrastim (48). The deposits on EM are seen predominately in
the mesangium and subendothelial space, although subepi-
thelial deposits can also be detected in some patients. The
texture of deposits is typically finely granular without
substructure (Figure 4B), although focal ill-defined fibrils
or lattice-like arrays can be seen. On immunofluorescence,
the deposits are confined to glomeruli and exhibit IgG3
subclass in 66%) and k light chain in 73% and l in 27%
(Figure 4, C–E) (22,47). Most cases show bright glomerular
C3 and C1q staining in the same distribution as IgG staining.
Cryoglobulinemic GN
Cryoglobulinemic GN is a consequence of one of the
three types of cryoglobulins. Only types 1 and 2 contain
monoclonal Igs (49). Type 1 is all monoclonal, usually
composed of an IgM but can be IgG or IgA. Type 2 is mixed
and contains a monoclonal IgM acting as a rheumatoid
factor against polyclonal IgG. Type 3 is also mixed, made
up of polyclonal Igs, usually the result of infection or
autoimmune diseases. All type 1 and some type 2 are the
results of a plasma cell dyscrasia or lymphoproliferative
disorder, particularly lymphoplasmocytic lymphoma.
However, hepatitis C is the most common cause of type
2 cryoglobulinemia in the world. GN is most common with
type 2 but can occur in all three types. Median age is 62
years old, and it is more common in women (50). Extrarenal
manifestations are common and often present as purpura,
ulcers, peripheral neuropathy, arthralgias, and vasculitis of
Clin J Am Soc Nephrol 13: 128–139, January, 2018 Dysproteinemias and Glomerular Disease, Leung et al. 133

Figure 3. | Light-chain deposition disease on renal biopsy exhibits nodular mesangial sclerosis and punctate linear monoclonal deposits along
renal basement membranes. (A) Glomeruli exhibit marked nodular mesangial expansion by periodic acid–Schiff-positive material, mimicking
diabetic glomerulosclerosis (3200). (B) On electron microscopy, punctate powdery electron dense deposits are seen along tubular basement
membranes (315,000). Similar deposits are frequently seen along glomerular basement membranes and in the mesangium (not shown). On
immunofluorescence in this case of l–light-chain deposition disease, there is diffuse linear glomerular and tubular basement membrane staining
for (C) l (3100) with (D) negative k (3100).

other organs (49). Severe hypertension is also commonly
observed.
Cryoglobulinemic GN presents mainly in a membrano-
proliferative pattern (Figure 5A) (51). Eosinophilic cryo-
globulins are commonly observed in the glomerular capillary
lumina. These are strongly PAS positive and trichrome red
(Figure 5A). Leukocytoclastic vasculitis is common with
neutrophils in the acute phase, whereas macrophages and
monocytes are in the acute and chronic phases. Crescents are
present in some cases. The Ig deposits are dependent on the
makeup of the cryoglobulin; however, C3 is often prominent.
In type 2, both IgM and IgG will be present, but light-chain
restriction may not be shown, because the IgG is polyclonal.
Light-chain restriction is usually present in type 1. In some
cases, the deposits do not stain on routine immunofluores-
cence on frozen tissue and require paraffin immunofluores-
cence with protease digestion for detection (52). Intraluminal,
mesangial, and subendothelial deposits are seen on EM
along with double contouring of the GBM. The deposits in
most cases are focally organized, showing curved or straight
microtubules (Figure 5B).
Immunotactoid GN
Immunotactoid GN is another glomerular disorder
resulting from deposition of microtubules (53). By defini-
tion, cryoglobulinemic GN must be ruled out, because they
are difficult to differentiate histopathologically. Other than
the absence of cryoglobulins, extrarenal manifestations are
uncommon in immunotactoid GN. Rarely, vasculitic skin
lesions, immunotactoid corneal and liver deposits, and
mononeuritis multiplex have been reported (54–56). Me-
dian age ranges from 57 to 61 years old, with a slight
increased prevalence in men (53,54). Most patients present
with nephrotic-range proteinuria, with a range of 6–11 g/d.
Median creatinine at presentation is 1.5 mg/dl. Micro-
scopic hematuria can be seen in some patients on urinal-
ysis. A monoclonal gammopathy is identified in 80%–90%
of cases. Hypocomplementemia is not uncommon. One
particular characteristic of immunotactoid GN is its association
with chronic lymphocytic leukemia. Approximately 50% of the
patients had chronic lymphocytic leukemia or monoclonal
B cell lymphocytosis (MBL; a chronic lymphocytic leukemia
clonal disorder) (54,57).
The most common pattern in immunotactoid GN is
membranoproliferative with mesangial expansion, hyper-
cellularity, and double contouring (53). Large subendothelial
deposits mimicking wire loop–type deposits of lupus nephritis
can be seen in some cases (Figure 6A). Immunotactoid GN
could also present with membranous, like features, with
thickening basement membranes and spikes either globally or
segmentally. The least common pattern is endocapillary pro-
liferative GN characterized by leukocyte infiltration, resulting
in luminal occlusion but without GBM duplication. Focal
crescents and fibrinoid necrosis are seen in a small number of
patients (53,58). Patients who have underlying chronic lym-
phocytic leukemia or lymphoplasmocytic lymphoma often
have neoplastic lymphocytic infiltration in the kidney. On
immunofluorescence, nearly 90% have IgG staining of 2–31
intensity. The rest stain for IgA and IgM. C3 staining follows
the same pattern as the IgG. C1q deposits are seen in over one
half of cases. Light-chain restriction can be shown in 69%–93%
of cases. IgG1 represents about one half of the IgG subtypes
in immunotactoid GN. The deposits are uniformly composed
of microtubules with hollow centers that have an average
diameter of 31 nm but can range from 9 to 52 nm (53,54). They
are typically arranged in parallel arrays (Figure 6B). Deposits
can be found in the mesangium and the subendothelial and
subepithelial spaces.
134 Clinical Journal of the American Society of Nephrology

Figure 4. | Proliferative GN with monoclonal Ig deposits histologically exhibits a membranopliferative GN with monoclonal IgG3 granular
deposits. (A) The glomerulus depicted shows a membranoproliferative pattern of injury with lobular accentuation of the tuft due to prominent
mesangial hypercellularity and mild mesangial sclerosis. There is widespread duplication of the glomerular basement membrane with associated
cellular interposition. The glomerular capillary lumina are occluded by endothelial cell proliferation and infiltrating mononuclear inflammatory cells
(periodic acid–Schiff; 3400). (B) Large mesangial and subendothelial granular electron dense deposits (without substructure) are seen by transmission
electron microscopy (36000). In this case of proliferative GN with monoclonal Ig deposits, there is bright granular mesangial and glomerular
capillary wall staining for (C) IgG and (D) l-light chain with (E) negative staining for k-light chain on immunofluorescence (3400 for C–E).

Fibrillary GN immunofluorescence in some patients. C3 follows the IgG

FGN is the first of two entities that are only occasionally
associated with a monoclonal gammopathy. The lesion is
characterized by glomerular deposition of nonamyloid fi-
brils. Although it shares many features with immunotactoid
GN histologically, the etiology is quite different; ,20% of
patients have a monoclonal gammopathy in FGN (59). Other
conditions associated with FGN include solid malignancies,
autoimmune diseases, and hepatitis C. Hypocomplementemia
is rare. The average age of patients ranges from 50 to 59 years
old (54,59,60). Proteinuria is less severe than immunotactoid
GN, averaging between 5 and 5.6 g/d. Scr at presentation
ranges from 1.6 to 3.2 mg/dl. Microscopic hematuria and
hypertension are observed in over one half of the patients.
Mesangial proliferative GN is the most common pattern
in FGN seen in approximately 70% of patients (54,59,60).
This is followed by membranoproliferative GN, endocapil-
lary proliferative GN, and segmental membranous ne-
phropathy pattern and diffuse sclerosing GN. Crescents
can be seen in up to one quarter of cases. IgG is present in
100% of patients, whereas IgA and IgM can be seen on
staining pattern, and C1q is seen in some patients. The
majority of cases have polyclonal light-chain staining, with
only approximately 10% of cases showing light-chain
restriction. In addition to glomerular deposits, TBM staining
can also be found in some cases. Fibrils are solid and
randomly arranged, with a diameter ranging from 9 to 26 nm.
Fibrils are most commonly found in the mesangium but
can be in the lamina densa and subepithelial space as well
as the TBM.
C3 Glomerulopathy
C3 glomerulopathy is represented by C3 GN and dense
deposits disease. This topic is discussed in greater detail
elsewhere in this issue. Direct evidence implicating the mono-
clonal gammopathy as a cause is lacking in most patients
(27,28,30). Rather, the association is on the basis of epidemio-
logic data. This is especially pertinent in patients over 50 years
of age, in whom the prevalence of monoclonal gammopathy
ranges from 31% to 83% versus approximately 3% in the age-
matched population (28,30,61).
Clin J Am Soc Nephrol 13: 128–139, January, 2018 Dysproteinemias and Glomerular Disease, Leung et al. 135

Figure 5. | Cryoglobulinemic GN shows membranoproliferative GN with microtubular deposits. (A) Most cases of cryglobulinemic GN exhibit
a membranoproliferative GN pattern of injury characterized by mesangial hypercellularityand expansion and duplication of the glomerular basement
membranes (3200). The hallmark histologic finding in cryoglobulinemic GN is glomerular intracapillary immune deposits (so called “pseudo-
thrombi”), which appear red on trichrome stain. In most but not all cases of cryoglobulinemic GN, the deposits on electron microscopy focally exhibit
organized substructure. The most common substructures observed are short, straight to mildly curved microtubules as shown in B (349,000).

Hematologic Conditions
Monoclonal gammopathy is a sequela of lymphoproli-
ferative disorders or plasma cell dyscrasia. These disorders
are classified as an MGUS or MBL if they do not meet
criteria for symptomatic lymphoma or multiple myeloma.
However, if the clone produces a nephrotoxic M protein, it
would be renamed as MGRS. Each hematologic disorder
has its own preferential kidney diseases, although no renal
lesion is exclusive to any hematologic disorder.
Multiple Myeloma
Multiple myeloma is a malignant condition of the plasma
cells. Symptomatic multiple myeloma is diagnosed either by
the presence of a CRAB lesion or when the patient is at high
risk of end organ damage (3). The most common kidney
disease in multiple myeloma is cast nephropathy, which
has now become a myeloma-defining event (3). How-
ever, cast nephropathy can also be seen in patients with
Waldenström macroglobulinemia and chronic lymphocytic
leukemia (62,63). The most common glomerular lesion is AL
amyloidosis, which is present in 3%–5% of patients with
multiple myeloma during autopsy (64). Monoclonal Ig de-
position disease was identified in only 2% in this study. Rate
of monoclonal Ig deposition disease was found to be
similar to AL amyloidosis (22% versus 21%, respectively)
in a renal biopsy series of patients with multiple myeloma
(65). The rates were also similar in patients with MGRS/
MGUS (11.6% versus 10.7%, respectively) (66). Interestingly,

Figure 6. | Photographs of kidney biopsy specimen from a patient with immunotactoid glomerulopathy show large subendothelial deposits
composed on microtubules. (A) In this case of immunotactoid glomerulopathy, large trichrome red subendothelial deposits (mimicking wire
loop–type deposits of lupus nephritis) are seen (3400). Segmental duplication of the glomerular basement membranes is seen. (B) On electron
microscopy, the deposits in immunotactoid glomerulopathy are composed of microtubules that show parallel alignment (324,500).
136 Clinical Journal of the American Society of Nephrology
cryoglobulinemic GN was seen in 16.5% of patients with
MGRS/MGUS but has not been reported in patients with
multiple myeloma. FGN, immunotactoid GN, and light-
chain proximal tubulopathy are rarely reported with multiple
myeloma.
Lymphoplasmocytic Lymphoma/Waldenström
Macroglobulinemia
Lymphoplasmocytic lymphoma is a lymphoproliferative
disorder that possesses both B cell (CD19) and plasma cell
(CD38) characteristics. Waldenström macroglobulinemia is
the condition characterized by a serum monoclonal IgM
produced by the lymphoplasmocytic lymphoma. More
than one set of diagnostic criteria exist for Waldenström
macroglobulinemia. One requires .10% involvement of
lymphoplasmocytic lymphoma in the bone marrow. Pa-
tients with less lymphoplasmocytic lymphoma involvement
are considered to have IgM MGUS, and those with .10%
but no end organ damage are classified as smoldering
Waldenström macroglobulinemia (67). In the past, dense
eosinophilic occlusive capillary thrombi were commonly
found (68). All patients with these endocapillary thrombi
had either cryoglobulins or high concentrations of mono-
clonal IgM. EM was not performed in this study. Two more
recent series, however, found that AIg amyloidosis was
the most common renal lesion in Waldenström macro-
globulinemia. Cryoglobulinemic GN had dropped to sec-
ond (43,63). Reasons for this are unclear, but kidney biopsy
may have been skipped if cryoglobulins were detected in
the blood. Cast nephropathy and monoclonal Ig deposition
disease were the next most common in one series, whereas
cast nephropathy and MPGN were the next most common
in another series. Intracapillary IgM deposits were much
less commonly found. Other lesions seen were thrombotic
microangiopathy and light-chain proximal tubulopathy
with Fanconi syndrome. Lymphoplasmocytic lymphoma
infiltration was common.
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia is the blood component
of the same disease represented by small lymphocytic
lymphoma in the lymphoid tissue. MBL is the MGUS
equivalent in chronic lymphocytic leukemia. Kidney dis-
ease is less common in chronic lymphocytic leukemia
than in Waldenström macroglobulinemia or multiple
myeloma. A large study of 1043 patients newly diagnosed
with chronic lymphocytic leukemia/small lymphocytic
lymphoma found that 10% of patients had renal impair-
ment, whereas another 14.5% developed renal impairment
during the course of their disease (69). Another study from
the same institution found that only 1.2% of all patients with
chronic lymphocytic leukemia or MBL (n54024)
underwent a kidney biopsy (62). Despite the lower prev-
alence, the variety of kidney diseases was similar to that of
multiple myeloma and Waldenström macroglobulinemia.
chronic lymphocytic leukemia infiltration was the most
common histopathologic finding, accounting for 73% of
patients (70). The chronic lymphocytic leukemia infiltration
often coexisted with other lesions, and granulomatous
reaction was noted in some (62,71). Cryoglobulinemia
GN (20%) was the most common glomerular lesion fol-
lowed by minimal change disease (13.3%). Immunotactoid
GN, FGN, AHL amyloidosis, and MPGN each accounted
for 6.6%. In another study, MPGN was the most common
glomerular lesion (20%) followed by minimal change
disease (10%). Amyloidosis, membranous nephropathy,
and mesangial proliferative GN were also reported along
with TMA (12%) and light-chain cast nephropathy (7%).
Monoclonal Gammopathy of Renal Significance
Monoclonal gammopathy of renal significance is a term
used to describe hematologic conditions that produce a
nephrotoxic M protein but do not meet criteria for symp-
tomatic multiple myeloma or lymphoma (72). It differs
from MGUS, which cannot have any end organ damage, by
the presence of the kidney disease. Like MGUS, however,
monoclonal gammopathy of renal significance could arise
from any clone from the B cell lineage. However, by
definition, cast nephropathy could not be the result of
monoclonal gammopathy of renal significance, because it
is a myeloma-defining event (3). It is now recognized that
most glomerular lesions associated with an M protein are
due to MGRS rather than its malignant counterpart (16). In
AL amyloidosis and monoclonal Ig deposition disease,
evidence suggests that patients with coexistence of multiple
myeloma have a worse prognosis compared with those with
MGRS (73,74). This suggests that patients with kidney
diseases associated with MGRS may require different
management from those secondary to multiple myeloma/
Waldenström macroglobulinemia/chronic lymphocytic
leukemia.
Management
The management of glomerular disease secondary to
monoclonal gammopathy has changed significantly since
the introduction of the concept of MGRS (72,75). Treatment
is no longer decided by the renal histology but rather, is
decided by the nature of the clone producing the M protein.
Initiation of therapy also no longer relies on presence of
malignant characteristics. Traditional immunosuppressive
drugs and renin-angiotensin system blockade are generally
ineffective at preventing ESRD (76). Clone-directed therapy
is the key. Thus, clonal identification is extremely impor-
tant in choosing the right treatment. The renal histology,
however, remains useful for predicting the natural history,
clinical features, and recurrence after kidney transplanta-
tion. One should not forget about extrarenal involvement in
patients with AL amyloidosis and monoclonal Ig deposi-
tion disease (17,21,42). Patients with severe heart involve-
ment may need to have modified chemotherapy,
aggressive fluid management, and care for CKD (77–79).
The speed of recurrence after kidney transplant should be
taken into account when deciding on transplantation
(35,44,80). A good understanding of the differences can
help select the best options for these patients.
The most important drug in the treatment of glomerular
diseases associated with monoclonal gammopathy is
bortezomib, a proteosome inhibitor. Other proteosome
inhibitors are now available, but bortezomib has the
most robust data in the treatment of these diseases (81).
Bortezomib represents the most important advance in the
treatment of AIg amyloidosis since the introduction
of high-dose melphalan followed by autologous stem cell
Clin J Am Soc Nephrol 13: 128–139, January, 2018
transplant, melphalan, and dexamethasone (82,83). In com-
bination with cyclophosphamide and dexamethasone,
bortezomib produced response rates as high as 94%, with
66%–71% having a very good partial response (VGPR)
(84,85). Achievement of VGPR, which is measured by
either a difference of the involved minus the uninvolved
sFLC of ,40 mg/L or .90% reduction of difference of the
involved minus the uninvolved sFLC, has been found to be
associated with significant improvement in overall and
renal survival (86,87). Patients with complete response are
less likely to have recurrence after kidney transplant (88).
Bortezomib seems to be the most effective agent in mono-
clonal Ig deposition disease (21,42,74,89). In one study,
immunomodulatory drugs represented by thalidomide and
lenalidomide were found to be less effective in achieving
VGPR or better responses (21). Fortunately, the hematologic
response can be improved by the addition of autologous
stem cell transplant. Achievement of VGPR in monoclonal Ig
deposition disease similarly has been found to improve renal
and patient survival (21,42,74,89). Kidney transplant has been
successfully performed in patients with hematologic com-
plete response without recurrence. A complete response is
defined by negative serum and urine immunofixation and
normal sFLC ratio. In multiple myeloma, it is confirmed by a
negative bone marrow biopsy. More recently, achievement of
VGPR or better was found to be effective at preventing the
development of ESRD in patients with C3 glomerulopathy
with monoclonal gammopathy (76). In this study, 76% of the
patients used a bortezomib-based regimen, whereas 7%
used a rituximab-based chemotherapy. Rituximab should
be the first choice in clones expressing strong CD20. The
current evidence strongly supports the strategy of clone-
directed therapy, and the goal of therapy should be a
hematologic response of VGPR or better.
Monoclonal gammopathy is a well recognized cause of
kidney disease. The monoclonal gammopathy is produced
by a number of clones from the B cell lineage. Symptomatic
multiple myeloma or lymphoma is no longer required for
the development of kidney disease. However, because of
the clonal nature of these diseases, clone-directed ther-
apy is required for disease control. Multiple studies have
found that a VGPR is needed for preservation of kidney
function and improvement in patient survival. Achieve-
ment of a complete hematologic response has been found
to reduce the risk of recurrence after kidney transplanta-
tion. Given the complexity of these diseases, a multidis-
ciplinary approach is preferred for the best outcome of
these patients.
Disclosures
None.
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Published online ahead of print. Publication date available at www.
cjasn.org.
 Thrombotic Microangiopathy and the Kidney
Vicky Brocklebank,1,2 Katrina M. Wood,3 and David Kavanagh1,2

Abstract
Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia,
microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant
morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive
management and, in some cases, effective specific treatment can result in good outcomes. This review considers the 1
National Renal
classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, Complement
and outlines a pragmatic approach to diagnosis and management. Therapeutics Centre,
Newcastle upon Tyne,
Clin J Am Soc Nephrol 13: 300–317, 2018. doi: https://doi.org/10.2215/CJN.00620117
Hospitals National
Health Service
Foundation Trust,
Newcastle upon Tyne,
Introduction nomenclature make interpretation difficult: aHUS UK; 2Institute of
Cellular Medicine,
Thrombotic microangiopathy (TMA), a pathologic de- may refer specifically to complement mediated Newcastle University,
scription, is characterized by a clinical presentation with TMA, or be more loosely applied to any TMA that Newcastle upon Tyne,
thrombocytopenia, microangiopathic hemolytic anemia is not TTP or STEC-HUS. In this review, we adopt the UK; and 3Department
(MAHA), and organ injury (1,2). It can manifest in a term complement-mediated aHUS when the cause is of Cellular Pathology,
diverse range of conditions and presentations, but AKI Newcastle upon Tyne
defined as such, and use aHUS where the cause is ill
Hospitals National
is a common prominent feature because of the apparent defined. Current classifications describe primary Health Service
propensity of the glomerular circulation to endothelial TMAs, known as either acquired (e.g., factor H Foundation Trust,
damage and occlusion (3). Early recognition is impor- (FH) autoantibodies, ADAMTS13 autoantibodies) or Newcastle upon Tyne,
tant: TMAs are associated with significant mortality and inherited (e.g., complement mutations, ADAMTS13 UK
morbidity, including ESRD, although prompt initiation mutations); secondary TMAs; and infection-associated
of supportive and specific management can transform Correspondence:
TMAs (2) (Figure 1). Although a useful framework
Prof. David Kavanagh,
outcome. In particular, the prognoses of thrombotic for discussion, these terms do not account for the National Renal
thrombocytopenic purpura (TTP) and atypical hemo- increasing recognition that patients with an under- Complement
lytic uremic syndrome (aHUS) have been revolutionized lying complement risk factor often require a second- Therapeutics Centre,
following the elucidation of the pathogenic mechanisms ary trigger for TMA to manifest. Additionally, with Atypical Haemolytic
Uremic Syndrome
and the introduction of effective therapy. Challenges and increasing reports of eculizumab nonresponse, a more Service, Building 26,
controversies remain, however. In this review, we will clinically orientated classification such as eculizumab- Royal Victoria
discuss the classification, pathology, epidemiology, char- responsive and eculizumab-resistant aHUS are likely to Infirmary, Queen
acteristics, and pathogenesis of the TMAs, and outline an be introduced. Victoria Road,
approach to diagnosis and management. Newcastle upon Tyne,
NE1 4LP, United
Pathology Kingdom. Email:
Classification of Thrombotic Microangiopathies TTP is characterized by unusually large multimers david.kavanagh@
The classification of the TMAs is challenging and of vWf- and platelet-rich thrombi in capillaries and newcastle.ac.uk
constantly evolving. Historical classifications were on arterioles (5), although with current practice, pathologic
the basis of clinical findings: TTP for predominant specimens are rarely available. In complement-mediated
neurologic involvement and hemolytic uremic syndrome aHUS and other TMAs with more pronounced AKI,
(HUS) for kidney dominant disease. Classifications kidney biopsy is more frequently performed, although
evolved with greater understanding of the molecular is not requisite for the diagnosis. The pathologic find-
basis of disease: TTP was defined by severe ADAMTS13 ings reflect tissue responses to endothelial injury, in-
deficiency, hemolytic uremic syndrome caused by shiga cluding endothelial swelling and mesangiolysis in active
toxin–producing Escherichia coli (STEC-HUS) was de- lesions, and double contours of the basement mem-
fined by the presence of shiga toxin–producing bacte- brane in chronic lesions (Figure 2) (reviewed by
ria, and aHUS was broadly used for all other causes Goodship et al. (6)). Overt fibrin platelet thrombosis
of TMA. The discovery of the role of complement may be absent from renal biopsies of TMA, which has
dysregulation in a proportion of patients with aHUS recently led to a suggested reclassification to micro-
subsequently led to the acceptance of the term angiopathy with or without thrombosis (6). Evidence
complement-mediated TMA to refer to this subgroup of TMA has also been reported in a number of glomer-
(2,4). It should be recognized that differences in the ular diseases (7) and autoimmune diseases; however,
historical and contemporary literature over in published clinicopathologic studies, only a small

300 Copyright © 2018 by the American Society of Nephrology www.cjasn.org Vol 13 February, 2018
Clin J Am Soc Nephrol 13: 300–317, February, 2018 TMA and the Kidney, Brocklebank et al. 301

Figure 1. | Thrombotic microangiopathies are classified into: Inherited or acquired primary; secondary; or infection associated TMAs. Current classi-
fications define primary TMAs as hereditary (mutations in ADAMTS13, MMACHC (cb1c deficiency), or genes encoding complement proteins) or acquired
(autoantibodies to ADAMTS13, or autoantibodies to complement FH, which is associated with homozygous CFHR3/1 deletion). TMA is associated with
various infections: in STEC-HUS and pneumococcal HUS, distinct mechanisms result in TMA; in other infections, the processes are not defined and in some
cases the infection may trigger manifestation of a primary TMA. Secondary TMAs occur in a spectrum of conditions, and in many cases the pathogenic
mechanismsaremultifactorial orunknown. Theclassificationpresentedhereisnotunequivocal: insomesecondaryTMAs,for examplepregnancy-associated
TMA or de novo TMA after transplantation, a significant proportion of individualswill have a genetic predisposition to a primary TMA. AAV, ANCA-associated
vasculitis; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome;
C3G, C3 glomerulopathy; CAPS, catastrophic antiphospholipid syndrome; cblC, cobalamin C type; DGKE, gene encoding diacylglycerol kinase «; FH, factor
H; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; HUS, hemolytic uremic syndrome; IgAN, IgA nephropathy; MN, membranous
nephropathy; MPGN, membranoproliferative GN; SRC, scleroderma renal crisis; STEC, shiga toxin–producing Escherichia coli; TMA, thrombotic micro-
angiopathy; TTP, thrombotic thrombocytopenic purpura.

proportion of individuals with pathologic evidence of TMA in
these contexts had concurrent clinical and laboratory evidence
(8,9). It is not possible, on the basis of current knowledge, to
establish the cause of TMA from the histopathologic mor-
phology, although this may change with further research (6).
Clinical and Laboratory Features
The clinical presentation of TMA reflects hemolysis
and ischemic organ dysfunction, and depends on the
underlying disease etiology; AKI is a common manifesta-
tion of TMAs, although rarely a severe feature of TTP (10).
Extrarenal manifestations are reported in thrombotic
microangiopathies, with the published data referring
primarily to those observed in complement-mediated aHUS
and STEC-HUS (Table 1), although it is not known whether
they are a consequence of the TMA, a direct effect of comple-
ment activation or shiga toxin, or complications of AKI, such as
severe hypertension and uremia (6).
The defining laboratory features comprise thrombocyto-
penia, resulting from platelet aggregation and consumption,
and MAHA, identified by evidence of erythrocyte fragmen-
tation on peripheral blood film microscopy, which occurs in
areas of turbulent flow in the microcirculation due to partial
occlusion by platelet aggregates (1). Raised lactate dehy-
drogenase is a result of cell lysis and tissue ischemia (1),
haptoglobin is low, and the direct antiglobulin (Coombs)
test is negative (except in pneumococcal HUS). Presen-
tation with AKI reflects the consequences of ischemia in
the kidney.
Once routine biochemical and hematologic analysis have
demonstrated a TMA, investigations are aimed at determining
the underlying disease cause and excluding other differential
diagnoses, with the most urgent test being an ADAMTS13
assay (Figure 3). The epidemiology, pathogenesis, and man-
agement of TMAs are summarized in Table 2.
Primary TMAs
Complement-Mediated aHUS
Complement-mediated aHUS is prototypical of disease
occurring as a consequence of complement dysregulation.
302 Clinical Journal of the American Society of Nephrology

Figure 2. | The pathological features of thrombotic microangiopathies reflect the tissue responses to endothelial injury. (A) Glomerular
paralysis with capillary loops containing abundant erythrocytes (silver, 3400). (B) Thrombus in an artery (hematoxylin and eosin, 3400). (C)
Glomerular capillary lumina containing fibrin thrombi (red) and erythrocytes (yellow) (Martius Scarlet Blue, 3400). (D) Erythrocyte fragments
within the arterial vessel wall (arrow) (hematoxylin and eosin, 3400). (E) Mucoid thickening and obliteration of the lumen of a small artery
(hematoxylin and eosin, 3400). (F) Myxoid intimal thickening of small artery (hematoxylin and eosin, 3400). (G) Fibrinoid necrosis of arterial
wall (Martius Scarlet Blue, 3400). (H) Reduplication of glomerular basement membrane (arrow) and fibrillary mesangium (periodic acid–Schiff,
3400). (I) Glomerulus with endothelial swelling and erythrocyte fragmentation (arrow) (hematoxylin and eosin, 3400). (J) Electron micrograph
demonstrating fibrin tactoids (black) in glomerular capillary (310,000).
Clin J Am Soc Nephrol 13: 300–317, February, 2018
Table 1. Extrarenal manifestations reported in thrombotic
microangiopathies
* † Neurologic involvement, including seizures and
altered consciousness
* † Pancreatitis
* † Cardiac involvement/myocardial infarction
* † Gastrointestinal involvement (including diarrhea,
vomiting, abdominal pain)
* Cerebral artery thrombosis/stenosis
* Extracerebral artery stenosis
* Digital gangrene/skin
* Ocular involvement
* Hepatitis
* Pulmonary involvement
The published data refers primarily to those observed in
complement-mediated atypical hemolytic uremic syndrome (*)
and hemolytic uremic syndrome caused by shiga toxin–producing
Escherichia coli (†) (6,14,27,59).
The complement system is a regulated cascade network of
signaling and amplification that incorporates .30 plasma
and cell surface–bound proteins, and was reviewed in detail
earlier in this series (11). A key physiologic role involves
stimulating the inflammatory response and opsonization
and lysis of pathogens to protect the host from infection
(encapsulated organisms in particular); it is a fundamental
component of the innate immune system, and modulates
the adaptive immune system. In addition, it facilitates the
disposal of potentially injurious immune complexes and
damaged host cells (12).
Complement activation is initiated by three pathways:
the classical pathway is activated by immune complexes and
other molecules (e.g., C-reactive protein), and activation of
the lectin pathway results from protein interactions with
pathogens (11). The alternative pathway may also be initiated
by pattern recognition molecules, but crucially, it is a positive
feedback loop that is constitutively active due to spontaneous
hydrolysis (tickover) of C3, and is recruited by the classical
and lectin pathways; this enables a rapid response against
pathogens, but leaves the host vulnerable to bystander
damage if the amplification loop is unchecked. The system
is therefore tightly regulated by plasma proteins, including FH
and factor I (FI), and cell surface proteins, such as membrane
cofactor protein (CD46) (13). Defects in these regulators or in
the alternative pathway components can lead to complement
dysregulation, with activation of the terminal complement
pathway and generation of the anaphylatoxin C5a and the
membrane attack complex (C5b-9), resulting in a complement-
mediated aHUS (Figure 4). The relative roles of these effector
molecules in causing disease remains to be established.
In complement-mediated aHUS, dysregulated comple-
ment activation primarily occurs on endothelial cell sur-
faces, and although abnormal serum levels of complement
components such as C3 may be observed, normal levels do
not exclude complement-mediated disease (6,14). There is
evidence of complement activation (plasma levels and
tissue staining) in many other TMAs, but whether this
is a primary event, a disease modifier, or an inconsequen-
tial bystander phenomenon has not yet been definitively
established (13).
TMA and the Kidney, Brocklebank et al. 303
Hereditary Complement-Mediated aHUS
Molecular evidence that CFH mutations are associated
with aHUS was first described in genetic research published
in 1998 (15), and since then a multitude of studies have
determined heterozygous pathogenic activating mutations in
the genes encoding the alternative pathway components C3
and factor B, and loss-of-function mutations in the genes
encoding the regulators FH (including CFH/CFHR fusions),
FI, and CD46 (reviewed in Kavanagh et al. [14]).
These genetic mutations are not causative but are instead
predisposing, with penetrance incomplete. Penetrance of
disease is age-related and has been reported to be as high as
64% by the age of 70 years for individuals carrying a single
genetic mutation (6). This suggests that additional disease
risk modifiers are important. Around 3% of patients have
more than one mutation, with increased penetrance per
additional mutation. Haplotypes (particular combinations of
single nucleotide polymorphisms) in CFH and CD46 also
modify penetrance (14). Together, these still do not answer
the question of why some individuals do not develop dis-
ease until later in life. This is best explained by the need
for an environmental trigger (e.g., pregnancy or infection) to
unmask a latent complement defect. Complement activation
is a common factor in many of these triggering events: it
occurs in the placenta at the fetomaternal interface in normal
pregnancy and is the normal physiologic response to in-
fection. Counseling of family members and offering genetic
screening are important considerations.
Historically the outcome of complement mediated aHUS
at the initial presentation was very poor, as were outcomes
after kidney transplantation: recurrence was 68% and
5-year death-censored graft survival was 51% (16). The out-
come of kidney transplantation is predicted largely by the
underlying genetic abnormality, with the highest risk asso-
ciated with CFH, CFB, and C3 mutations and the lowest with
CD46 mutations (17). In the pre-eculizumab era, one option for
individuals with a defect in a complement protein predomi-
nantly synthesized in the liver (FH, FI, factor B, and C3) was
combined liver and kidney transplantation (14); however,
short-term risks were significant and international experience
was limited (18), and some people were therefore considered
to be untransplantable.
Acquired Complement-Mediated aHUS
aHUS associated with autoantibodies against FH was
first reported in 2005 (19), and functional analyses have
demonstrated disruption of complement regulation by mul-
tiple mechanisms (20). There is a strong association with
homozygous deletion of CFHR3 and CFHR1, which encode the
proteins FHR3 and FHR1 (21), although the mechanism is not
understood; CFHR3/1 deletion is a common polymorphism,
and it is not present in all individuals who develop FH
autoantibodies (22). It predominantly presents in childhood,
frequently with a gastrointestinal prodrome. Autoantibodies
against FI have also been reported, but they are rare and their
functional relevance remains to be established (23).
Plasma Exchange
Plasma exchange (PE) still remains the initial treat-
ment of choice until ADAMTS13 activity is available to
exclude TTP as a diagnosis. It should be initiated in adults
as soon as the diagnosis of TMA is suspected. In addition to
304 Clinical Journal of the American Society of Nephrology

Figure 3. | A diagnostic algorithm for the investigation and management of a patient presenting with thrombotic microangiopathy. Supportive
treatment is essential. This comprises fluid management and, if indicated, judicious packed red blood cell transfusion, intensive care unit admission,
and RRT. Platelet transfusion may worsen the TMA and so should be avoided if possible. The complete evaluation of a patient presenting with TMA
comprises complement analysis and investigations for all conditions in which TMA can manifest, and usually enables the disease cause to be
established. However, collating the results of the requisite investigations may take considerable time. The clinical evaluation during the acute
presentation of a TMA requires some time-critical decision-making, which should focus initially on the consideration of TTP, because immediate
management is imperative given the high mortality rate if untreated, and therefore in adults, PE should be instituted on the presumption that it is TTP
unless other evidence is available that strongly suggests an alternative cause. In children, in whom TTP is rarer, first-line treatment with eculizumab
should be considered if complement-mediated aHUS is suspected and should not be delayed while ADAMTS13 activity is determined. In the
absence of a defined cause, complement-mediated aHUS is presumed and treatment with eculizumab is recommended, pending the complete
evaluation. Eculizumab is not universally available; in these circumstances, treatment should comprise PE, and there may be a role for liver
transplantation. *Full complement evaluation is recommended (Kidney Disease: Improving Global Outcomes consensus [6]) in individuals with
pregnancy-associated aHUS and de novo transplantation-associated aHUS because of the high prevalence of rare genetic variants described in
these subgroups, and in cases of STEC-HUS that result in ESRD, as rare genetic variants have been described after HUS recurrence in a subsequent
kidney transplant. Additionally, it is recognized that infection can trigger manifestation of complement-mediated aHUS. In other secondary cases
of aHUS, insufficient evidence exists to recommend a full genetic evaluation, although rare genetic variants have been described in many of these
Clin J Am Soc Nephrol 13: 300–317, February, 2018 TMA and the Kidney, Brocklebank et al. 305

removing ADAMTS13 autoantibodies and replacing
ADAMTS13 in TTP, PE will also replace faulty complement
regulators and remove FH autoantibodies and hyperfunc-
tional complement components in complement-mediated
aHUS. In children, PE is associated with a high rate of
complications (24) and TTP is rare, therefore PE is not
considered as a first-line treatment when eculizumab is avail-
able. In many parts of the world, the cost of eculizumab
precludes its use, and PE remains the only treatment for
complement-mediated aHUS (25).
Complement-Inhibiting Therapy
The evidence for the central role of primary complement
defects in pathogenesis summarized above provided the
mechanistic rationale for treating complement-mediated
aHUS with complement-inhibiting therapy. Eculizumab is a
recombinant humanized mAb that functionally blocks C5,
and trials published in 2013 demonstrated its efficacy (26).
Although these were single-arm studies rather than random-
ized, controlled trials, the historically poor outcomes (up to
77% of patients with CFH mutations had died or reached
ESRD by 3–5 years) justified such study designs (27,28). These
findings have been replicated in subsequent extension studies
(29), prospective (nonrandomized) studies (30,31), and cohort
analysis (32). In the prospective trials, complete TMA re-
sponse was achieved in approximately 65% after 26 weeks of
eculizumab therapy in both adults (26) and children (31).
Eculizumab was approved by the US Food and Drug
Administration and the European Medicines Agency for
use in aHUS in 2013 (see Table 3 for practical consider-
ations) (33). In those presenting late in the course of disease
who do not recover kidney function, the high recurrence
rate after kidney transplantation necessitates preemptive
eculizumab (Table 4) (6,16). The trials included patients in
whom no complement mutation or FH autoantibody had
been identified, and the majority responded to complement-
inhibiting therapy; therefore, negative genetic and autoan-
tibody investigations do not exclude the diagnosis of
complement-mediated aHUS.
The current license for eculizumab is for lifelong treatment,
but this is not evidence based. Withdrawal of eculizumab
has been described in a large series of patients with aHUS, with
relapse reported in around one third, exclusively in those
with complement mutations (34). That rapid reintroduction
of eculizumab returned kidney function to baseline suggests
that a disease-driven intermittent regime could replace long-
term therapy, although prospective trials are required.
With increased clinical use, evidence is emerging of
nonresponse to eculizumab. In the recent pediatric
trial, Greenbaum et al. (31) highlighted that, for those
with a rare genetic variant in the complement system or an
autoantibody to FH, all had an improvement in eGFR,
whereas 27% of individuals without an identified comple-
ment abnormality failed to show an improvement. It is not
clear whether this represents late presentation of disease or
true nonresponse. A polymorphism in the C5 gene (p.R885H)
has been demonstrated to prevent eculizumab binding to
C5 (35), and nonresponders to eculizumab should have
genetic screening for this single nucleotide polymorphism
and alternative treatment strategies considered. More re-
cently, individuals presenting with a TMA with failure to
respond to eculizumab have been demonstrated to have
genetic variants in the noncomplement genes DGKE (36) and
INF2 (37).
The primary concern with terminal complement blockade is
increased susceptibility to infection with encapsulated organ-
isms, particularly Neisseria infections (33,38). For this reason,
meningococcal vaccination is considered mandatory; how-
ever, serologic response is variable (39), and the efficacy of
vaccination in the context of complement blockade is un-
certain (6). Long-term antibiotic prophylaxis is therefore
recommended for the duration of treatment and up to 3
months after withdrawal (6), although meningococcal in-
fection can occur despite these precautions (40,41). Thus,
patient education regarding vigilance is essential. Other
concerns may become apparent as use of complement-
inhibiting therapy in clinical practice expands: hepatotox-
icity in association with eculizumab has been reported in
children (42), and deposition of eculizumab has been
reported in individuals with C3 glomerulopathy (C3G)
(but not yet in aHUS), although the clinical significance is
unclear (43).
The use of complement-inhibiting therapy in TMAs other
than complement-mediated aHUS is controversial; case
studies have reported success but the inherent publication
bias needs to be considered when interpreting these, and
given that the role of complement in the pathogenesis of
other TMAs has not yet been defined, interventional trials are
likely to be needed before a consensus can be achieved (13).
Thrombotic Thrombocytopenic Purpura
TTP is mediated by ADAMTS13 deficiency: in hereditary
TTP, this results from recessive mutations (homozygous or
compound heterozygous) in the ADAMTS13 gene, and in
acquired TTP, ADAMTS13 activity is inhibited by autoan-
tibodies (2). ADAMTS13 is a metalloproteinase enzyme
that functions to cleave vWf; deficiency results in unusu-
ally large vWf multimers and consequent occlusive micro-
vascular platelet aggregation (2). The incidence of TTP is
higher in adults than in children (2), and there is a female
predominance (44). Neurologic manifestations are common
and laboratory characteristics in comparison to aHUS are

Figure 3 Continued. presentations. In cases where the roleofcomplementis as yet unclear, theclinician should decide on the evaluationon the basis of
the potential clinical consequences of a positive result (e.g., listing for renal transplantation). 1ve, positive; AAV, ANCA-associated vasculitis; Ab,
antibody; ACA, anticentromere antibody; ACEI, angiotensin-converting enzyme inhibitor; ADAMTS13, a disintegrin and metalloproteinase with a
thrombospondin type 1 motif, member 13; Ag, antigen; aHUS, atypical hemolytic uremic syndrome; ANA antinuclear antibody; anti-ds DNA,
antidouble-stranded DNA; anti–Scl70, anti-topoisomerase I antibody; BMT; bone marrow transplant; C3G, C3 glomerulopathy; CAPS, catastrophic
antiphospholipid syndrome; DGKE, gene encoding diacylglycerol kinase «; DIC, disseminated intravascular coagulation; FH, factor H; FI, factor I; Hb,
hemoglobin; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; MN, membranous
nephropathy; MPGN,membranoproliferativeGN; PE, plasmaexchange; SRC,sclerodermarenalcrisis; STEC, shigatoxin–producing Escherichiacoli;Stx,
shiga toxin; T-Ag, Thomsen–Friedenreich antigen; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.
 306

Table 2. The thrombotic microangiopathies: epidemiology, pathogenesis, and management

TMA Epidemiology Pathogenesis Management Recommendations

Complement- Incidence (UK): 0.42 per million per yr (32)
mediated aHUS Hereditary: incomplete penetrance; can
present at any age; “trigger” required
Acquired: anti-FH Ab aHUS more common
in children
Complement dysregulation caused by: Eculizumab
Hereditary: heterozygous mutations in CFH, CFI, If eculizumab is not available: PE, liver
CD46, C3, and CFB (27,28) transplantation may be considered.
Acquired: anti-FH Ab (19,21)

TTP/ADAMTS13 Incidence (US): 0.37 per 100,000 per yr (46); ADAMTS13 deficiency caused by: PE
deficiencymediated adults 2.9 per million per yr, children 0.1 Hereditary: recessive (homozygous or
TMA per million per yr (2) compound heterozygous) ADAMTS13
Female.Male (44) mutations
Adults . children (2) Acquired: autoantibody-mediated inhibition Immunosuppression (steroids/
rituximab) indicated if acquired

Cobalamin C Incidence of cblC deficiency: 1:37,000– Disorder of cblC metabolism results from recessive Metabolic therapy recommended:
Clinical Journal of the American Society of Nephrology

deficiency 1:100,000 births (50) (homozygous or compound heterozygous) efficacy of hydroxocobalamin and
mutations in the MMACHC gene betaine established (50)
Can present in adulthood as well as Pathogenic mechanisms causing TMA remain
childhood undetermined

DGKE TMA Rare Recessive (homozygous or compound Insufficient evidence to determine

heterozygous) mutations in DGKE (36) optimal management
Presents aged ,1 yr (36) Loss of DGKE results in prothrombotic state Reports of both nonresponse (36) and
independently of complement activation (51) response (31) to eculizumab

STEC-HUS E. coli O157 predominant causative
pathogen: incidence (UK): 7.1 per million
per yr; Latin America, 10–17 per 100,000
children per yr (113)
Peak incidence in children ,5 yr (115) and
approximately 15% of children with
enteric infection develop HUS (59)
E. coli O104: European outbreak in 2011
exceptional for high HUS occurrence rate
(24%), severity, and high proportion of
adults (60)
Other Stx producing pathogens e.g., Shigella
dysenteriae
Outbreaks and sporadic cases
Enteric infection with Stx-producing pathogens
Stx binds to Gb3, which is highly expressed in the
kidney, is internalized, and inhibits protein
synthesis (63)
The consequent endothelial injury results in
intravascular fibrin generation (59)
Complement activation observed (116) but role is
not defined
Supportive care is recommended; high
proportion may require dialysis. No
intervention evaluated in an RCT was
superior to supportive care for any
outcome (systematic review [114])
Antibiotics: controversy remains,
studies inconclusive, may worsen
outcome, therefore currently not
recommended; RCT of azithromycin
ongoing (NCT02336516)
PE: not recommended, no benefit
established (no RCTs) (46)
Eculizumab: not recommended; no
benefit demonstrated in retrospective
analyses (60,68,69); RCT ongoing
(NCT02205541)
Table 2. (Continued)

TMA Epidemiology Pathogenesis Management Recommendations

Pneumococcal HUS Rare. Limited data available from published
cohorts, and incidence unknown
(117,118). 10-yr cumulative incidence rate
of 1.2 per 100,000 children reported (NZ)
(119). Associated with pneumonia and
empyema in children ,2 yr (72)
Neuraminidase cleaves sialic acid residues from Supportive management and treatment
glycoproteins on erythrocyte, platelet, and of infection recommended
endothelial cell membranes, exposing the
cryptic T antigen to which IgM in the plasma
can then bind, resulting in cell damage and
TMA (73).

HIV-associated TMA Pre-HAART era: incidence of 1.5%–7% Pathogenic mechanisms remain undetermined Supportive management and treatment
(75,120) of infection recommended
HAART era: incidence 0.3% (77)

Pregnancy- Complement-mediated aHUS: pregnancy Complement gene mutations in up to 86% (81) Eculizumab; start immediately (do not
Clin J Am Soc Nephrol 13: 300–317, February, 2018

associated TMA triggers complement-mediated TMA in wait for genetic analysis) if TTP has
approximately 20% of women with aHUS been excluded and presentation is not
(81) suggestive of HELLP

A proportion are TTP: 10%–36% of women with TTP present vWf increases in normal pregnancy and PE
primary TMAs; during pregnancy (44) consumes ADAMTS13; in women with a
differential genetic predisposition, its activity can fall low
diagnosis includes enough for TTP to manifest (81)
complement-
mediated aHUS,
TTP, and HELLP
HELLP: incidence: 0.5%–0.9% of all Mechanisms are poorly understood (80) Definitive treatment is delivery (86). No
pregnancies; complicates 5%–10% of Increased levels of endoglin and sFlt-1 may play a role for PE (46)
cases of severe preeclampsia (121) role in endothelial dysfunction (79,86).

Drug-mediated TMA True incidence unknown
Reported incidences of TMA include:
Approximately 1:1000 patient-yr for high-
dose IFN-b (90)
2%–10% of patients treated with mitomycin
(122)
1%–4.7% of patients treated with tacrolimus
(122)
VEGF inhibitors: unknown (91)
Immune mediated: drug-dependent antibodies, Recommendation is drug
e.g., quinine (2) discontinuation
Toxicity mediated: multiple mechanisms, e.g., Ticlopidine-associated TMA: as per TTP
CNIs, IFN, chemotherapy agents, VEGF (46,92) (PE)
inhibitors (2)
Ticlopidine-associated TMA is mediated by
acquired ADAMTS13 deficiency (92)
TMA and the Kidney, Brocklebank et al.
307
 308

Table 2. (Continued)

TMA Epidemiology Pathogenesis Management Recommendations

De novo TMA after Incidence after kidney transplantation: 0.8% Multifactorial Treatment of precipitating factors, e.g.,
solid organ in USRDS data (123); up to 14% in single- AMR, infection, drug withdrawal
transplant center studies (94)
Incidence: 4% in liver transplant and 2.3% in Complement gene mutations reported in up to Eculizumab where complement-
lung transplant recipients (93) 29% (renal transplants) (96) mediated aHUS is possible

TMA after bone Multisystem TMA complicates 10%–40% of Multifactorial No evidence-based effective
marrow transplant allogenic BMTs (97,98) management strategy
No established benefit with PE (46)
Favorable outcomes with eculizumab
compared with historical controls
reported in retrospective analysis
(101), but prospective trials needed to
establish consensus
Clinical Journal of the American Society of Nephrology

Severe hypertension- Incidence: variously reported; case series of Pathogenic mechanisms unclear No evidence supporting any strategy
associated TMA severe hypertension have identified TMA other than BP management
in 27%–44% (13,124–127)

Malignancy- Unknown Multifactorial Discontinuation of causative

associated TMA chemotherapy agents

TMA with TMA can occur in association with IgA Pathogenic mechanisms unclear Limited evidence for management of the
glomerular diseases nephropathy, ANCA-associated TMA
vasculitis, membranous nephropathy, Hereditary and acquired complement defects in Role of complement inhibition in C3G/
FSGS, and MPGN/C3G (13) MPGN/C3G aHUS crossover unclear

TMA with SLE: concurrent TMA reported in up to 8%– Pathogenic mechanisms unclear SLE: no evidence for specific TMA
autoimmune 15% of biopsies (9,128) management in addition to SLE
conditions management as recommended in
international guidelines
CAPS: TMA in 14% in international registry Some evidence of complement activation in SLE CAPS: efficacy of eculizumab suggested
(112) and CAPS (13) in case reports and series; prospective
trial (not RCT) to enable renal
transplantation ongoing (NCT01029587)
SRC: occurs in approximately 10% of people SRC: ACEIs significantly reduce
with SSc; TMA in 45%–50% (111,129) mortality (111)

aHUS, atypical hemolytic uremic syndrome; UK, United Kingdom; PE, plasma exchange; FH, factor H; Ab, antibody; TTP, thrombotic thrombocytopenic purpura; ADAMTS13, a disintegrin and
metalloproteinase with a thrombospondin type 1 motif, member 13; TMA, thrombotic microangiopathy; US, United States; cblC, cobalamin C type; STEC-HUS, hemolytic uremic syndrome
caused by shiga toxin–producing Escherichia coli; Stx, shiga toxin; RCT, randomized controlled trial; HUS, hemolytic uremic syndrome; Gb3, globotriaosylceramide; NZ, New Zealand; T antigen,
Thomsen–Friedenreich antigen; HAART, highly active antiretroviral therapy; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; CNI, calcineurin inhibitor; VEGF,
vascular endothelial growth factor; USRDS, United States Renal Data System; AMR, antibody-mediated rejection; BMT, bone marrow transplants; MPGN, mesangioproliferative GN; C3G, C3
glomerulopathy; CAPS, catastrophic antiphospholipid syndrome; SRC, scleroderma renal crisis; SSc, systemic sclerosis; ACEI, angiotensin-converting enzyme inhibitor.
Clin J Am Soc Nephrol 13: 300–317, February, 2018 TMA and the Kidney, Brocklebank et al. 309

Figure 4. | Unfettered complement activation ultimately results in thrombus formation, platelet consumption, vascular occlusion and
mechanical hemolysis. Complement is activated by the alternative, classic, and lectin pathways. The alternative pathway of complement is a
positive amplification loop. C3b interacts with factor B, which is then cleaved by factor D to form the C3 convertase C3bBb. Unchecked, this leads to
activation of the terminal complement pathway with generation of the effector molecules, the anaphylatoxin C5a and the membrane attack complex
(C5b-9). To protect host cells from bystander damage, the alternative pathway is downregulated by complement regulators including factor H (FH),
factor I (FI), and CD46. In complement-mediated aHUS, activating mutations in C3 and CFB and loss-of-function mutations in CFH, CFI, and CD46, in
addition to autoantibodies to FH, result in overactivation of the alternative pathway. This leads to immune cell and platelet activation and endothelial cell
damage and swelling, with consequent thrombus formation, platelet consumption, vascular occlusion, and mechanical hemolysis. There is evidence
that complement is activated in other TMAs, but whether this is a causative, disease modifier, or bystander phenomenon has not yet been elucidated.
Eculizumab is a humanized mAb that binds to C5 and prevents activation of the terminal pathway; it thereby inhibits the generation of the effector
molecules that cause TMA in individuals in whom a primary defect in complement underlies the TMA pathogenesis. Its role in the treatment of other
TMAs is undefined. aHUS, atypical hemolytic uremic syndrome; TMA, thrombotic microangiopathy.

reportedly more severe thrombocytopenia (,303109/L)
and less severe AKI (serum creatinine, 1.7–2.3 mg/dl) (45),
but these are not absolute and should not be relied upon in
clinical practice (10), where the diagnosis is confirmed by
ADAMTS13 activity ,10% (5). TTP was historically almost
universally fatal, but after the introduction of PE treatment,
mortality decreased to ,10% (46). In acquired TTP, immuno-
suppressive therapies (e.g., glucocorticoids and rituximab)
have reduced the relapse rate (47–49).
Cobalamin C Deficiency
TMA can manifest in methylmalonic aciduria and homo-
cystinuria, cobalamin C type, which is the most common in-
herited form of functional cobalamin (vitamin B12) deficiency
(50). It is caused by recessive (homozygous or compound
heterozygous) mutations in the MMACHC gene, can pre-
sent in adulthood as well as childhood, and the phenotype
may comprise developmental, ophthalmologic, neurologic,
cardiac, and kidney manifestations, although severity varies.
The pathophysiologic mechanisms that cause endothelial
damage and subsequent TMA have not yet been determined
(50). Mortality is high if untreated or if there is cardiopulmo-
nary involvement, but metabolic therapy (hydroxocobalamin
and betaine) is very effective (50).
by complement-independent mechanisms (51). Only a small
number of cases have been published, but it appears to
present in patients aged ,1 year and commonly results
in progressive CKD and ESRD (36). There is insufficient ev-
idence to determine optimal management; there are reports
of both response (31) and nonresponse (36) to eculizumab,
as well as response (52,53) and nonresponse (36) to plas-
ma therapy. Concomitant mutations in complement genes
have been reported (54). Genetic pleiotropy is seen, whereby
DGKE mutations have also been associated with mesangio-
proliferative GN (MPGN) (55).
Other Genetic Associations
Genetic variants in thrombomodulin (THBD) have been
reported in association with aHUS (56,57), although this
finding was not replicated by Fremeaux-Bacchi et al. (27).
Bu et al. (58) reported rare genetic variants in plasminogen
(PLG) in aHUS; however, replication analysis will be
required to clarify this disease association. Functionally
significant mutations in INF2 have been seen to segregate in
families with TMAs, but it remains to be seen whether this
is a primary TMA or secondary phenomenon in association
with FSGS (37).

DGKE TMA Infection-Associated TMAs

Recessive (homozygous or compound heterozygous) STEC-HUS
DGKE mutations causing TMA was first reported in 2013 STEC-HUS is more common than aHUS, with a peak
(36), and this defined a cohort of patients with aHUS caused incidence in children aged ,5 years (Table 2). The
310 Clinical Journal of the American Society of Nephrology
Table 3. Eculizumab: practical considerations
Eculizumab: Practical Considerations
Before administration
Meningococcal vaccination mandatory
Tetravalent ACWY conjugated vaccine 1
multicomponent serogroup B vaccine
Prophylaxis
Long-term antibiotic prophylaxis recommended
Administration
Intravenous infusion
Maintenance therapy is administered every 14 d
Monitoring
CH50 and AH50 ,10%
Eculizumab trough level 100 mg/ml
Hematologic indicators of TMA
Patient education
Vigilance regarding meningococcal infection
Counseling family members
Genetic screening
When to stop?
Continue during intercurrent illness, unless infection
with encapsulated organism, due to high risk of
TMA relapse in this context
Withdrawal
Systematic investigation in clinical trials is being
undertaken
May be appropriate in some patientsa, with
monitoring: liaise with specialist center
This guidance is based on our practice in the United Kingdom,
and the 2015 Kidney Disease: Improving Global Outcomes
Controversies Conference consensus recommendations (6).
Eculizumab (Soliris; Alexion Pharmaceuticals) is a recombinant
humanized mAb that functionally blocks C5, and is approved by
the US Food and Drug Administration and the European
Medicines Agency for use in atypical hemolytic uremic syn-
drome. ACWY, meningococcal serotypes; CH50, total comple-
ment hemolytic activity; AH50, alternative pathway hemolytic
activity; TMA, thrombotic microangiopathy; aHUS, atypical
hemolytic uremic syndrome.
a
For example, if there is no renal recovery after 6 months of
treatment.
predominant causative pathogen is E. coli O157; enteric
infection can occur sporadically or in the context of an
outbreak, and around 15% of children with enteric infection
develop HUS (59). The E. coli O104 outbreak in Europe in 2011
was exceptional because of the high STEC-HUS occurrence
rate (24%) and the high proportion of adults affected (60).
Shiga toxin translocates through the intestinal epithelium
and is thought to bind to leukocytes and circulate to
the kidneys (61). The shiga toxin is then internalized via the
Gb3 receptor and is cleaved to release a protease into the
cytoplasm. This protease inhibits ribosomal function and
protein synthesis, leading to cell death. It can also activate
signaling pathways, inducing an inflammatory response in
affected cells (62,63).
The distinction between STEC-HUS and complement-
mediated aHUS may not be clinically obvious: approxi-
mately 5% of patients with STEC-HUS do not have
diarrhea (64), and approximately 30% of patients with
complement-mediated aHUS have concurrent diarrhea at
presentation (6). Therefore, all individuals with TMA
should be investigated for STEC-HUS (Figure 3). Rarely,
complement gene mutations are detected, and in these cases
the clinical picture is unusually severe (13,65). In STEC-HUS
resulting in ESRD, it is recommended to screen for mutations
before transplantation. STEC-HUS is considered to be a self-
limiting illness, with good outcomes relative to other TMAs:
70% fully recover, the mortality rate is approximately 1%–4%,
ESRD occurs in 3% of patients, and CKD occurs in 9%–18% of
patients (66). There is some evidence of complement activation
(13), but the role of complement-inhibiting therapy has not yet
been defined. A case series in 2011 first reported efficacy of
eculizumab in three children with severe disease (67), and
a significant proportion of those affected in the 2011 E. coli
O104 outbreak were treated with eculizumab; no benefit over
supportive care or PE was demonstrated in retrospective
analyses (60,68,69), although a direct comparison is difficult
because of the inherent disadvantages of retrospective anal-
yses, for example there were no controls, patients received
multiple therapies administered with inconsistency, and those
treated with eculizumab had more severe disease. In this
self-limiting condition, only a randomized, controlled trial
will resolve this controversy; one is underway in France
(Clinicaltrials.gov identifier: NCT02205541) and another is
due to start recruiting in the United Kingdom. For now, the
recommendation remains supportive management.
Pneumococcal HUS
TMA may occur in adults and children in the context of
invasive Streptococcus pneumoniae infection, and the high
morbidity and mortality rate usually reflects the severity of
the infection (70,71). In a recently published North American
cohort, pneumococcal HUS was most commonly observed
in children aged ,2 years with pneumonia and empyema
who were extremely unwell and frequently required
prolonged hospitalization and intensive care unit admis-
sion; the mortality rate was 3%, and 33% developed ESRD
(72). The hypothesized mechanism is that pneumococci
produce neuraminidase, which cleaves sialic residues from
glycoproteins on erythrocyte, platelet, and endothelial cell
membranes, exposing the cryptic Thomsen–Friedenreich
antigen (T antigen), to which IgM in the plasma can then
bind, resulting in cell damage and TMA (73). The Coombs
test is positive. Additionally, it has been suggested that
cleavage of sialic acid may reduce FH binding, resulting in
impaired endothelial complement regulation, thus contrib-
uting to disease pathogenesis (74). Supportive management
and treatment of the infection should be the focus.
HIV-Associated TMA
TMA has been reported in association with HIV, more
commonly in the pre-highly active antiretroviral therapy
era (75–77), and in association with lower CD41 cell counts
and higher viral RNA levels (77). The pathogenic mecha-
nisms are poorly understood, although endothelial damage
is thought to be the primary event. Again, there is no evidence
for any treatment strategy other than supportive care and
antiretroviral treatment.
Other Infections
TMA has been reported in association with a wide range
of viral, bacterial, fungal, and parasitic infections, although
Clin J Am Soc Nephrol 13: 300–317, February, 2018
Table 4. Approach to kidney transplantation when thrombotic microangiopathy results in established renal disease
Complete Complement Evaluation before Renal Transplant Listing Is Recommended if Thrombotic Microangiopathy
Results in ESRDa
Risk Stratification Inclusion Criteria
High Pathogenic complement mutations
Previous early recurrence
Moderate No complement mutation, or variant
of unknown significance
Isolated CFI mutation
Detectable anti-factor H antibody
Low Isolated CD46 mutationb
Previously positive but now consistently
negative anti-factor H antibody
Delay transplantation until at least 6 months after starting dialysis as late renal recovery with eculizumab treatment has been reported.
Living related kidney donation should only be considered if a genetic or acquired cause is identified in the recipient and is not present in
the intended donor. Recommendations are on the basis of the 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies
Conference consensus recommendations (6).
a
Complete complement evaluation should include: serum levels of C3, C4, factor H, factor I; anti-factor H antibody; CD46 FACS; and
CFH, CFI, CD46, C3, and CFB genetics.
b
Allograft cells express functional CD46.
it is frequently unclear if this is a direct effect of the pathogen,
a side effect of treatment, or a trigger that unmasks a latent
complement defect (reviewed by Nester et al. [4]). For instance,
Caprioli et al. (78) reported undefined infectious triggers in
.70% of patients with complement-mediated aHUS and
CFH, CFI, or CD46 mutations. Supportive management
with appropriate treatment of the infection is recommended,
and complement evaluation should be undertaken.
Secondary TMAs
Pregnancy-Associated TMA
The differential diagnosis of TMA in pregnancy includes
the primary TMAs complement-mediated aHUS and TTP,
as well as the TMA-like presentation occurring in the
syndrome of hemolysis, elevated liver enzymes, and low
platelets (HELLP) (79), which is part of the clinical spec-
trum of preeclampsia (80).
In around 20% of women with aHUS, the disease onset
appears to be triggered by pregnancy, occurring most often
in the postpartum period (81,82). Outcomes were histor-
ically poor, with 76% developing ESRD despite PE (81).
More recently, it has become clear that a high proportion
will have identifiable complement mutations (.50%), and
that pregnancy acts as a trigger in those with an underlying
genetic predisposition (81). In the era of eculizumab, this
high prevalence of complement mutations in pregnancy-
associated HUS provides the biologic rationale for com-
plement inhibition. Increasing data in both paroxysmal
nocturnal hemoglobinuria (83) and aHUS (84) suggests that
eculizumab is safe during pregnancy.
Similarly, a significant proportion of women with TTP
present during pregnancy (80), particularly in the second
and third trimesters (81). This might be explained by the
physiologic increase in vWf during pregnancy, which
consumes ADAMTS13, so in women with a genetic pre-
disposition, its activity can fall low enough for TMA to
TMA and the Kidney, Brocklebank et al. 311
Management Strategy
Prophylaxis with eculizumab (KDIGO global
panel suggest plasma exchange and liver
transplantation may also be considered)
No prophylaxis
manifest (81). PE is recommended on the basis of obser-
vational data and knowledge of pathogenesis (85).
The pathogenesis of preeclampsia and HELLP are poorly
understood (80), although there is some evidence to sug-
gest that increased circulating levels of the syncytiotrophoblast-
derived antiangiogenic factors, soluble endoglin and the soluble
form of the vascular endothelial growth factor receptor (sFlt-1),
may contribute to the observed endothelial dysfunction (79,86).
Although there is significant overlap in the clinical presentations
of HELLP and TMA, in HELLP, the predominant glomerular
pathology is endotheliosis (79). In contrast to pregnancy-
associated aHUS, only a minority (8%–10%) of patients with
preeclampsia and HELLP syndrome harbor complement
gene variants, mostly of unknown or nonpathogenic signif-
icance (87). There is some evidence that complement is
activated in preeclampsia and HELLP, although it is un-
clear whether it plays a role in pathogenesis; of note, pre-
eclampsia has occurred in women taking eculizumab for
paroxysmal nocturnal hemoglobinuria (83) and aHUS (84).
Management should be supportive, and the definitive
treatment of HELLP is expedited delivery, although expec-
tant management may be considered if the woman is not at
or near term (86).
In clinical practice, a pragmatic approach is usually taken
in peripartum cases of TMA: if expedited delivery does not
result in resolution of the TMA then standard management
is instituted (Figure 3).
Drug-Mediated TMA
In published reports TMA has been associated with a
large number of drugs, although definitive causality has
only been established in relatively few (reviewed by Al-
Nouri et al. [88]). Drug-mediated TMA occurs by two main
mechanisms: immune-mediated damage and direct toxicity
(Table 5). For example, quinine induces the development of
autoantibodies reactive with either platelet glycoprotein
312 Clinical Journal of the American Society of Nephrology

Ib/IX or IIb/IIIa complexes, or both (89). In contrast, IFN-b
(90) and bevacizumab (91) cause TMAs by a dose-dependent
toxicity. There are no trials to guide management, and the
recommendation is supportive care and discontinuation of
the causative drug. However, ticlopidine has been reported
to be associated with anti-ADAMTS13 antibodies with
resultant TTP, and therefore PE is recommended (92). It is
crucial that a full evaluation is undertaken (Figure 3) even
if drug-mediated TMA is suspected, including an urgent
ADAMTS13 assay.
De Novo TMA after Solid Organ Transplant
De novo TMA has been reported to occur after kidney,
liver, pancreas, lung, and heart transplantation (93,94). The
pathogenic mechanisms are not well understood, but it is
likely to be multifactorial, with ischemia-reperfusion in-
jury, antibody-mediated rejection, viral infections such as
cytomegalovirus, and immunosuppressant drugs, especially
calcineurin inhibitors (CNIs), contributing to an “endothelial
damaging milieu” (95). In one series of de novo TMA after
kidney transplantation, complement mutations were iden-
tified in 29% (96), providing a rationale for complement-
inhibiting therapy especially where the primary diagnosis
was not incompatible with complement-mediated aHUS.
In many cases, however, supportive treatment and address-
ing the precipitating factors (CNI discontinuation or dose
reduction, treatment of antibody-mediated rejection and viral
infections) may be sufficient to stop the TMA (13).
The optimal treatment strategy remains controversial;
favorable outcomes with eculizumab have been described
in uncontrolled retrospective analyses (101) and there is
some evidence to suggest that complement is activated (13),
but prospective trials are likely needed in order to establish
a consensus.
Severe Hypertension-Associated TMA
TMA can occur in association with severe hypertension,
and should be managed with antihypertensive and sup-
portive treatment. The pathogenic mechanisms that result
in endothelial damage and TMA are unclear (102,103). Con-
versely, any patient with a TMA can have severe hypertension,
thus a clinical conundrum can arise in the initial evaluation of a
patient presenting acutely with TMA. In practice, failure of BP
control and supportive management to control the TMA will
often result in the pragmatic initiating of PE or eculizumab until
complement evaluation is available. In the majority of patients
with TMA associated with severe hypertension, renal function
and MAHA usually recover with management of BP (102,104).
In a retrospective case series, genetic analysis identified rare
variants in complement genes in patients for whom TMA was
initially attributed to severe hypertension; eight out of nine
patients progressed to ESRD despite management of hyper-
tension (103). This may be particularly relevant when consid-
ering kidney transplant assessment in an individual with ESRD
attributed to severe hypertension with TMA, or if TMA occurs
again after transplantation.

TMA after Bone Marrow Transplant Malignancy-Associated TMA

A multisystem TMA complicates 10%–40% of allogenic
bone marrow transplants (97,98) and is associated with
significant mortality, variously reported as 21%–75% (13).
Again, this is likely to be multifactorial, with risk factors
including CNIs, graft versus host disease, HLA mismatch,
chemotherapy, radiation therapy, and infections (99). Rare
genetic variants in aHUS associated genes (98) and FH
autoantibodies (100) have been infrequently reported in
post bone marrow transplant TMA.
When TMA occurs in association with malignancy it can
be difficult to distinguish between TMA caused by chemo-
therapy and TMA caused by malignancy (105). It is possible
that the causative mechanism in disseminated malignancy
involves erythrocyte shearing after direct contact with
microvascular embolic tumor cells (106). Prognosis is poor
because of malignancy-related mortality (107,108), and there
is no evidence to support any treatment strategy other than
withdrawal of causative chemotherapy agents.

Table 5. Drugs with evidence supporting a causal association with thrombotic microangiopathya

Immune-Mediated TMA Direct Drug-Induced Toxicity Other

Quinine: Drug-dependent Immunosuppressive agents, Ticlopidine: ADAMTS13

antibodies e.g., calcineurin inhibitors: autoantibodyb
ciclosporin and tacrolimus Sirolimus
IFN-a, IFN-b
VEGF inhibitors, e g., bevacizumab,
sunitinib
Chemotherapeutic agents, e.g., gemcitabine,
mitomycin
Recreational drugs, e.g., cocaine

Even if drug-mediated TMA is suspected, a full evaluation should still be undertaken as shown in Figure 3, including an urgent
ADAMTS13 assay. TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor; TTP, thrombotic thrombocytopenic
purpura; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
a
TMA has been reported in association with many drugs, but definite causality has been established in relatively few (2,88,90,91), some
examples of which are included in this table.
b
Ticlopidine association with TTP reported, with severe ADAMTS13 deficiency due to inhibitory autoantibodies. This should be
managed as for TTP, with plasma exchange (46,92).
Clin J Am Soc Nephrol 13: 300–317, February, 2018
TMA Associated with Glomerular Diseases
TMA can occur in association with IgA nephropathy,
ANCA-associated vasculitis, membranous nephropa-
thy, FSGS, and MPGN/C3G, although it may be a his-
topathologic finding without biochemical or clinical
manifestation (13).
In MPGN/C3G, the hereditary and acquired comple-
ment defects are similar, although subtly different to those
seen in complement-mediated aHUS, and it is perhaps
unsurprising that concurrent (7) and sequential (109)
manifestation of C3G and TMA has been reported. Muta-
tions in CFH are observed in both complement-mediated
aHUS and C3G; the reason for this genetic pleiotropy is not
fully understood, but the location of the mutation within
the gene may be important. In aHUS, the majority of mutations
are located at the C-terminal of FH, which binds to C3b and
glycosaminoglycans on host cells to mediate cell surface
protection (14), whereas in C3G, mutations are more often
located at the N-terminal of FH, which mediates comple-
ment regulation in the fluid phase (110).
Genetic pleiotropy has also been reported in INF2- and
DGKE-mediated disease. In addition to the FSGS normally
seen in INF2-mediated disease (37) and the MPGN seen in
DGKE-mediated disease (55), TMAs have been reported in
both cases that seemed nonresponsive to eculizumab.
TMA Associated with Autoimmune Diseases
TMA can occur in association with autoimmune diseases
including SLE, catastrophic antiphospholipid syndrome
(CAPS), and scleroderma renal crisis (SRC); again, the
mechanisms remain unclear, although there is some evi-
dence of complement activation in SLE and CAPS (13). For
SLE, CAPS, and SRC with TMA, treatment should be of the
underlying condition. The influence of TMA on outcome of
SLE is uncertain, as case series have reported both no
difference and worse outcome (13); treatment should be
immunosuppression according to international guidelines,
and there is no evidence to suggest that any additional
treatment specifically directed at the TMA is beneficial. The
high mortality of SRC is significantly reduced with angiotensin-
converting enzyme inhibitors (111). In CAPS, the interna-
tional registry (522 episodes) reported the incidence of TMA
to be 14%, and overall mortality was 37%, with no subgroup
analysis according to treatment. The most frequent treatment
regimens used were anticoagulation plus glucocorticoids
(19%) or anticoagulation, glucocorticoids and PE with or
without intravenous Ig (18%), with only 0.2% receiving
eculizumab (112). There is some evidence from mouse
models and observational clinical data that complement
may be involved in the pathophysiology of CAPS; success-
ful use of eculizumab has been reported in case reports and
series, and a prospective trial of preemptive eculizumab to
enable renal transplantation is ongoing (Clinicaltrials.gov
identifier: NCT01029587) (13).
Diagnosis and Management
Establishing the cause of a TMA is usually possible after a
complete evaluation. However, the results of the requisite
investigations are not available immediately, and in clinical
practice, the scenario is often one of a severely ill patient
with TMA for whom immediate management decisions are
TMA and the Kidney, Brocklebank et al. 313
required. The acute decision-making is time-critical: the
initial priority should be the consideration of TTP, because
urgent management is imperative given the high mortality if
untreated, and therefore in adults, PE should be instituted
(after obtaining a sample for ADAMTS13 activity testing) on
the presumption that it is TTP unless other evidence is avai-
lable that strongly suggests an alternative cause. If the
ADAMTS13 result excludes TTP, then complement-mediated
aHUS is presumed and treatment with eculizumab is rec-
ommended, pending the complete evaluation. In children, in
whom PE may not be appropriate and is high risk, treatment
with eculizumab has been recommended by Kidney Disease:
Improving Global Outcomes before the availability of the
ADAMTS13 result, with the caveat that clinical deterioration
on eculizumab should necessitate immediate plasma therapy
(6). An algorithm for the real-time investigation and man-
agement of a patient presenting with TMA is illustrated in
Figure 3. Once the full evaluation has been completed, the
indication for eculizumab can be reviewed.
Summary
In summary, TMA can manifest in a diverse range of
diseases and can be associated with significant morbidity
and mortality. For some forms of TMA, such as TTP and
complement-mediated aHUS, research has now defined the
molecular mechanisms of disease leading to targeted ther-
apy and improved patient outcomes. However, the opti-
mal eculizumab treatment duration and the specific patient
populations who will benefit remain undefined.
Acknowledgment
V.B. has received funding from the Northern Counties Kidney
Research Fund and is a Medical Research Council/Kidney Research
UK Clinical Research Training Fellow. D.K. has received funding
from the Wellcome Trust, The Medical Research Council and Kidney
Research UK.
Disclosures
D.K. has received honoraria for consultancy work from Alexion
Pharmaceuticals, and is a director of and scientific advisor to Gyroscope
Therapeutics.
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