Sei sulla pagina 1di 15

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 to the glomerulus such as proteinuria or reduced GFR
(MN) are associated with other diseases or exposures (1,4–7).
(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, Epidemiology
autoimmune glomerular disease that presents with In the United States, the incidence of MN is
increased protein in the urine associated with a pa- estimated at about 12/million per year with a mean
thognomonic pattern of injury in glomeruli (Figures age between 50 and 60 and a 2:1 male predominance
1–3). Both clinical and pathogenetic aspects of the (1–4). The incidence of ESRD due to MN in the United
disease have been recently reviewed elsewhere (1–8). States is about 1.9/million per year (1). Because only
PMN is the commonest cause of idiopathic nephrotic 10%–20% of patients with PMN currently progress to
syndrome in nondiabetic adults worldwide, repre- ESRD, the real incidence may be as high as 20/million
senting between 20% and 37% in most series and rising per year. PMN is most common in whites followed by
to as high as 40% in adults over 60 (1,2,7). MN is rare Asians, blacks, and Hispanics (1,2).
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 Pathogenesis
1 domain containing 7A (THSD7A) (3%–5%), or by Studies in the past decade have dramatically im-
other as yet unidentified mechanisms (10%) (1,2,4–8). proved understanding of the pathogenesis of PMN
The recognition that PMN is an autoimmune disease (1,2,4–8). Current concepts derive in large part from
has dramatically altered both the diagnostic and ther- earlier studies carried out in the Heymann models of
apeutic approach to what was previously called idio- MN in rats which revealed that the pathognomonic,
pathic MN. Patients with immunologically active exclusively subepithelial deposits of IgG resulted
disease can now be separated from those with inactive from in situ immune complex formation involving
disease and therapeutic initiatives in active disease can megalin, a rat podocyte membrane antigen, and that
be adjusted to the presence and levels of the patho- the associated proteinuria was mediated primarily by
genic antibody causing the disease rather than relying 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 Examples
b
Infections (1,2,27,56,90) HBV, HCV, HIV, parasites (filariasis, schistosomiasis, malaria),
leprosy, syphilis, hydatid disease, sarcoid
Malignancy (20% in patients .57, b
Solid tumors (lung 26%, prostate 15%, hematologic [plasma cell
4%,57) (1,2,14–18,55,58,66) dyscrasias, non-Hodgkin lymphoma, CLL] 14%, colon 11%),
mesothelioma, melanoma, pheochromocytoma; some benign tumors
b
Autoimmune diseases (1,2,4,56–58,91) 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)
Alloimmune diseases (1,4,7,58,82) Graft versus host disease, autologous stem cell transplants, bde novo MN
in transplants/transplant glomerulopathy
b
Drugs/toxins (92) 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)

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 the infant (10). In 2009, a seminal paper from Beck et al. in
an analogous mechanism came from Debiec et al. in Paris Boston reported that about 70% of adult patients with PMN
in 2002, who showed that alloimmune MN in babies of have IgG4 antibodies to podocyte-expressed PLA2R that
neutral endoproteinase (NEP)–deficient mothers was me- are present in the circulation and also deposited in
diated by maternal anti-NEP antibody that formed immune glomeruli (11), a finding since confirmed, with a range of
complexes in situ with NEP on the podocyte membranes 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
Figure 1. | Glomerulus from a patient with primary membranous
nephropathy showing the pathognomonic “spikes” of basement expressed in rodents. However, human anti-THSD7A has
membrane projecting from the outer surface of the glomerular recently been shown to transfer MN with proteinuria in
basement membrane (arrows) when stained with silver-methenamine mice (19).
(original magnification, 340). (Provided by Dr. Charles Alpers, De- PLA2R/THSD7A-mediated disease can also be confirmed
partment of Pathology, University of Washington, Seattle, WA.) 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). mediated (21) (Table 2). However, occasional anti-PLA2R–
Staining persists for weeks to months after antibody positive, or presumed positive, patients, especially early in
disappears (5–9,19,20). Most antibody-positive, and about the course, have been reported without staining for PLA2R
70% of antibody-negative, patients have positive PLA2R/ antigen in glomeruli (23–25). As summarized in Table 2,
THSD7A staining in glomeruli, suggesting that up to patients presenting with PMN include those who are free of
85%–90% of all cases of PMN are anti-PLA2R/THSD7A– 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 Percent of Patients Who


Diagnosis
Antibody (6) Antigen (6) Underwent Biopsy, %

Anti-PLA2R (1) PLA2R (1) 70 PLA2R-mediated PMN


(active)
Anti-PLA2R (2) PLA2R (1) 15 PLA2R-mediated PMN
(inactive)
Anti-THSD7A (1) THSD7A (1) 3–5 THSD7A-mediated PMN
(active)
Anti-THSD7A (2) THSD7A (1) Unknown THSD7A-mediated PMN
(inactive)
Anti-PLA2R/THSD7A (2) PLA2R/THSD7A (2) 10 Non-PLA2R/THSD7A–
mediated (pathogenesis
unknown)a

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 biomarker for the pathogenetic disease processes that are
negative but have positive glomerular staining for PLA2R/ targeted by current immunosuppressive therapies (IST).
THSD7A (another 15%), and those without PLA2R/THSD7A C activation leading to sublytic C5b-9 attack on podo-
antibody or glomerular staining (10%) who may: (1) develop cytes has been established to be the primary mediator of
detectable anti-PLA2R/THSD7A antibody later, (2) have anti-podocyte antibody–induced cellular injury and pro-
disease mediated by a different anti-podocyte antibody, or (3) teinuria in most studies of the Heymann rat models (5,9,29–
develop another autoimmune disease to which the MN 31). Currently available serologic and immunohistochemical
might be considered secondary. data in PMN are most consistent with complement
Initiation of an antibody response likely precedes devel- activation by under-glycosylated IgG4 through the man-
opment of proteinuria in PMN by weeks or months (pre- nose binding lectin pathway, but roles for the classic and
clinical disease) (22,26) and may occur following several alternate pathways have not been entirely excluded (29–
etiologic events in the presence of immunogenetic risk 31). In the rat models, the complement effect involves a
alleles (see below). There is one report of homology sublytic agonistic effect of C5b-9 insertion on the podocyte
between genes for PLA2R and the LTLENCK domain in membrane to activate several signaling pathways that lead
some gram-positive bacterial enzymes (27). Viral infections collectively to increased production of oxidants, proteases,
including hepatitis B virus, hepatitis C virus, and HIV have growth factors, and extracellular matrix components as
been reported in association with anti-PLA2R/THSD7A, well as to slit diaphragm disruption, apoptosis, auto-
but these may represent patients who have coincidental phagy, remodeling of the actin cytoskeleton, DNA damage
PMN (4–8,22) (Table 1). Other potential etiologic factors, with cell cycle arrest, and detachment of damaged cells
e.g., exposures to environmental toxins such as drugs, (29,30). A similar role for complement in human PMN is
mercury, formaldehyde, and air pollutants, have been suggested by the facts that C3, C4d, and C5b-9 (but not
identified (Table 1) but generally the anti-PLA2R/THSD7A C1q) are prominent in glomerular deposits; complement
status in these patients is not known. For example, a recent activation products are elevated in the serum (M.H. Zhao,
report from China correlated the rising incidence of MN in personal communication); and serum and urine C5b-9
that country with increasing levels of air pollution (28). seem to parallel disease activity (28–30). However, pro-
Over time, a threshold quantity of IgG4 and C5b-9 teinuria in some human PMN may also be C-independent
deposition is reached in some patients that is sufficient as suggested by some studies of the Heymann models by
to cause enough podocyte injury/activation to increase Hall and colleagues (32), the transfer of anti-NEP alloim-
urine protein excretion and lead to nephrotic syndrome mune MN without complement activation (10), and an in
(5–7,22,26). Just as appearance of proteinuria lags behind vivo transfer study with human anti-THSD7A where
initial antibody production by weeks/months, so resolu- heterologous phase proteinuria appears to precede detect-
tion of proteinuria (clinical remission) also lags behind able complement deposition (19).
antibody disappearance (immunologic remission) by
week/months. This offset between immunologic and clin- Genetics of PMN
ical remissions reflects the prolonged time required to form Genetic findings in PMN are reviewed in more detail
sufficient deposits to cause proteinuria initially and the elsewhere (4–8,33–35). Familial MN is rare and usually seen
time required to clear subepithelial deposits, repair podo- in children (3,33,34). Genome-wide association studies
cyte and capillary wall damage, and restore glomerular (GWAS) implicate risk alleles in HLA genes, particularly
permselectivity (5). Thus, proteinuria is a poor clinical HLA–DQA1, that increase the risk for PMN three-fold in
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 987

white patients (27). GWAS studies have also identified colocalized with IgG4 may be seen by immunofluores-
single nucleotide polymorphisms in noncoding regions of cence microscopy with appropriate antigen enhance-
the PLA2R gene (27,36–38). Homozygosity for high-risk ment techniques and persist for weeks to months after
alleles in both HLA and PLA2R genes increases the odds serum antibody is undetectable and immune complex
ratio for PMN almost 80-fold in white patients and ten-fold formation has ceased (4–8,20–23). Complement components
in Chinese patients and is associated with higher levels of including C3, C4d, and C5b-9 (Figure 2C) are also commonly
antibody production, strongly suggesting interaction be- present, but not C1q (29,30,41). Although these findings
tween HLA and PLA2R genes (36–38). Two recent GWAS describe the typical case, they are not universal, and
studies in Chinese patients have identified additional in- occasional patients with IgG4-dominant deposits but without
dependent HLA risk alleles including DRB1*1501/ detectable PLA2R/THSD7A antibody or staining have been
DRB1*0301 (37) and DRB3*02:02 (38) and suggested that described (20,21).
DRB1 may be more important in generating the HLA signal Electron microscopy in PMN confirms the exclusively
than DQA1 in that population. Ninety-nine percent of subepithelial localization of electron-dense deposits pro-
PLA2R-positive patients carry at least one of these HLA risk duced by capping and shedding of immune complex
alleles, and the presence of one HLA risk allele increases the lattices formed on the podocyte membrane, which then
odds ratio for developing PMN almost 100-fold (35) accumulate beneath slit pores (Figure 3). Glomerular
However, risk alleles identified so far are common in the basement membrane thickening is seen with progression,
general population, and studies to date are also consistent and the deposits are gradually incorporated within new glo-
with a predisposition to autoimmunity conferred by HLA merular basement membrane and become more electron-
genes and an environmental trigger rather than any unique lucent as they are resorbed before eventually disappearing
coding variant in PLA2R genes (33). in patients with earlier complete remissions (41).
Additional biopsy findings that should prompt careful
Structure of the PLA2R Antigen search for secondary causes (Table 1) include electron-
PLA2R is a transmembrane glycoprotein member of the dense deposits in subendothelial or mesangial locations;
mannose receptor family, which has a conserved extracellular significant mesangial or endothelial cell proliferation; cres-
structure consisting of the cysteine-rich (Ricin B) domain cents; tubular basement membrane staining; dominant de-
(Cys-R), a fibronectin II domain, and a tandem repeat of 8 C- position of IgG1/IgG3, IgM, IgA, or C1q; and endothelial
type lectin domains (CDLD 1–8) (1,4–7,39,40). Anti-PLA2R– tubuloreticular inclusions by electron microscopy (1,2,4–
reactive epitopes are conformation-dependent and have been 7,21,22,41). One report has described an association between
identified in three domains: Cys-R, CTLD1, and CTLD7 MN with intraglomerular inflammatory cell infiltrates and
(1,4,39,40). The potential for these different epitopes to be of cancer (18).
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 Clinical Manifestations
severe disease and undergo more spontaneous remissions All adult patients with idiopathic nephrotic syndrome
than those with antibodies primarily reactive with the CDL1 should be screened initially for anti-PLA2R/THSD7A anti-
and CDL7 domains, and that epitope spreading beyond the bodies as well as for the common causes of secondary MN
Cys-R domain may confer a worse prognosis, but this including hepatitis B and C, lupus, and sarcoid (Figure 4,
observation requires confirmation (36). The small contact Table 1). Although the specificity of the anti-PLA2R assay
residues that bind the antibody, and would be essential to for PMN is essentially 100%, this finding has somewhat
developing specific peptide-based immunotherapies, have blurred the distinction between primary and secondary
not yet been identified. 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-
Pathology tal presence of PMN in some patients with an unrelated
In most centers a diagnostic renal biopsy remains the systemic disease rather than MN as a manifestation of, or
standard of care, even in anti-PLA2R/THSD7A–positive secondary to, the systemic disease (4–8). Observational
nephrotic patients. The characteristic morphologic changes correlations between the anti-PLA2R/THSD7A pathogenic
in PMN are described elsewhere (41) and are illustrated in mechanisms discussed above and clinical features of PMN
Figures 1–3. By light microscopy, glomeruli may appear that now support incorporating anti-PLA2R/THSD7A into
entirely normal in early disease despite nephrotic-range clinical decision-making are summarized in Table 3.
proteinuria. With time, changes in basement membrane, The most common clinical features at onset and during
with thickening and formation of subepithelial “spikes” of the course of PMN are presented in Table 4. The most
basement membrane on the outer surface of the capillary prominent is nephrotic syndrome and its associated man-
wall, become apparent using an extracellular matrix stain ifestations including various degrees of edema, hypoalbu-
such as silver methenamine (Figure 1). Immunofluores- minemia, and hyperlipidemia (1,2,42–45) (Table 4). About
cence microscopy (Figure 2) in anti-PLA2R/THSD7A– 80% of patients with PMN present with nephrotic-range
positive patients usually reveals diffuse, uniform, finely proteinuria (.3.5 g/d) and the remaining 20% have
granular deposits of IgG4 along the outer surfaces of all subnephrotic proteinuria, but 61% of these latter patients
capillary walls (Figure 2A) (41). Lesser amounts of IgG1 later become nephrotic, usually within the first year, and
and IgG3 may also be seen, particularly in early disease especially if anti-PLA2R antibody is present (1,26,27,43–
(21,22,26). The antigen PLA2R or THSD7A (Figure 2B) 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 levels (46–48). Anti-PLA2R/THSD7A levels generally cor-
normal at presentation in .90% (2,42–45) (Table 4). relate with proteinuria, clinical course, and outcomes
Spontaneous remissions occur in about 32% in an average (Table 3) (4–8,22,46–51).
of 14 months and up to 62% by 5 years, and occur more The clinical consequences of PMN can be considered as
commonly in patients with low anti-PLA2R/THSD7A 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 therapy). Supportive care should be initiated in all patients
of thrombotic and thromboembolic events that are pro- at the time of diagnosis and continued for the course of
portional to the degree of hypoalbuminemia and increase the disease. It includes careful BP control, angiotensin-
significantly below albumin levels of about 2.8 g/L (1,2,42, converting enzyme inhibitor/angiotensin receptor blocker
52–54) (Table 4). There is also an increased risk of infection, therapy to minimize proteinuria and enhance chances of
due primarily to urinary loss of Igs, and of cardiovascular a spontaneous remission, statins for hyperlipidemia, salt
disease (42,49). An association with malignancies is well restriction and diuretics to control edema, and a low
documented (55). Cancer may be seen within 3 years in up protein diet allowing for replacement of urinary protein
to 20% of patients over 60 and may be more common in the losses (1,2,4,56–60) Some patients are also anticoagulated if
anti-THSD7A group where up to 20% have had a malig- serum albumin is ,2.5 g/L in the presence of other risk
nancy detected within 3 months (14–16). factors and a favorable risk/benefit ratio as defined by
The most feared long-term consequence of MN is online calculators (54).
progressive loss of renal function as occurs in 60% of Current criteria for adding IST to supportive care (SC)
untreated patients with about 35% eventually develop- are based on either evidence of progressive loss of GFR
ing ESRD within 10 years (1,2,4,44–46). Patients (usually .50% increase in serum creatinine or a level
who never become nephrotic virtually never progress .1.5 mg/dl) or proteinuria refractory to 6 months of SC
(1,2,4,43–45). Other established risk factors for progres- as defined by the Toronto risk score (56). The latter
sion include age, male sex, decreased GFR on presenta- approach divides patients after 6 months of supportive
tion, increased excretion of some low molecular weight care into three categories: low risk (,4 g/d, stable GFR),
markers such as b 2 microglobulin, persistent elevation of moderate risk (4–8 g/d with stable GFR), or high risk
anti-PLA2R levels after therapy, C3 staining in the biopsy (. 8 g/d, ,50% decrease from baseline or .30% decline in
sample, and increased urinary excretion of C3dg and C5b-9 GFR since baseline) categories. Initiation of IST is recom-
(1,2,43–45). 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
Treatment creatinine .3.5 mg/dl, small fibrotic kidneys, or an abun-
Selection of patients for IST dance (.50%) of sclerotic glomeruli. Other situations that
Traditional approaches to treatment of PMN begin with would dictate early initiation of IST would include pro-
supportive care alone and withhold IST until the patient teinuria.10 g/d or failure to reduce proteinuria below 8 g/d
meets certain criteria that predict progression (restrictive 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- Figure 4, and the legend to Figure 4, outline a different
nemia, or unexplained loss of GFR. approach to IST applicable to all patients with protein-
Definitions of terms conventionally used to classify uria.3.5 g/d, normal or stable GFR and active disease,
responses to therapy of PMN are presented in Table 5 defined as ongoing glomerular immune deposit formation
(4,52,53). Goals of therapy would be complete or partial indicated by elevated circulating levels of anti-PLA2R/
remission. Thompson et al. have recently presented evi- THSD7A. Based on the data reviewed above, such patients
dence supporting the validity of considering complete and have active immunologic disease and should be consid-
partial remissions of proteinuria in PMN as surrogate ered for immediate IST without waiting 6 months on
markers of good outcomes and consequently as valid goals supportive care alone as prescribed by restrictive therapy
of therapy or end points for therapeutic trials (43). protocols. Although much remains to be learned about
For decades, clinicians have treated PMN with nephrotic translating anti-PLA2R/THSD7A levels into predictive
syndrome with potentially toxic IST using the above clinical algorithms, patients with anti-PLA2R levels in
proteinuria/GFR-based guidelines, because there was no the highest tertile have only a 4% chance of undergoing
way to distinguish patients with immunologically active spontaneous immunologic remission while being treated
disease from those with inactive disease who have persis- with SC alone (47,48,50,51,59,60). Informed consent should
tent proteinuria despite immunologic remission. Table 6 always be obtained before IST is initiated.
provides an overview of IST regimens of established benefit Both supportive care and IST should continue with antibody
in preserving renal function in PMN. monitoring every 1–2 months until anti-PLA2R/THSD7A
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 991

The quantitative ELISA assay for PLA2R (Euroimmune


Table 5. Definitions of clinical responses in primary AG, Luebeck, Germany), or the recently developed cell-
membranous nephropathy (4,56–58)a based ALBIA assay (Mitogen Advanced Diagnostics Lab-
oratory, Calgary, Canada) should be used for monitoring
Clinical Response Definition
antibody levels (4–7). As we move more toward antibody-
Complete remission Proteinuria ,0.3 g/d guided therapy, it is essential that measurements be
Partial remission .50% reduction from baseline standardized between commercial laboratories and that
and between 0.3 and 3.5 g/d the threshold antibody level below which IST does not
With stable GFRb provide sufficient benefit to offset potential risks be de-
No remission ,50% reduction or .3.5 g/d fined. In the ELISA assay, levels .20 RU/ml are considered
Relapse Recurrence of .3.5 g/d after positive, and available data indicates a relationship be-
remission
tween anti-PLA2R levels and clinical outcomes with pa-
ESRD GFR,15 ml/min or
requirement for dialysis/ tients in the lowest tertile frequently undergoing
transplant spontaneous remission and levels in the highest tertile
associated with progression and rarely (,5%) with spon-
a
Measurements of proteinuria for clinical decision-making taneous remission (4,47,50,51).
should be done on 24-hr collections. Overnight or random
samples can be used for monitoring.
b
Decline of ,15%. 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
levels become undetectable (or fall below some as yet basis of differences in their efficacy in suppressing anti-
undefined level below which progression is unlikely), PLA2R/THSD7A production. The three most utilized regi-
recognizing that a response in proteinuria (clinical re- mens (cyclophosphamide/steroids, calcineurin inhibitors
mission) may only occur several weeks to months after an [CNIs]/steroids, and rituximab) appear similar in their
immunologic remission is achieved (4,6,7). Considering the effect on anti-PLA2R levels (1,4,59–63). Small studies have
current high cost of anti-PLA2R assays, obtaining levels at shown that a combination of a CNI and rituximab was more
the time of diagnosis and when a clinical decision point is effective in suppressing antibody than cyclophosphamide/
reached (e.g., after 6 months of IST) would be acceptable if steroids (63), that cyclophosphamide/steroids was more
cost to the patient is a limiting factor. However, monitor- effective than mycophenolate mofetil (MMF) (64), and that
ing levels initially every 1–2 months may justify shorter tacrolimus (TAC) and cyclophosphamide/steroids were of
courses of therapy and better predict remissions and similar efficacy (62). However, each of these studies is small
relapses. In most anti-PLA2R/THSD7A–positive patients, and short-term. All three regimens lead to marked reductions
circulating antibody disappears after 4–6 months of IST, in circulating antibody in most patients within 3–4 months,
which should then be tapered and discontinued even if followed by disappearance of antibody within 6–9 months,
some proteinuria persists (4,6,56–60). If antibody levels and remission of proteinuria in 12–24 months in .80% of
persist but show a downward trajectory after 4–6 months, patients (4,63). Thus, IST prolonged for 6 months may not be
the IST regimen can be maintained until antibody disap- necessary in all patients, whereas longer courses might be
pears (immunologic remission). If no substantial reduction required in others.
in antibody levels is seen after 4–6 months or GFR falls Most current therapeutic guidelines, on the basis of older
(.30% increase in serum creatinine on two determinations) randomized controlled trials (RCTs), recommend initiating
and nephrotic-range proteinuria persists at .50% of baseline, IST in patients with proteinuria resistant to supportive care
changing to an alternate IST regimen would be justified after 6 months utilizing a modified Ponticelli regimen of 6
(Figure 4). months of alternating pulse steroids and cyclophosphamide
In the 10% of patients with PMN who are PLA2R/ (56–60,65). This leads to remissions of proteinuria in about
THSD7A antibody– and glomerular antigen–negative, and 50%–60% of patients at 1 year and 70%–80% at 2–3 years,
therefore have uncertain immunologic activity, initiation versus about 30% of controls treated with supportive care
of IST should follow the current restrictive proteinuria or only (2,56–60,65). Development of ESRD 10 years later is
GFR-based guidelines outlined above (56,57) (Figure 4). reduced from 30%–40% to 10% or less when all patients with
Clinical outcomes using these restrictive therapy protocols PMN are treated at the time of diagnosis with alkylating
have been equivalent to earlier results achieved by initi- agents/steroids (65). Proteinuric relapses, seen in about 25%
ating IST in all patients with PMN at the time of diagnosis of patients, are not predicted by any clinical parameter, but
while sparing about 50% of patients with PMN the toxic usually follow the return of anti- PLA2R/THSD7A antibody
effects of IST (61). However, using the current recommen- and are treated by repeating the same therapy that induced
dations of 6 months of SC alone, nephrotic syndrome the initial remission (1,2,56–60). A course of cyclophospha-
resolves more slowly, patients are exposed to the nephrotic mide should be repeated only once because cumulative
state for longer periods of time and therefore are at greater doses .36 g are associated with an increased incidence of
risk for developing complications of nephrotic syndrome malignancy (55), although increased incidence ratios for
such as thromboembolic disease (Table 4), and some malignancy have been reported in PMN at all levels of
nephrons will inevitably be damaged or destroyed while cumulative cyclophosphamide dose (66). Advantages of the
waiting for a spontaneous remission to occur (4–6). 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 about equal efficacy between TAC and CSA (1,4,56–60).
considerable experience with its use (4,59,60,62). Disad- Advantages of CNIs include the lower incidence of in-
vantages include a relatively high adverse event rate (25%) fection and malignancy compared with cytotoxic drugs
that includes infection, need for close monitoring of and the efficacy of monotherapy if steroids are not used
hematologic parameters, infertility, and later malignancy (1,56,58). Disadvantages include long-term nephrotoxicity
(56,57,62,66). with consequent need to closely monitor drug levels,
CNIs (cyclosporin [CSA] or tacrolimus [TAC]), used increased incidence of hypertension and diabetes, espe-
either as monotherapy or combined with low-dose steroids, cially with TAC, and some recent concerns about whether
which is thought to improve response and reduce nephro- CNIs are effective at all in preventing ESRD in the long
toxicity, have also been shown to decrease proteinuria, term (67). The relapse rate with CNIs (40%–50%) is also
reduce the rate of loss of renal function, and decrease anti- higher than with cyclophosphamide (25%) but may di-
PLA2R levels in PMN (1,2,4,56–60). In the United States, minish with longer periods of therapy (1,59,60), and some
many clinicians prefer to initiate therapy with CNIs to avoid have advocated using low-dose CSA as maintenance
the more severe adverse events associated with alkylating therapy to reduce or prevent relapses. CNIs have been
agents and higher doses of steroids. Most studies show shown to not only reduce anti-PLA2R levels (62,63) but also to
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 993

have a direct effect to stabilize the podocyte actin cytoskeleton, persistent nephrotic syndrome after 6 months of supportive
which reduces protein filtration (68). CNIs induce partial or care, demonstrated much greater efficacy of rituximab in
complete remissions in up to 80% of cases of PMN within 12 reducing anti-PLA2R levels (56% versus 4% at 3 months,
months and could be employed if cyclophosphamide/steroid P,0.05) and more complete and partial remissions of pro-
treatment fails, previous cumulative doses of cyclo- teinuria at a mean of 17 months in the rituximab group (65%
phosphamide approach 36 g, there is inability to tolerate versus 34%, P,0.01), with short-term adverse event rates
cytotoxic drugs, or issues such as osteoporosis similar to those in the group receiving SC alone (72). Analysis
or preservation of fertility are present (1,56–60). However, of the cost of therapy over the course of the disease using a
CNIs have not yet been established by proper RCTs to Markov decision analysis model suggests it is lower than the
reduce the long-term development of ESRD, although a cost of cyclophosphamide/steroids (73). Thus, experience to
strong case can be made that complete and partial date supports considering rituximab monotherapy as a third
remissions of proteinuria can serve as surrogate markers option for induction therapy, as well as a popular choice for
of failure to progress to ESRD in PMN (44). The limited maintenance or rescue therapy (71).
data comparing cytotoxic drug therapy directly to CNIs Adrenocorticotrophic hormone monotherapy, usually
suggests they have similar short-term clinical efficacy given as 1 mg twice a week for a year (Table 6), has also
(1,44,56–60). However, in one recent RCT, the response been shown in one small randomized controlled study to
to CNIs was not different from the response to SC alone reduce anti-PLA2R levels and produce results (.80%
(67). An excellent initial response rate to CNIs (80%) has remission at 6 months) equivalent to cyclophosphamide/
been reported in some patients who failed the Ponticelli steroids, with minimal adverse events (Table 6) (74–75).
regimen and, conversely, some patients who have failed However, another study comparing the two using histor-
CNIs may respond to the Ponticelli regimen (59,60,69). ical controls favored cyclophosphamide (75). The cost of
MMF monotherapy has not been established to be adrenocorticotrophic hormone is very high, and its place
effective in PMN (64). In one study only 44% of patients in the therapeutic armamentarium for PMN remains to be
receiving MMF were in remission at 23 months versus established (76).
75% in the cyclophosphamide group (63). Another treatment option is to utilize combinations of
B cell depletion using the anti-CD19/20 monoclonal drugs in lower doses (multidrug therapy), usually ritux-
rituximab as monotherapy has recently emerged as a less imab plus a cytotoxic drug or CNI to retain efficacy and
toxic approach, with efficacy equivalent to cytotoxic drugs reduce adverse events, especially those due to steroids.
and CNIs but with a significantly lower adverse event rate For example, a recent observational study using rituximab
(58,70–72). Rituximab was initially given weekly for 4 with low-dose cyclophosphamide and an accelerated taper
weeks as doses of 375 mg/M2 intravenously (iv) or, more of steroids reported a 100% remission rate over a mean
recently, as two iv doses of 1000 mg, or 375 mg/m2, 15 follow-up of 37 months (77). Another, using a combination
days apart (71). Rituximab, 375 mg/M2 as a single dose of rituximab and CSA, achieved remissions in 92% and
repeated only when B cell counts return (B cell–driven antibody depletion in 100% in 9 months (78), and a
therapy), has also been established to reduce anti-PLA2R combination of rituximab and plasma exchange showed
antibody levels and to induce remission of proteinuria in promise in a third small study (79). These studies all require
about 64% of patients in a mean of 7 months, but that confirmation, and RCTs comparing these approaches to
figure increases over 3–4 years and the safety profile is conventional IST reviewed above are necessary before
better than that of cyclophosphamide or CNIs (1,70–72). multidrug therapy can be recommended as an established
Also, similar effects on proteinuria have been reported in approach to initial therapy in PMN.
PLA2R/THSD7A antibody–negative patients, suggesting
that these patients too may have an antibody-mediated
disease (71). Advantages of B cell–driven therapy include Transplantation in PMN
the freedom from steroids, low adverse event rate, ability to Renal transplantation is effective in the 10%–20% of
monitor B cell levels to assess efficacy and predict remission patients who do reach ESRD from PMN (1,4,75–78). In anti-
and relapse, and modest cost when only a single dose is given PLA2R–positive patients, subepithelial deposits can ap-
(71). Disadvantages include the lack of confirmation that pear in the allograft within 6 days (70,80,81). As deposits
early reductions in proteinuria predict a lower incidence of increase, clinical recurrence (proteinuria) is seen within 13–
ESRD (with the caveat mentioned above that remissions of 15 months in about 40%–50% of allografts and can diminish
proteinuria in PMN may be acceptable surrogate markers for allograft survival (70,80–85). The recurrence rate of sub-
ESRD in PMN [44]). The response rate closely parallels CD epithelial deposits in patients positive for anti-PLA2R
19/20 B cell counts and anti-PLA2R levels, and seems similar antibodies at the time of transplantation may approach
in patients treated initially and those in whom rituximab 90% (70,80,81). Delaying transplantation until anti-PLA2R/
was used later as rescue therapy (70–72). The relapse rate in THSD7A is no longer detectable seems advisable unless
rituximab responders is about 30%, associated with return there are clinical reasons for greater urgency. Anti-PLA2R–
of circulating B cells and anti-PLA2R antibody, and relapse negative de novo MN is also a common cause of transplant
can sometimes be associated with development of anti- nephrotic syndrome, affecting about 2% of all renal trans-
rituximab antibodies (72). Most patients who relapse respond plant recipients whose original disease was not MN, and is
to another dose (70–72). A recent RCT (Evaluate Rituximab about equal in frequency to recurrent MN in patients with
Treatment for Idiopathic Membranous Nephropathy Study) PMN (82–85). In these patients, IgG1 deposits often pre-
comparing supportive care alone to supportive care plus dominate, anti-PLA2R/THSD7A is negative, and the
rituximab, 375 mg/M2 iv on days 0 and 8 in patients with 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- New Therapies on the Horizon
PLA2R positivity has a sensitivity of 83% and specificity of Current knowledge of the roles of autoantibody IgG and
.90% in differentiating between recurrent and de novo MN complement in the pathogenesis of PMN make better B
in transplants (78–80,84). cell–depleting agents and complement inhibitors of par-
Because patients with recurrent subepithelial deposits ticular interest. New therapeutic approaches to suppress
do not all go on to manifest clinical recurrence, treatment antibody production or interfere with antibody-induced
for recurrent MN is usually considered only when protein podocyte injury include improved B cell–depleting agents,
excretion reproducibly exceeds 1 g/d in patients with PMN B cell depletion targeted specifically to anti-PLA2R re-
or 4 g/d in patients with de novo MN (82–85). However, an active cells, and suppressors of B cell activation. A recent
approach analogous to the one recommended above for pilot study of belimumab, an inhibitor of B cell activation,
PMN in native kidneys would suggest initiating additional in 11 anti-PLA2R–positive patients reported a 90% re-
IST in patients with PMN with elevated anti-PLA2R/ duction in anti-PLA2R levels and a (delayed) 70% re-
THSD7A levels and nephrotic-range proteinuria post- duction in proteinuria in patients receiving monthly iv
transplant. Based entirely on observational data, rituximab doses of the drug over a period of 28 weeks (87). Other
is usually added to regular immunosuppressive protocols, approaches under development include antibody traps or
which often already include CNIs (70,82–84). The doses decoys and efforts to directly protect the podocyte itself
employed have ranged from one dose of 200 mg to the older from consequences of immune injury such as endoplasmic
375 mg/M2 given four times at weekly intervals with reticulum stress, autophagy, and oxidant injury (88).
monitoring of CD20 counts. Because these patients are Pending identification of PLA2R peptides that neutralize
being treated early and are already on IST for the trans- antibody, peptide-blocking agents will likely also be de-
plant, lower doses are probably preferable. Use of pretrans- veloped. Although one trial of the C5 inhibitor eculizumab
plant rituximab has been attempted in antibody-positive was negative in PMN, adequate complement -inhibiting
patients, and may have been effective in preventing re- doses were not used, and other trials with newer comple-
currence in some patients with a history of recurrent PMN ment inhibitors, including oral agents, recombinant com-
in previous allografts (84). In patients receiving CNIs and plement regulatory proteins, small molecules, new
resistant to rituximab, cyclophosphamide, 2 mg/kg per monoclonal antibodies, small interfering RNA agents,
day, is usually employed after other antimetabolites such as and approaches that upregulate natural complement in-
MMF or azathioprine are discontinued (78,82–84). hibitors, are in progress or under development (31).

Disclosures
Gaps and Shortfalls in Current Therapy None.
Despite the numerous translational observations that
have already been made (Table 3), many questions remain References
unanswered (86). Some of the more clinically relevant ones 1. Cattran DC, Brenchley PE: Membranous nephropathy: Integrating
include: What is the best way to measure anti-PLA2R, basic science into improved clinical management. Kidney Int 91:
and, in the future, anti-THSD7A, antibody? How do 566–574, 2017
antibody levels translate into risk of progression and are 2. Salant DJ, Cattran DC: Membranous nephropathy. Chapter 20. In:
Comprehensive Clinical Nephrology, 5th Ed., edited by Floege J,
there levels below which IST is not worthwhile? If therapy Johnson RJ, Feehally J, St. Louis, MI, Saunders, an imprint of
is antibody-directed, will this achieve better clinical out- Elsevier Inc., 2015, pp 239–251
comes or fewer adverse events in patients with active 3. Kumar V, Ramachandran R, Kumar A, Nada R, Suri D, Gupta A,
disease compared with current restrictive therapy regi- Kohli HS, Gupta KL, Jha V: Antibodies to m-type phospholipase
A2 receptor in children with idiopathic membranous nephrop-
mens? Is it important for prognosis or treatment to know athy. Nephrology (Carlton) 20: 572–575, 2015
the pathogenic epitopes and molecular configurations of 4. De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC: A
the PLA2R peptides against which antibodies in individual proposal for a serology-based approach to membranous ne-
patients are directed? Does a biopsy contribute to im- phropathy. J Am Soc Nephrol 28: 421–430, 2016
proved outcomes in typical anti-PLA2R/THSD7A–positive 5. Francis JM, Beck LH Jr., Salant DJ: Membranous nephropathy: A
journey from bench to bedside. Am J Kidney Dis 68: 138–147, 2016
PMN with nephrotic syndrome? If a patient has apparent 6. Debiec H, Ronco P: Immune response against autoantigen
secondary MN with another systemic disease, but also has PLA2R is not gambling: Implications for pathophysiology, prog-
elevated anti-PLA2R/THSD7A antibody or positive glomer- nosis and therapy. J Am Soc Nephrol 27: 1275–1277, 2016
ular staining, should such a patient be treated for PMN? If 7. Ronco P, Debiec H: Pathophysiological advances in membranous
nephropathy: Time for a shift in patient’s care. Lancet 385: 1983–
a biopsy is done in antibody-negative patients, is positive 1992, 2015
glomerular staining for IgG4 and PLA2R/THSD7A suffi- 8. Sinico RA, Mezzina N, Trezzi B, Ghiggeri GM, Radice A: Im-
cient to establish anti-PLA2R/THSD7A–related PMN and munology of membranous nephropathy: From animal models to
exclude secondary causes? humans. Clin Exp Immunol 183: 157–165, 2016
Can multidrug therapy protocols combining currently 9. Kerjaschki D: Pathomechanisms and molecular basis of mem-
branous glomerulopathy. Lancet 364: 1194–1196, 2004
available drugs reduce adverse events without sacrificing 10. Debiec H, Guigonis V, Mougenot B, Decobert F, Haymann JP,
efficacy as has been done in lupus nephritis? Can outcomes Bensman A, Deschênes G, Ronco PM: Antenatal membranous
be further improved if complement inhibitors are added to glomerulonephritis due to anti-neutral endopeptidase antibodies.
current IST protocols, especially during the interval of N Engl J Med 346: 2053–2060, 2002
11. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW,
active disease between initiation of IST and disappearance Cummins TD, Klein JB, Salant DJ: M-type phospholipase A2 re-
of the antibody? Can routine maintenance therapy reduce ceptor as target antigen in idiopathic membranous nephropathy.
relapses and the need for retreatment? N Engl J Med 361: 11–21, 2009
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 995

12. Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma 30. Takano T, Elimam H, Cybulsky AV: Complement-mediated cel-
H, Zahner G, Dolla G, Hoxha E, Helmchen U, Dabert-Gay AS, lular injury. Semin Nephrol 33: 586–601, 2013
Debayle D, Merchant M, Klein J, Salant DJ, Stahl RA, Lambeau G: 31. Reddy YN, Siedlecki AM, Francis JM: Breaking down the com-
Thrombospondin type-1 domain-containing 7A in idiopathic plement system: a review and update on novel therapies. Curr
membranous nephropathy. N Engl J Med 371: 2277–2287, 2014 Opin Nephrol Hypertens 26: 123–128, 2017
13. Larsen CP, Cossey LN, Beck LH: THSD7A staining of membranous 32. Spicer ST, Tran GT, Killingsworth MC, Carter N, Power DA, Paizis
glomerulopathy in clinical practice reveals cases with dual au- K, Boyd R, Hodgkinson SJ, Hall BM: Induction of passive Hey-
toantibody positivity. Mod Pathol 29: 421–426, 2016 mann nephritis in complement component 6-deficient PVG rats. J
14. Hoxha E, Wiech T, Stahl PR, Zahner G, Tomas NM, Meyer- Immunol 179: 172–178, 2007
Schwesinger C, Wenzel U, Janneck M, Steinmetz OM, Panzer U, 33. Salant DJ: Genetic variants in membranous nephropathy:
Harendza S, Stahl RA: A mechanism for cancer-associated Perhaps a perfect storm rather than a straightforward con-
membranous nephropathy. N Engl J Med 374: 1995–1996, 2016 formeropathy? J Am Soc Nephrol 24: 525–528, 2013
15. Timmermans SA, Ayalon R, van Paassen P, Beck LH Jr, van Rie H, 34. Bomback AS, Gharavi AG: Can genetics risk-stratify patients with
Wirtz JJ, Verseput GH, Frenken LA, Salant DJ, Cohen Tervaert JW; membranous nephropathy? J Am Soc Nephrol 24: 1190–1192,
Limburg Renal Registry: Anti-phospholipase A2 receptor anti- 2013
bodies and malignancy in membranous nephropathy. Am J Kid- 35. Lv J, Hou W, Zhou X, Liu G, Zhou F, Zhao N, Hou P, Zhao M,
ney Dis 62: 1223–1225, 2013 Zhang H: Interaction between PLA2R1 and HLA-DQA1 variants
16. Stahl PR, Hoxha E, Wiech T, Schröder C, Simon R, Stahl RA: associates with anti-PLA2R antibodies and membranous ne-
THSD7A expression in human cancer. Genes Chromosomes phropathy. J Am Soc Nephrol 24: 1323–1329, 2013
Cancer 56: 314–327, 2017 36. Seitz-Polski B, Dolla G, Payré C, Girard CA, Polidori J, Zorzi K,
17. Hoxha E, Beck LH Jr, Wiech T, Tomas NM, Probst C, Mindorf S, Birgy-Barelli E, Jullien P, Courivaud C, Krummel T, Benzaken S,
Meyer-Schwesinger C, Zahner G, Stahl PR, Schöpper R, Panzer Bernard G, Burtey S, Mariat C, Esnault VL, Lambeau G: Epitope
U, Harendza S, Helmchen U, Salant DJ, Stahl RA: An indirect spreading of autoantibody response to PLA2R1 is associates with
immunofluorescence method facilitates detection of throm- poor prognosis in membranous nephropathy. J Am Soc Nephrol
bospondin type 1 domain-containing 7A-specific antibodies in 27: 1517–1533, 2016
membranous nephropathy. J Am Soc Nephrol 28: 520–531, 37. Cui Z, Xie LJ, Chen FJ, Pei ZY, Zhang LJ, Qu Z, Huang J, Gu QH,
2017 Zhang YM, Wang X, Wang F, Meng LQ, Liu G, Zhou XJ, Zhu L, Lv
18. Lefaucheur C, Stengel B, Nochy D, Martel P, Hill GS, Jacquot C, JC, Liu F, Zhang H, Liao YH, Lai LH, Ronco P, Zhao MH. MHC
Rossert J; GN-PROGRESS Study Group: Membranous ne- Class II risk alleles and amino acid residues in idiopathic
phropathy and cancer: Epidemiologic evidence and determi- membranous nephropathy. J Am Soc Nephrol 28: 1642–1650,
nants of high-risk cancer association. Kidney Int 70: 1510–1517, 2017
2006 38. Le WB, Shi JS, Zhang T, Liu L, Qin HZ, Liang S, Zhang YW, Zheng
19. Tomas NM, Hoxha E, Reinicke AT, Fester L, Helmchen U, Gerth J, CX, Jiang S, Qin WS, Zhang HT, Liu ZH. DRB1*15:01 and HLA-
Bachmann F, Budde K, Koch-Nolte F, Zahner G, Rune G, Lambeau DRB3*02:02 in -related membranous nephropathy. J Am Soc
G, Meyer-Schwesinger C, Stahl RA: Autoantibodies against Nephrol 28: 1642–1650, 2017
thrombospondin type 1 domain-containing 7A induce mem- 39. Kao L, Lam V, Waldman M, Glassock RJ, Zhu Q: Identification
branous nephropathy. J Clin Invest 126: 2519–2532, 2016 of the immunodominant epitope region in phospholipase A2
20. Larsen CP, Messias NC, Silva FG, Messias E, Walker PD: De- receptor-mediating autoantibody binding in idiopathic mem-
termination of primary versus secondary membranous glomer- branous nephropathy. J Am Soc Nephrol 26: 291–301, 2015
ulopathy utilizing phospholipase A2 receptor staining in renal 40. Fresquet M, Jowitt TA, Gummadova J, Collins R, O’Cualain R,
biopsies. Mod Pathol 26: 709–715, 2013 McKenzie EA, Lennon R, Brenchley PE: Identification of a major
21. Dong HR, Wang YY, Cheng XH, Wang GQ, Sun LJ, Cheng H, Chen epitope recognized by PLA2R autoantibodies in primary mem-
YP. Retrospective study of phospholipase A2 receptor and IgG branous nephropathy. J Am Soc Nephrol 26: 302–313, 2015
subclasses in glomerular deposits in chinese patients with 41. Fogo AB, Lusco MA, Najafian B, Alpers CE: AJKD atlas of renal
membranous nephropathy. PLoS One. 11: e0156263, 2016 pathology: Membranous nephropathy. Am J Kidney Dis 66: e15–
22. Beck LH Jr, Salant DJ: Membranous nephropathy: Recent travels e17, 2015
and new roads ahead. Kidney Int 77: 765–770, 2010 42. Barbour S, Reich H, Cattran D: Short-term complications of
23. Svobodova B, Honsova E, Ronco P, Tesar V, Debiec H: Kidney membranous nephropathy. Contrib Nephrol 181: 143–151, 2013
biopsy is a sensitive tool for retrospective diagnosis of PLA2R- 43. Ponticelli C, Glassock RJ: Glomerular diseases: Membranous
related membranous nephropathy. Nephrol Dial Transplant 28: nephropathy–a modern view. Clin J Am Soc Nephrol 9: 609–616,
1839–1844, 2013 2014
24. Debiec H, Ronco P: PLA2R autoantibodies and PLA2R glomer- 44. Thompson A, Cattran DC, Blank M, Nachman PH: Complete and
ular deposits in membranous nephropathy. N Engl J Med 364: partial remission as surrogate end points in membranous ne-
689–690, 2011 phropathy. J Am Soc Nephrol 26: 2930–2937, 2015
25. Ryan MS, Satoskar AA, Nadasdy GM, Brodsky SV, Hemminger JA, 45. Hladunewich MA, Troyanov S, Calafati J, Cattran DC; Metro-
Nadasdy T: Phospholipase A2 receptor staining is absent in many politan Toronto Glomerulonephritis Registry: The natural history
kidney biopsies with early-stage membranous glomerulone- of the non-nephrotic membranous nephropathy patient. Clin J Am
phritis. Kidney Int 89: 1402–1403, 2016 Soc Nephrol 4: 1417–1422, 2009
26. Guerry MJ, Vanhille P, Ronco P, Debiec H: Serum anti-PLA2R 46. Polanco N, Gutiérrez E, Covarsı́ A, Ariza F, Carre~no A, Vigil A,
antibodies may be present before clinical manifestations of Baltar J, Fernández-Fresnedo G, Martı́n C, Pons S, Lorenbnvzo D,
membranous nephropathy. Kidney Int 89: 1399, 2016 Bernis C, Arrizabalaga P, Fernández-Juárez G, Barrio V, Sierra M,
27. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Castellanos I, Espinosa M, Rivera F, Oliet A, Fernández-Vega F,
Kottgen A, Dragomirescu L, Voinescu C, Patel N, Pearce K, Praga M; Grupo de Estudio de las Enfermedades Glomerulares de
Hubank M, Stephens HA, Laundy V, Padmanabhan S, Zawadzka la Sociedad Espa~ nola de Nefrologı́a: Spontaneous remission of
A, Hofstra JM, Coenen MJ, den Heijer M, Kiemeney LA, Bacq- nephrotic syndrome in idiopathic membranous nephropathy. J
Daian D, Stengel B, Powis SH, Brenchley P, Feehally J, Rees AJ, Am Soc Nephrol 21: 697–704, 2010
Debiec H, Wetzels JF, Ronco P, Mathieson PW, Kleta R: Risk 47. Hofstra JM, Beck LH Jr, Beck DM, Wetzels JF, Salant DJ: Anti-
HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous phospholipase A2 receptor antibodies correlate with clinical
nephropathy. N Engl J Med 364: 616–626, 2011 status in idiopathic membranous nephropathy. Clin J Am Soc
28. Xu X, Wang G, Chen N, Lu T, Nie S, Xu G, Zhang P, Luo Y, Wang Y, Nephrol 6: 1286–1291, 2011
Wang X, Schwartz J, Geng J, Hou FF: Long-term exposure to air 48. Hoxha E, Harendza S, Pinnschmidt H, Panzer U, Stahl RA: PLA2R
pollution and increased risk of membranous nephropathy in antibody levels and clinical outcome in patients with membra-
china. J Am Soc Nephrol 27: 3739–3746, 2016 nous nephropathy and non-nephrotic range proteinuria under
29. Ma H, Sandor DG, Beck LH Jr.: The role of complement in treatment with inhibitors of the renin-angiotensin system. PLoS
membranous nephropathy. Semin Nephrol 33: 531–542, 2013 One 9: e110681, 2014
996 Clinical Journal of the American Society of Nephrology

49. Lee T, Derebail VK, Kshirsagar AV, Chung Y, Fine JP, Mahoney S, 66. Khan S, Bolton WK: Balancing cancer risk and efficacy of using
Poulton CJ, Lionaki S, Hogan SL, Falk RJ, Cattran DC, cyclophosphamide to treat idiopathic membranous nephropathy.
Hladunewich M, Reich HN, Nachman PH: Patients with primary Clin J Am Soc Nephrol 9: 1001–1004, 2014
membranous nephropathy are at high risk of cardiovascular 67. Howman A, Chapman TL, Langdon MM, Ferguson C, Adu D,
events. Kidney Int 89: 1111–1118, 2016 Feehally J, Gaskin GJ, Jayne DR, O’Donoghue D, Boulton-Jones
50. Radice A, Trezzi B, Maggiore U, Pregnolato F, Stellato T, M, Mathieson PW: Immunosuppression for progressive mem-
Napodano P, Rolla D, Pesce G, D’Amico M, Santoro D, Londrino branous nephropathy: A UK randomised controlled trial. Lancet
F, Ravera F, Ortisi G, Sinico RA: Clinical usefulness of autoanti- 381: 744–751, 2013
bodies to M-type phospholipase A2 receptor (PLA2R) for moni- 68. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S,
toring disease activity in PMN. Autoimmun Rev 15: 146–154, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J,
2016 Mundel P: The actin cytoskeleton of kidney podocytes is a direct
51. Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, target of the antiproteinuric effect of cyclosporine A. Nat Med 14:
Nikam M, Poulton K, McWilliam L, Short CD, Venning M, Brenchley 931–938, 2008
PE: Anti-PLA2R antibodies measured by ELISA predict long-term 69. Ramachandran R, Kumar V, Jha V: Cyclical cyclophosphamide
outcome in a prevalent population of patients with idiopathic and steroids is effective in resistant or relapsing nephrotic syn-
membranous nephropathy. Kidney Int 83: 940–948, 2013 drome due to M-type phospholipase A2 receptor-related mem-
52. Li SJ, Guo JZ, Zuo K, Zhang J, Wu Y, Zhou CS, Lu GM, Liu ZH: branous nephropathy after tacrolimus therapy. Kidney Int 89:
Thromboembolic complications in membranous nephropathy 1401–1402, 2016
patients with nephrotic syndrome-a prospective study. Thromb 70. Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F,
Res 130: 501–505, 2012 Suardi F, Gagliardini E, Orisio S, Benigni A, Ronco P, Remuzzi G:
53. Rankin AJ, McQuarrie EP, Fox JG, Geddes CC, MacKinnon B; Anti-phospholipase A2 receptor antibody titer predicts post-
Scottish Renal Biopsy Registry: Venous thromboembolism in rituximab outcome of membranous nephropathy. J Am Soc
primary nephrotic syndrome - Is the risk high enough to justify Nephrol 26: 2545–2558, 2015
prophylactic anticoagulation? Nephron 135: 39–45, 2017 71. Cravedi P, Remuzzi G, Ruggenenti P: Rituximab in primary
54. Lee T, Biddle AK, Lionaki S, Derebail VK, Barbour SJ, Tannous S, membranous nephropathy: First-line therapy, why not? Nephron
Hladunewich MA, Hu Y, Poulton CJ, Mahoney SL, Charles Clin Pract 128: 261–269, 2014
Jennette J, Hogan SL, Falk RJ, Cattran DC, Reich HN, Nachman 72. Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A,
PH: Personalized prophylactic anticoagulation decision analysis Wakselman L, Michel PA, Mihout F, Dussol B, Matignon M,
in patients with membranous nephropathy. Kidney Int 85: 1412– Mousson C, Simon T, Ronco P; GEMRITUX Study Group: Rit-
1420, 2014 uximab for severe membranous nephropathy: A 6-month trial
55. Leeaphorn N, Kue-A-Pai P, Thamcharoen N, Ungprasert P, Stokes with extended follow-up. J Am Soc Nephrol 28: 348–358, 2017
MB, Knight EL: Prevalence of cancer in membranous nephrop- 73. Hamilton P, Kanigicherla DAK, Venning M, Brenchley PE, Meads
athy: A systematic review and meta-analysis of observational DM: Rituximab versus the modified Ponticelli regime in the
studies. Am J Nephrol 40: 29–35, 2014 treatment of primary membranous nephropathy: A health eco-
56. Kidney Disease Improving Global Outcomes (KDIGO) Glomer- nomic model. J Am Soc Nephrol 27: 776a, 2016
ulonephritis Work Group: KDIGO clinical practice guideline for 74. Ponticelli C, Passerini P, Salvadori M, Manno C, Viola BF, Pasquali
glomerulonephritis. Kidney Int Suppl 2: 139–274, 2012 S, Mandolfo S, Messa P: A randomized pilot trial comparing
57. Cybulsky AV, Walsh M, Knoll G, Hladunewich M, Bargman J, methylprednisolone plus a cytotoxic agent versus synthetic ad-
Reich H, Humar A, Samuel S, Bitzan M, Zappitelli M, Dart A, renocorticotropic hormone in idiopathic membranous ne-
Mammen C, Pinsk M, Muirhead N: Canadian Society of Ne- phropathy. Am J Kidney Dis 47: 233–240, 2006
phrology Commentary on the 2012 KDIGO clinical practice 75. van de Logt AE, Beerenhout CH, Brink HS, van de Kerkhof JJ,
guideline for glomerulonephritis: Management of glomerulone- Wetzels JF, Hofstra JM. Synthetic ACTH in high risk patients with
phritis in adults. Am J Kidney Dis 63: 363–377, 2014 idiopathic membranous nephropathy: A prospective, open label
58. Cattran D, Brenchley P: Membranous nephropathy: thinking cohort study. PLoS One 10: e0142033, 2015
through the therapeutic options. Nephrol Dial Transplant 76. Kittanamongkolchai W, Cheungpasitporn W, Zand L: Efficacy and
32(suppl_1): i22–i29, 2017 safety of adrenocorticotropic hormone treatment in glomerular
59. Tran THJ, J Hughes G, Greenfeld C, Pham JT: Overview of current diseases: A systematic review and meta-analysis. Clin Kidney J 9:
and alternative therapies for idiopathic membranous nephropa- 387–396, 2016
thy. Pharmacotherapy 35: 396–411, 2015 77. Cortazar FB, Leaf DE, Owens CT, Laliberte K, Pendergraft 3rd WF,
60. van de Logt AE, Hofstra JM, Wetzels JF: Pharmacological treat- Niles JL: Combination therapy with rituximab, low-dose cyclo-
ment of primary membranous nephropathy in 2016. Expert Rev phosphamide, and prednisone for idiopathic membranous ne-
Clin Pharmacol 16: 1–16, 2016 phropathy: A case series. BMC Nephrol 18: 44, 2017
61. van den Brand JA, van Dijk PR, Hofstra JM, Wetzels JF: Long- 78. Waldman M, Beck LH Jr, Braun M, Wilkins K, Balow JE, Austin 3rd
term outcomes in idiopathic membranous nephropathy using a HA: Membranous nephropathy: Pilot study of a novel regimen
restrictive treatment strategy. J Am Soc Nephrol 25: 150–158, combining cyclosporine and Rituximab. Kidney Int Rep 1: 73–84,
2014 2016
62. Ramachandran R, Hn HK, Kumar V, Nada R, Yadav AK, Goyal A, 79. Müller-Deile J, Schiffer L, Hiss M, Haller H, Schiffer M: A new
Kumar V, Rathi M, Jha V, Gupta KL, Sakhuja V, Kohli HS: Tacro- rescue regimen with plasma exchange and rituximab in high-risk
limus combined with corticosteroids versus Modified Ponticelli membranous glomerulonephritis. Eur J Clin Invest 45: 1260–
regimen in treatment of idiopathic membranous nephropathy: 1269, 2015
Randomized control trial. Nephrology (Carlton) 21: 139–146, 80. Kattah A, Ayalon R, Beck LH Jr, Sethi S, Sandor DG, Cosio FG,
2016 Gandhi MJ, Lorenz EC, Salant DJ, Fervenza FC: Anti-phospholipase
63. Bech AP, Hofstra JM, Brenchley PE, Wetzels JF: Association of A2 receptor antibodies in recurrent membranous nephropathy. Am J
anti-PLA2R antibodies with outcomes after immunosuppressive Transplant 15: 1349–1359, 2015
therapy in idiopathic membranous nephropathy. Clin J Am Soc 81. Dabade TS, Grande JP, Norby SM, Fervenza FC, Cosio FG: Re-
Nephrol 9: 1386–1392, 2014 current idiopathic membranous nephropathy after kidney
64. Dussol B, Morange S, Burtey S, Indreies M, Cassuto E, Mourad G, transplantation: A surveillance biopsy study. Am J Transplant 8:
Villar E, Pouteil-Noble C, Karaaslan H, Sichez H, Lasseur C, 1318–1322, 2008
Delmas Y, Nogier MB, Fathallah M, Loundou A, Mayor V, Berland 82. PonticelliC,MoroniG,GlassockRJ:Denovoglomerulardiseasesafter
Y: Mycophenolate mofetil monotherapy in membranous ne- renal transplantation. Clin J Am Soc Nephrol 9: 1479–1487, 2014
phropathy: A 1-year randomized controlled trial. Am J Kidney Dis 83. Filippone EJ, Farber JL: Membranous nephropathy in the kidney
52: 699–705, 2008 allograft. Clin Transplant 30: 1394–1402, 2016
65. Hofstra JM, Wetzels JFM: Alkylating agents in membranous ne- 84. Cosio FG, Cattran DC: Recent advances in our understanding of
phropathy: Efficacy proven beyond doubt. Nephrol Dial Trans- recurrent primary glomerulonephritis after kidney trans-
plant 25: 1760–1766, 2010 plantation. Kidney Int 91: 304–314, 2017
Clin J Am Soc Nephrol 12: 983–997, June, 2017 Membranous Nephropathy, Couser 997

85. Gupta G, Fattah H, Ayalon R, Kidd J, Gehr T, Quintana LF, Kimball P, 90. Couser WG, Johnson RJ: The etiology of glomerulonephritis:
Sadruddin S, Massey HD, Kumar D, King AL, Beck LH Jr: Pre-transplant Roles of infection and autoimmunity. Kidney Int 86: 905–914,
phospholipase A2 receptor autoantibody concentration is associated 2014
with clinically significant recurrence of membranous nephropathy 91. Larsen CP, Ambuzs JM, Bonsib SM, Boils CL, Cossey LN, Messias
post-kidney transplantation. Clin Transplant 30: 461–469, 2016 NC, Silva FG, Wang YH, Gokden N, Walker PD: Membranous-
86. Hofstra JM, Wetzels JF: Phospholipase A2 receptor antibodies in like glomerulopathy with masked IgG kappa deposits. Kidney Int
membranous nephropathy: Unresolved issues. J Am Soc Nephrol 86: 154–161, 2014
25: 1137–1139, 2014 92. Hogan JJ, Markowitz GS, Radhakrishnan J. Drug-induced glo-
87. Willcocks L, Barrett C, Brenchley P, Schmidt T, Gisbert S, Cai G, merular disease: Immune-mediated injury. Clin J Am Soc Nephrol
Savage C, Jones R Effect of Belimumab on proteinuria and anti- 10: 1300–1310, 2015
PLA2R autoantibody in idiopathic membranous nephropathy - 6 93. Medrano AS, Escalante EJ, Cáceres CC, Pamplona IA, Allende MT,
months data. Nephrol Dial Transplant 30[Suppl 3]: iii32–iii33, 2015 Terrades NR, Carmeno NV, Roldán EO, Agudelo KV, Vasquez JJ:
88. Cattran DC, Brenchley PE: Membranous nephropathy: integrating Prognostic value of the dynamics of M-type phospholipase A2
basic science into improved clinical management. Kidney Int 91: receptor antibody titers in patients with idiopathic membranous
566–574, 2017 nephropathy treated with two different immunosuppression
89. French LE, Tschopp J, Schifferli JA: Clusterin in renal tissue: regimens. Biomarkers 20: 77–83, 2015
Preferential localization with the terminal complement complex
and immunoglobulin deposits in glomeruli. Clin Exp Immunol 88: Published online ahead of print. Publication date available at www.
389–393, 1992 cjasn.org.