MINI-SYMPOSIUM: NEPHROUROLOGY
be considered1: Not all paraproteins are nephrotoxic, although
An update on paraprotein-
related renal pathology
Andreas Kousios
Candice Roufosse
Abstract
Paraproteins are intact monoclonal immunoglobulins (MIg) or isolated
MIg heavy or light chains, detected in the blood or urine and caused by
a clonal proliferation of B cells or plasma cells. Paraproteins often
cause renal injury, referred to here as paraprotein-related renal disease
(PPRD), whether the underlying clonal disorder is characterized by
high tumour burden requiring treatment or low tumour burden and
thus not requiring immediate treatment from the haematological
standpoint. For the latter, an important recent update is the introduc-
tion of the concept of Monoclonal Gammopathy of Renal Significance
(MGRS), in which the renal pathology in itself may justify the use of
clone-directed therapies targeting the nephrotoxic clone, in order to
preserve renal function. A bewildering array of renal pathology can
be caused by paraproteins, affecting all compartments of
the kidney e glomeruli, tubules, interstitium and blood vessels. This re-
view aims to provide an overview of the different renal lesions that can
be seen, organized by predominant compartment affected, with guid-
ance on how to spot them and classify them.
Keywords biopsy; kidney; paraprotein
Introduction
Paraproteins are intact monoclonal immunoglobulins (MIg)
(see Table 1 for abbreviations) of any of the five isotypes (IgG,
IgM, IgA, IgD, IgE) or isolated MIg heavy or light chains (or
fragments of these), detected in the blood or urine and caused
by a clonal proliferation of B cells or plasma cells.1 The spec-
trum of haematological disorders causing paraprotein over-
production is wide and includes malignant conditions such as
Multiple Myeloma (MM), B cell Non Hodgkin Lymphoma
(NHL), lymphoplasmacytic lymphoma/Waldenstro €m Macro-
globulinemia (WM), or non-malignant, premalignant and low
tumour burden asymptomatic haematological B cell or plasma
cell disorders such as chronic lymphocytic leukemia (CLL),
marginal zone lymphomas, smouldering multiple myeloma
(SMM) and monoclonal gammopathy of undetermined signifi-
cance (MGUS).
Paraproteins produced in any of these conditions can cause
a wide variety of renal disorders. Two important points should
Andreas Kousios MD MSc Consultant Nephrologist, Renal and
Transplant Centre, Hammersmith Hospital, Imperial College
Healthcare NHS Trust, London, UK. Conflicts of interest: none
declared.
Candice Roufosse MD PhD Senior Clinical Lecturer, Imperial College,
Centre for Inflammatory Diseases, Division of Immunology, Faculty of
Medicine, London, UK. Conflicts of interest: none declared.
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Please cite this article as: Kousios A, Roufosse C, An update on paraprotein-related renal pathology, Diagnostic Histopathology, https://doi.org/
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the risk of light chain cast nephropathy (LCCN) and hyper-
viscosity syndromes increases with very high paraprotein
concentrations and2 nephrotoxic paraproteins can cause renal
disease regardless of the tumour burden. Intact MIg are not
filtered by the glomerulus because of their size. On the con-
trary, the smaller free light chains (FLCs) are freely filtered and
subsequently reabsorbed and catabolized by proximal tubular
cells through saturable clathrin-mediated endocytosis by the
megalin/cubulin receptor system of the proximal tubular
epithelium.2e4 Consequently, intact MIg mostly cause disease
by their interaction with resident glomerular cells and through
precipitation in capillary and arteriolar lumina, although the
exact pathogenetic mechanisms are incompletely understood.
Monoclonal FLCs on the other hand can cause damage in any
of the renal compartments (glomerular, tubular, interstitial and
vascular). The site and pattern of renal injury caused by FLCs
depends on several factors. One of the most important factors
appears to be certain amino acid sequences particularly of the
variable light chain domain resulting in innate structural
characteristics and distinct physicochemical properties of the
individual FLC. In their landmark study, Solomon et al.
demonstrated that mice injected with MIg isolated from pa-
tients with LCCN, AL amyloidosis or light chain deposition
disease (LCDD), develop the same pattern of renal disease as
the donor.5 Intrinsic host factors, different response of resident
renal cells to individual FLCs and local luminal environment
factors, such as pH, urea concentration, flow rate, and local
tissue proteolysis are also important in determining the site and
type of injury.6
The concept of monoclonal gammopathy of renal
significance (MGRS)
The fact that paraprotein-related renal disease (PPRD) can
develop in the context of malignant haematological disease (MM
or overt lymphoma) but may also develop irrespective of the
tumour burden provides further support to individual nephro-
toxic properties of each MIg. Despite an underlying small clone,
cases may progress to end stage renal disease (ESRD) and are
associated with morbidity and mortality.7 Based on these ob-
servations, an important recent update is the introduction of the
concept of MGRS by the International Kidney and Monoclonal
Gammopathy Research Group (IKMG).8 The updated MGRS term
describes monoclonal gammopathies which cause renal disease
but have low tumour burden and do not meet the CRAB-SLiM
criteria of myeloma or symptomatic lymphoma, thus treatment
from the haematological standpoint is not imminently indicated.9
These patients may have less than 10% plasma cells in bone
marrow biopsy (BM), SMM or low grade lymphomas.10 Histori-
cally, MGRS may have gone under-diagnosed and patients not
offered optimal treatment, unlike their counterparts fulfilling
consensus myeloma or lymphoma diagnostic criteria.11 MGRS,
therefore, are not of undetermined significance and their rele-
vance to renal pathology has opened the use of clone-directed
therapies targeting the nephrotoxic MIg-producing clone with
the objective of preserving renal function.12 A growing body of
evidence suggests that clone-directed therapy improves renal
outcomes.13,14
1 Ó 2019 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: NEPHROUROLOGY

people older than 50 years have an MGUS, increasing to 8% in

Abbreviations males older than 80 years.16
BM bone marrow biopsy Management of patients with PPRD requires very close multi-
CLL chronic lymphocytic leukemia disciplinary communication between pathologists, nephrologists
EM electron microscopy and haematologists. In some cases, the final histopathological
ESRD end stage renal disease classification is dependent on clinical findings. Most of the his-
FLCs free light chains topathological entities can be associated with a range of clinical
GBM glomerular basement membrane diagnoses, from MGRS to MM or symptomatic lymphoma, and
GN glomerulonephritis clinical management will be variable. In this regard, it is
HCDD heavy chain deposition disease important to note that currently, the only histopathological
IF immunofluorescence feature that is considered to be a defining event for a diagnosis of
IT immunotactoid glomerulonephritis MM is LCCN. Therefore, by definition, LCCN is excluded from
LCCN light chain cast nephropathy the MGRS spectrum.
LCDD light chain deposition disease This review will provide a description of the histological
LHCDD light and heavy chain deposition disease features of the lesions in Table 2. We have organized the lesions
MGRS monoclonal gammopathy of renal significance by main renal compartment affected (glomeruli, tubules, and
MGUS monoclonal gammopathy of unknown significance other) although several of the diseases can affect several com-
MIDD monoclonal immunoglobulin deposition disease partments. We have focussed on providing differential diagnostic
MIg monoclonal immunoglobulins features in tables and a succinct histopathological description of
MM multiple myeloma each entity. We refer the reader to several recent excellent re-
MGPN membranoproliferative glomerulonephritis views for more detailed clinicopathological considerations.17e19
NHL B cell non hodgkin lymphoma
PGNMID proliferative glomerulonephritis with
non-organised monoclonal immunoglobulin deposits List of paraprotein-related renal diseases
PPRD paraprotein-related renal disease
Predominantly glomerular pathology Compartments affected
SFLC serum free light chain
SIFE serum immunofixation electrophoresis Amyloidosis (AL, AH, AHL) G, T, I, V
SMM smouldering myeloma Monoclonal Ig Deposition G, T, V
SPEP serum protein electrophoresis Disease - MIDD (LCDD, HCDD, LHCDD)
TBM tubular basement membrane Immunotactoid GN G
TMA thrombotic microangiopathy Fibrillary GN G
UIFE urine immunofixation electrophoresis Type 1 and 2 cryoglobulinaemic GN G, V
WM Waldenstro €m macroglobulinemia Crystal(cryo)globulinaemic GN G, V
Intracapillary monoclonal IgM deposits G, V
Table 1
Proliferative glomerulonephritis G
with monoclonal Ig deposition (PGNMID)
Monoclonal gammopathy-associated G
Histology of renal involvement in paraprotein-related C3 GN and masked monoclonal GN
diseases TMA with monoclonal gammopathy G, V
Intraglomerular/intracapillary lymphoma G, V, PTC
The renal histopathology of PPRD is wide (Table 2), and all
Podocytopathy G
compartments of the kidney can be involved. Pathology can be
directly related to paraprotein deposition detectable in the kidney Predominantly tubular pathology
(direct mechanism), either in crystalline, fibrillary or non- Light chain cast nephropathy T
organized deposits. Pathology can also be related to the para- MIDD (LCDD, HCDD, LHCDD) G, T, V
protein but not involve deposition of the paraprotein in the Light chain proximal tubulopathy, T (plus podocytes,
kidney (indirect mechanism). For example, paraproteins are crystalline parietal epithelial
thought to cause C3 glomerulonephritis and thrombotic micro- cells, endothelial
angiopathy by activating the alternative pathway of complement cells, interstitial
activation. Haematological diseases can also present with pa- cells)
thologies unrelated to the paraprotein, but likely related to the Light chain proximal tubulopathy, T
treatments the patient is receiving (e.g. drug-related acute non-crystalline
tubular injury or active tubulointerstitial nephritis, diabetic glo- Others
merulopathy).15 Finally, the biopsy has an important role in Crystal-storing histiocytosis I
establishing negative findings e i.e. that the renal manifestations
The table indicates which kidney compartments are affected by each patholog-
are unrelated to the paraprotein. This is particularly important in ical entity. T: tubules; G: glomeruli; V: blood vessels; I: interstitium; PTC: peri-
view of the high frequency of monoclonal gammopathy of un- tubular capillaries.
known significance (MGUS) and chronic renal failure in the
general population, both of which increase with age. Three % of Table 2

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Please cite this article as: Kousios A, Roufosse C, An update on paraprotein-related renal pathology, Diagnostic Histopathology, https://doi.org/
10.1016/j.mpdhp.2019.07.004
 MINI-SYMPOSIUM: NEPHROUROLOGY

Glomerular lesions with multiple myeloma.22,23 AL amyloidosis patients have little

or no intact immunoglobulin and thus serum protein electro-
Glomerular lesions related to paraproteins present very diverse
phoresis (SPEP) will detect a paraprotein in less than 50% of
morphological appearances. Glomeruli can be normal on light
patients. However, monoclonal light chains are commonly
microscopy (e.g. podocytopathy), show non-cellular mesangial
detectable and combining serum (SIFE) and urine (UIFE)
and/or capillary wall expansion (e.g. amyloidosis), show varying
immunofixation techniques with serum free light chain (SFLC)
degrees of increased cellularity right through to diffuse prolifer-
ratio analysis detects the paraprotein in 100% of cases.24
ative glomerulonephritis (e.g. cryoglobulinaemic glomerulone-
phritis), or show features of thrombotic microangiopathy. Table Monoclonal immunoglobulin deposition disease
3 summarizes the main features of the different types of (MIDD)
glomerular involvement. This entity is characterized by deposition in the kidney of light
The most commonly encountered glomerular lesions are AL chain only (light chain deposition disease, LCDD), heavy chain
amyloidosis and monoclonal immunoglobulin deposition disease only (heavy chain deposition disease, HCDD) or both (light and
(MIDD). heavy chain deposition disease, LHCDD). In MIDD, the physi-
cochemical properties of the paraprotein promote interaction
Immunoglobulin light-chain (AL) amyloidosis
with matrix proteins without amyloid fibril formation. Glomer-
In AL amyloidosis, the abnormal light chains contain specific
ular involvement in MIDD has a variable appearance on light
amino acid sequences that predispose to amyloid fibril forma-
microscopy, from near normal glomeruli to nodular glomerulo-
tion. AL amyloidosis is noted in glomeruli on light microscopy by
sclerosis similar to changes seen in diabetic nephropathy,
mesangial and/or capillary wall amorphous, Congo red-positive
depending on the amount of MIg deposited. Glomeruli can also
(orangiophilic), silver stain-negative deposits, that stain pale
appear hypercellular usually with either a mesangial proliferative
pink on PAS stain. In some cases, long and wavy silver-positive
or a membranoproliferative GN (MPGN) pattern and may even
“spikes” of matrix are noted along capillary walls, forming
contain crescents. Mesangiolysis with microaneurysm formation
“cock’s combs”, or coronas in cross-section. In addition to
can be noted. The deposits are PAS-positive, Congo red-negative
glomerular involvement, amyloid can be noted in tubular base-
and stain variably on silver stain. Deposits can involve glomeruli
ment membranes, blood vessels and/or the interstitium. Under
(mesangium and/or capillary walls), Bowman’s capsule, tubular
polarized light, the Congo red stain shows anomalous colours
basement membranes (TBM), and/or vascular basement mem-
(green/orange mostly). On immunofluorescence (IF), staining for
branes. The TBM involvement can lead to a striking ribbon-like
Ig heavy chains and complement is negative and there is light
PAS-positive appearance of the TBM on light microscopy, that
chain restriction (more often lambda then kappa). Rare cases of
can be helpful in attracting attention to this diagnosis. Cases of
heavy chain (usually IgG, AH amyloid) and heavy and light chain
TBM-only involvement have been described. Immunofluores-
amyloidosis (AHL amyloid) have been described. False negative
cence findings depend on whether there is deposition of heavy
staining for light chains can occur with the commercially avail-
chain only, light chain only or both. LCDD is the most common
able antibodies, which may occasionally not be reactive to the
pattern, and kappa is more often seen than lambda. The heavy
abnormal light chain. Mass spectrometry may help to prove the
chain when present is most often IgG (and more rarely IgM or
presence of a light chain in these cases19; it may also be helpful to
IgA) and can be accompanied by complement fragments C3 and
establish a diagnosis of heavy chain amyloidosis. On electron
C1q. Positive staining with light and/or heavy chains manifests
microscopy (EM), randomly arrayed fibrils with a diameter of 7
as linear staining along the glomerular basement membrane
e13 nm are noted in the involved compartments. The differential
(GBM) and/or TBM, and positive staining in mesangial areas of
diagnosis includes other forms of amyloidosis, and fibrillary
the glomeruli. On EM, finely granular powdery electron dense
glomerulonephritis (GN). Other forms of amyloidosis can be
deposits are noted in the involved compartments. This manifests
distinguished through the use of immunohistochemistry and/or
as linear sub-endothelial deposits along the glomerular capillary
mass spectrometry. Fibrillary GN is usually Congo red-negative
walls, linear deposits in TBM, and ill-defined deposits in the
and shows positive staining with DNAJB9, although rare cases
mesangium. The EM features of MIDD are characteristic when
of congophilic fibrillary GN have been described.20 The features
observed, but can be subtle e.g. segmental minor involvement of
of AL amyloid are illustrated in Figure 1.
glomerular capillary walls or TBM. IF restricted light chain pos-
Renal involvement is common in patients with AL amyloid-
itivity (particularly in TBM) is the most sensitive feature, and can
osis (approximately 70%), followed by cardiac involvement,
raise awareness to search carefully on EM for the deposits. IF-
which confers poor prognosis. The typical renal manifestations
only cases of MIDD have been described, where there is clear
are nephrotic range proteinuria or full nephrotic syndrome.21
restriction of light chains on IF, but no deposits can be found on
Renal impairment is common (present in up to 50%) but is
EM. The features of MIDD are illustrated in Figure 1.
usually mild, at least in the initial stages of the disease. Hyper-
The clinical characteristics of MIDD are proteinuria or
tension is not a typical feature of AL amyloidosis, whilst postural
nephrotic syndrome with or without microscopic haematuria,
hypotension may occur when the autonomic nervous system is
renal impairment and hypertension.14,25e27 Nasr et al. described
affected. The underlying haematological disorder is a plasma cell
a cohort of 64 patients with pure MIDD (51 LCDD, 7 HCDD and 6
dyscrasia, although the tumour burden is typically low. Most of
LHCDD) in which 97% of patients had renal impairment at
the patients have less than 10% of plasma cells in BM biopsy,
diagnosis, 16% required dialysis, 39% had nephrotic range
approximately 20% of patients have >20% of plasma cells in BM
proteinuria, 23% had full nephrotic syndrome, 62% had
and only about 10% of cases of AL amyloidosis are associated

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Please cite this article as: Kousios A, Roufosse C, An update on paraprotein-related renal pathology, Diagnostic Histopathology, https://doi.org/
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Differential diagnosis for glomerular involvement in paraprotein-related diseases
Type of involvement
Amyloidosis (AL, AH, AHL)
MIDD (LCDD, HCDD, LHCDD)
Immunotactoid GN
Fibrillary GN
Type 1 and type 2 cryoglobulinaemic GN
4
Crystalglobulinaemic GN
Intracapillary monoclonal IgM deposits
PGNMID
Monoclonal gammopathy-associated C3 GN
Ó 2019 Published by Elsevier Ltd.
Masked monoclonal GN
LM
Amorphous, Congo red-positive, weakly
PAS-positive, silver negative, deposits in
mesangium and/or capillary walls.
Blood vessels and/or the interstitium can
also be involved.
Near normal glomeruli to nodular
glomerulosclerosis; often TBM
involvement with striking ribbon-like PAS-
positivity. Bowman’s capsule and vascular
BM can also be involved
Mesangial proliferative, endocapillary
proliferative or membranoproliferative,
with or without crescents
Mesangial proliferative, endocapillary
proliferative or membranoproliferative,
with or without crescents
Proliferative glomerulonephritis most
often with hyaline pseudo-thrombi;
arteriolar involvement can be seen
Proliferative glomerulonephritis with
crystals in the capillary lumen; arteriolar
involvement can be seen
Intraluminal hyaline pseudo-thrombi, with
little/no hypercellularity
Mesangial proliferative, endocapillary
proliferative or membranoproliferative,
with or without crescents
Mesangial proliferative, endocapillary
proliferative or membranoproliferative,
with or without crescents
Membranous or membranoproliferative
pattern
IF EM
Light chains (l>k), rarely heavy chains Randomly arrayed fibrils (7e13 nm)
(mostly IgG)
Light chains (k> l), heavy chains or both Finely granular (powdery) ill-defined
mesangial and basement membrane
deposits (the latter often linear)
Whole Ig, usually IgG Microtubules (10e60 nm) often in parallel
bundles; for some authors, diagnosis
MINI-SYMPOSIUM: NEPHROUROLOGY
requires exclusion of cryoglobulinaemia
Most often polyclonal and related to Randomly arrayed fibrils (12e24 nm)
DNAJB9; rarely whole monoclonal IgG
Whole Ig, IgG or IgM Electron dense deposits often with focal
microtubules; deposits often noted in
capillary and/or arteriolar lumen þ in
mesangium and in subendothelial space
Whole IgG Deposits with paracrystalline substructure
(e.g. needle-shaped, grids, zippers etc.) in
capillary and/or arteriolar lumen
Whole IgM Electron dense deposits without
substructure in capillary and/or arteriolar
lumen
Whole Ig, usually IgG Well-defined electron dense deposits
without substructure; diagnosis requires
exclusion of cryoglobulinaemia
C3 predominance Well-defined electron dense deposits
without substructure
C3 predominance on IF performed on Well-defined electron dense deposits
frozen sections; IF on paraffin sections without substructure; some cases with
after protease unmasks a MIg MPGN pattern can show substructure
 MINI-SYMPOSIUM: NEPHROUROLOGY

microscopic haematuria and 83% were hypertensive.25 The un-

derlying haematological disease was MM in 38 (59%) patients

podocytes; rarely light chain crystals in

effacement and microvillous change in
Lymphoma cells in glomeruli or blood
and one patient had lymphoplasmacytic lymphoma. In this
Flocculant sub-endothelial rarefaction

cohort, 73% of patients had a positive SPEP/SIFE but 100% of

the 51 patients tested had an abnormal SFLC ratio. Recently, a
large national French retrospective study of 255 patients included

Ultrastructural foot process

154 patients with pure LCDD, 58 with combined LCDD and light
chain cast nephropathy, 23 with HCDD and 20 patients with
LHCDD. The haematological diagnosis was MM in 34% and
MGRS in 64% of patients.14
podocytes
Proliferative glomerulonephritis with non-organized
vessels

monoclonal immunoglobulin deposits (PGNMID)

PGNMID is a GN-related to MIg deposition without formation of
amyloid fibrils, but with accumulation of well-defined granular
deposits, that activate complement and cause inflammation. This
leads to mesangial proliferative, endocapillary proliferative or
None or light chain crystals in podocytes

membranoproliferative GN, with or without crescents. Cases

with a purely membranous pattern have sometimes been
included in PGNMID,27 and at other times reported under the
designation of “membranous glomerulopathy with light chain
restricted deposits”.28 No other compartment in the kidney is
affected. On IF, there is positive staining for IgG (more rarely IgM
LM: light microscopy; IF: immunofluorescence; EM: electron microscopy; TBM: tubular basement membrane; BM: basement membrane.

or IgA) most often with complement component C3, and there is

kappa or lambda light chain restriction. IgG subtype restriction
can be documented by staining for IgG1-4 and is most often IgG3
for the MPGN pattern and IgG1 for the membranous pattern.27
None

None

On EM, there are ordinary electron dense deposits indistin-

guishable from those seen in non-monoclonal GNs. They can be
mesangial, sub-endothelial and less commonly, subepithelial. By
definition, these deposits do not have substructure. The differ-
arterioles; glomerular capillary wall double
Luminal fibrin thrombi in glomeruli and/or

Malignant lymphoid cells in blood vessels

thickening with mural oedema, red blood
Features of thrombotic microangiopathy:

ential diagnosis includes GN without monoclonal restriction like

contours; arterial and arteriolar intimal

lupus nephritis or idiopathic MPGN. Demonstration of the

Normal light microscopy (“minimal

monoclonality with IF for heavy chain subtypes and light chains

including glomerular capillaries

is key. Also, by definition, cryoglobulinaemic GN must be

excluded to reach a diagnosis of PGNMID. In addition to liaising
with the clinical team to thoroughly exclude a cryoglobulin based
change”); rarely FSGS

on clinical and serological features, it may be necessary to

cells and fibrin; etc.

examine several glomeruli on EM to hunt for deposits with a

substructure indicative of a diagnosis of cryoglobulinaemic GN,
where substructure may only focally affect the deposits.
Contrary to most other forms of PPRD, a paraprotein cannot
be identified using a combination of methods (SPEP, SIFP, UIFP
and SFLC ratio) in approximately 70% of cases. Similarly, a clone
is not detected in 70e90% of patients. If found, the clone is
usually small, in the context of MGRS. Remarkably, these find-
ings have been reported independently by several groups.13,29e31
Intraglomerular/intracapillary lymphoma

These findings have significant implications for the treatment of

TMA with monoclonal gammopathy

PGNMID reflected by heterogeneous therapeutic approaches.31

The common clinical features of PGNMID are significant pro-
teinuria with renal impairment. Complement levels may be low
in approximately 30% of patients (C3, C4 or both).
The features of PGNMID are illustrated in Figure 2.
Podocytopathy

Glomerulopathies with intracapillary deposits:

cryoglobulinaemic GN, crystal(cryo)globulinaemic GN
and intracapillary monoclonal IgM deposits
Table 3

Paraproteins can present with a predominant picture of pre-

cipitates within glomerular capillaries. Three main types of

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Please cite this article as: Kousios A, Roufosse C, An update on paraprotein-related renal pathology, Diagnostic Histopathology, https://doi.org/
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 MINI-SYMPOSIUM: NEPHROUROLOGY

Figure 1 AL amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). aee: AL amyloidosis shown on light microscopy (A,B,C),
immunofluorescence (D) and electron microscopy (E). A: Jones methenamine silver stain (200x) shows silver-negative amorphous pale pink
glomerular deposits in mesangial areas. The arteriole in the lower left-hand corner also contains this material in its wall. B. PAS stain (400x) shows
mesangial and capillary wall weak PAS-staining amorphous deposits. C. Congo red stain (200x) shows orangiophilic mesangial deposits. There is
also segmental involvement of capillary walls (black arrowhead) and involvement of the glomerular arteriole (black arrow). D. Immunofluorescence
for lambda light chain (200x) high-lights the mesangial amyloid deposits. E. Electron microscopy (40,000x) shows randomly arrayed fibrils of
appropriate size (7e13 nm) for amyloid. feh: MIDD shown on light microscopy (F and G) and electron microscopy (H). F: H&E stain (200x) shows
mesangial expansion, that is focally nodular. G: PAS stain (200x) shows positivity in the mesangium, Bowman’s capsule and tubular basement
membranes. H. Electron microscopy (10,000x) shows finely granular ill-defined electron dense deposits following the glomerular basement
membrane in a linear fashion (black arrows), and ill-defined powdery mesangial electron dense deposits (black arrowhead). For an illustration of
tubular involvement in MIDD see Figure 6, C and D.

capillary lumen involvement are described in case reports and
case series: hyaline pseudothrombi seen in association with a
cryoglobulin (Type 1 or 2 cryoglobulinaemic GN); crystals
(crystalglobulinaemic GN); and intracapillary IgM deposits
without a cryoglobulin and without substructure (intracapillary
monoclonal IgM deposition). The overlap in morphology and
clinical features means that not all publications have defined
these lesions in the same way, and this leads to a lack of clarity
in how individual cases should be classified. In any case, it is
important that the pathologist recognizes these various pat-
terns as likely related to a paraprotein, carries out appropriate
IF and EM studies, and prompts nephrologist and haematolo-
gists to investigate for an underlying haematological malig-
nancy, if not already known. For this review, we will use the
definitions from Higgins et al.,32 where cryoglobulinaemic GN
is defined as the presence of a proliferative GN (endocapillary
or membranoproliferative) with at least one of: 1) intraluminal
pseudothrombi; 2) focal deposits with substructure character-
istic of cryoglobulins; 3) positive cryoglobulin assay. This
definition is also helpful in distinguishing cases of PGNMID or
immunotactoid GN (see below) from cases likely to be cry-
oglobulinaemic GN.
Cryoglobulins are immunoglobulins which precipitate at
temperatures below 37  C and dissolve again after re-warming.
Cryoglobulinaemia may be asymptomatic or cause end-organ
damage by the precipitation of cryoglobulins in small-to me-
dium-size vessels.33 Cryoglobulins are classified in three sub-
groups according to Brouet’s classification. In Type I

Figure 2 Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGINMID). a: Light microscopy (H&E, 200x) image showing
a membranoproliferative pattern of glomerulonephritis. b. Immunofluorescence for IgG (200x) showing mesangial and capillary wall strong positive
staining. c. Electron microscopy (7,000x) showing usual type subendothelial (black arrow) and subepithelial (black arrowheads) electron dense
deposits.

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 MINI-SYMPOSIUM: NEPHROUROLOGY

cryoglobulinaemia, the cryoglobulins are MIg (most often IgM
or IgG); in type II, there is a mixture of monoclonal IgM which
has rheumatoid factor activity and a polyclonal IgG; in type III,
cryoglobulins consist of polyclonal IgM and IgG.34 In type I
cryoglobulinaemia, the underlying disease is, by definition, a
plasma cell dyscrasia or B cell lymphoproliferative disease and
in approximately 40% of cases the clonal process may not meet
the criteria of MM or overt lymphoma and thus falls in the
MGRS spectrum.35e38 Type II cryoglobulinaemia is most
frequently caused by chronic hepatitis C virus infection and less
frequently by autoimmune disorders or haematological diseases
(WM and B cell lymphomas). The pathogenetic process may
differ between monoclonal type I cryoglobulinaemic disease
and mixed cryoglobulinaemias (type II and III). Crystallization
and aggregation of monoclonal type I cryoglobulins are tem-
perature and concentration dependent, causing symptoms
frequently in distal extremities where temperature is lower, and
in kidneys where ultrafiltration increases their concentration.
Moreover, monoclonal type I cryoglobulins lack rheumatoid
factor activity and the associated cryocrit is much higher than
for mixed type II and III cryoglobulins, reaching up to 50%. As
a result, cutaneous manifestations are caused by hyperviscosity
and vascular occlusion by the cryoprecipitate rather than
immune-complex vasculitis, and inflammation is minimal.33,39
In type II cryoglobulinaemias, on the other hand, cry-
oprecipitation requires the interaction of IgM (as a rheumatoid
factor) and IgG to form immune-complexes which bind to
endothelial cells and promote an inflammatory vasculitic pro-
cess of tissue injury.
Clinically, skin manifestations are the most common feature
and include purpura, livedo reticularis, Raynaud phenomenon,
necrotic ulcers and digital gangrene. A skin biopsy can show
vascular involvement by cryoglobulins and may be helpful in
reaching the diagnosis. When type I or II cryoglobulin is detected
then a haematological underlying disease must be sought as it
will define the treatment approach. Differentiating between
haematological, infectious and autoimmune causes is pivotal for
the management of these patients. Renal involvement is common
in type I or II cryoglobulin associated with a haematological
disease.
In cryoglobulinaemic GN, Ig deposit in the glomerular capil-
lary lumen and elsewhere in the glomerulus as extracellular
electron dense deposits often with a microtubular substructure;
these activate complement and cause an MPGN with abundant
macrophages and/or neutrophils in glomeruli. Hyaline pseudo-
thrombi representing deposits of cryoglobulin in the lumen of
glomerular capillaries are commonly seen, but not always pre-
sent. On IF, cryoglobulins are positive for heavy chains (IgG and/
or IgM) often with complement fragments C3 and C1q, and there
can be light chain restriction, depending on the cryoglobulin
type. When hyaline pseudo-thrombi are present, they show
striking intraluminal positivity. On EM, electron dense deposits
are noted that can be mesangial, subendothelial, and/or intra-
luminal. Although not all deposits in an individual case have a
substructure, it is most often possible to find microtubules and
fibrils disposed in curvilinear fingerprint-like patterns, in at least
some areas.
In crystalglobulinaemia, the MIg forms extracellular crystals
within glomerular capillaries and arterioles, leading to
glomerular and arteriolar inflammation.40 Systemic features are
common (rash, arthralgia, neuropathy). The term crystalcryo-
globulinemia is used if it is possible to demonstrate a cry-
oglobulin. Not all cases have a cryoglobulin; this may be
because detecting the cryoglobulin is very difficult, or because
some MIg precipitate into crystals due to the local environment
in the glomerulus (flow) and their concentration, rather than to
low temperature. Whether related to a cryoglobulin or not, the
crystals are often visible on light microscopy and are brightly
eosinophilic and refractile. By IF, the crystals are usually IgG
and light chain restricted. On EM, the deposits can take on a
range of paracrystalline appearances, including needle-like,
grid-like and zipper-like structures. Any deposit with an orga-
nized substructure should alert the pathologist to the possibility
of an underlying paraprotein, and promote appropriate staining
for light chain restriction and clinicopathological correlation.
The features of crystalglobulinaemic GN are illustrated in
Figure 3.
In intracapillary monoclonal IgM deposits, there are
glomerular intracapillary monoclonal IgM deposits, often
without significant glomerular hypercellularity, but sometimes
accompanied by features of endothelial injury.41 On IF, the
intraluminal pseudo-thrombi are positive for IgM with com-
plement fragment C3 and there is light chain restriction. This
lesion is seen in association with WM. Deposits can also be
seen in arterioles, without vasculitis. This entity is distin-
guished from cryoglobulinaemic GN by the usual lack of

Figure 3 Crystalcryoglobulinaemic glomerulonephritis. a. Light microscopy (H&E) shows brightly eosinophilic intracapillary plugs (black arrows) in
a glomerulus also showing a membranoproliferative pattern of glomerulonephritis. b. Immunofluorescence for IgG shows staining in the mesan-
gium and along capillary walls as well as in the intracapillary plugs. c-d Electron microscopy showed several different appearances. In places
deposits had typical features of a cryoglobulin: short microtubules in curved arrays (C, 40,000x) whereas elsewhere crystals were noted (D, 5,000x)
which on high power showed a grid-like appearance (e, 60,000x).

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 MINI-SYMPOSIUM: NEPHROUROLOGY
glomerular hypercellularity, the lack of substructure to deposits
on EM, and absence of a cryoglobulin. Features are illustrated
in Figure 4.
In general, patients with IgM monoclonal gammopathy in the
context of WM and other IgM-producing B cell lymphoprolifer-
ative disorders may develop a diverse variety of kidney lesions,
as recently described by Higgins et al. in the largest cohort to date
of patients with these disorders who had undergone an indica-
tion renal biopsy.32 They grouped the 54 patients of the study in
four groups according to the type of renal lesion; amyloid glo-
merulopathy (n ¼ 19), non-amyloid glomerulopathy (n ¼ 20),
tubulointerstitial lesions (n ¼ 8) and non-paraprotein related
lesions (n ¼ 10). In the non-amyloid glomerulopathy the lesions
seen were: cryoglobulinaemic GN (n ¼ 12), immunotactoid GN
(n ¼ 2), intracapillary monoclonal deposits disease (n ¼ 2),
PGNMID (n ¼ 1) and other (n ¼ 3).
Immunotactoid glomerulonephritis (IT)
Immunotactoid glomerulonephritis (IT) is another form of pro-
liferative GN with Ig microtubules on EM, but in this case, the
other features of cryoglobulinaemic GN are not present. On light
microscopy there is most often MPGN, with or without crescents.
No other renal compartment than the glomeruli is affected,
although intracytoplasmic microtubules have been noted in
plasma cells and lymphocytes in the kidney and bone marrow.
Although initially described as part of a spectrum of disease with
fibrillary GN, it was rapidly recognized that IT was distinct partly
because of its strong association with lymphoproliferative dis-
orders.42,43 On IF, there is positive staining for mostly for IgG
(rare cases of IgA or IgM) with complement components C3 and
C1q, and there is light chain restriction in most cases. IgG heavy
chain subtype restriction can also be documented in most cases
(most often IgG1). On EM, there are hollow microtubules ranging
from 10 to 60 nm in diameter arranged in parallel arrays or in
stacks. The structures are not always easy to distinguish from
those seen in cryoglobulinaemia, and there is difficulty in teasing
these two entities apart. This is partly because some authors
have made a serum cryoglobulin and/or the presence of pseu-
dothrombi exclusion criteria for a diagnosis of IT GN, and others
have not. It is also partly because serological cryoglobulin tests
are notorious for false negatives, due to technical problems and/
or their cyclical nature.44 Some authors describe differences in
the appearance of fibrils on EM, with IT fibrils on average being
larger (25e60 nm versus 15e30 nm for cryoglobulins) and more
Figure 4 Intracapillary monoclonal IgM deposits. a. Light microscopy shows intracapillary plugs, with no glomerular hypercellularity (Jones
methenamine stain, 200x). bec. Immunofluorescence for IgM (B) and Kappa (C) (both 200x). d. Electron microscopy of the intracapillary deposits
show absence of substructure (4,000x).
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often arranged in parallel bundles intersecting with other bundles
at different angles.44 Ultimately, mass spectrometry may help in
distinguishing these entities.
Other glomerular lesions
Rare cases of fibrillary GN may display heavy and light chain
restriction of the IgG deposits, and present in association with a
paraprotein. These cases will have the classical features of
fibrillary GN, with a mesangial proliferative or MPGN pattern,
and Congo-red negative fibrils of 10e30 nm on EM. Most cases of
fibrillary GN have been found to be related to DNAJB9 protein,
which is present in both the glomerular deposits and in the
serum. Monoclonal fibrillary GN cases will need to be re-
evaluated, but are likely to be negative for DNAJB9 and due to
another mechanism.45,46 Certainly, when a case of fibrillary GN
is encountered, it is recommended to consider the possibility of a
paraprotein, and to carry out appropriate IF and haematological
testing.
As noted in Table 3 and in the introduction, paraproteins can
also induce glomerular pathology indirectly. Some paraproteins
are thought to be able to activate the alternative pathway of
complement. This can either occur in the plasma, inducing
deposition of fragments of complement in the glomerulus and a
C3 glomerulonephritis,47 or on the endothelial cell surface,
inducing a thrombotic microangiopathy (TMA).48 Some haema-
tological malignancies, most often Hodgkin’s lymphoma, can
induce a podocytopathy. The pathological features of C3 GN,
TMA and minimal change disease related to a paraprotein are
indistinguishable from cases not related to a paraprotein, and the
pathologist is advised to bear in mind this possible etiology when
discussing the case in the report and/or with the clinicians.
An important note for cases of C3 GN, is to consider the
possibility of a masked MIg deposition. In these cases, IF per-
formed on frozen tissue shows C3 predominance, but if per-
formed on paraffin sections after protease, a MIg is revealed,
with heavy and light chain restriction. In patients where the
glomerular pattern is MPGN, this is associated with a paraprotein
and an underlying clone in a majority of cases.49 This is in
contrast to cases where the pattern is that of a membranous GN,
where most patients are young females with features of
autoimmunity.50
Rarely podocyte injury can also be induced by intra-
cytoplasmic light chain crystals.51e54 Intracellular crystalline
light chains can be noted in the same patient in a single cell type,
8 Ó 2019 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: NEPHROUROLOGY

or several cell types and have been noted in almost any renal cell
type (podocytes, parietal epithelial cells, mesangial cells, endo-
thelial cells, tubular epithelial cells and histiocytes), sometimes
also in association with extracellular crystals in the form of casts
and/or intracapillary crystals. When they occur within several
cell types, some authors refer to them as “intracellular crystalline
light chain nephropathy”.54 Histological findings can be very
subtle. One of our patients presented with nephrotic syndrome
apparently due to focal and segmental glomerulosclerosis, not
otherwise specified. Only when full work up revealed a para-
protein did the crystalline podocytopathy causing the focal
segmental glomerulosclerosis (FSGS) become apparent. This
case is illustrated in Figure 5.
Tubular lesions
Table 4 summarises the main features of the different types of
tubular involvement
Light chain cast nephropathy (LCCN)
Light chain cast nephropathy is characterized by intraluminal
tubular casts containing monoclonal light chains. It is a defining
feature of multiple myeloma, and therefore is not part of the
spectrum of lesions associated with a diagnosis of MGRS. It is
characterized clinically most often by acute renal failure. Patients
have significant proteinuria which consists mainly of light chains
and hence it may be undetected by urinalysis with urine dipstick
which primarily detects albumin. On light microscopy, there are
intraluminal tubular casts that stain weakly with PAS, often with
angular shapes (including in some cases frank crystals) or
“cracks”, or with a beaded refractile appearance, and/or with a
cellular reaction around the edge of the cast. A useful feature to
suspect LCCN is the presence of an often prominent interstitial
reaction, with oedema and inflammation. Occasionally, the light
chains organize as amyloid fibrils within the lumen, and tubular
luminal Congo red positivity is seen. IF shows light chain re-
striction in the casts, more often kappa light chain. On EM, casts
have a homogeneous appearance and/or may be composed of
extracellular crystals or rarely fibrils. Cast nephropathy can be
associated with intracellular crystals (crystalline light chain
tubulopathy) or MIDD.
The features of cast nephropathy are illustrated in Figure 6.
Tubular involvement in MIDD
As noted in the section on glomerular lesions, MIDD can also
involve TBM, and TBM involvement is often a useful patholog-
ical feature either on light microscopy (ribbon-like PAS-positive
TBM thickening) or on IF (linear TBM positivity). Rarely TBM
may be the only renal compartment affected.
The features of tubular involvement in MIDD are illustrated in
Figure 6.
Light chain proximal tubulopathy, crystalline and non-
crystalline
Light chain proximal tubulopathy develops secondary to
increased filtration of pathogenic light chains, which are re-
absorbed and accumulate within the proximal tubular epithe-
lium.55,56 In the crystalline form, there are intraepithelial crys-
tals, whereas in the non-crystalline form, there is an
accumulation of abnormal lysosomes containing light chains,
without crystal formation. The clinical presentation can be iso-
lated proteinuria, progressive renal insufficiency with proteinuria
and/or Fanconi’s syndrome. The underlying haematological
disease is MM in 14e33% of cases, with the rest being MGRS,
SMM, WM, NHL and CLL.
On light microscopy there is acute tubular injury, with either
intraepithelial crystals or intraepithelial vacuoles. The crystals
can be brightly eosinophilic or optically clear. The vacuoles can
also be eosinophilic or clear. Occasionally, the light chains
organize as amyloid fibrils within the cytoplasm, and tubular
epithelial cytoplasmic granular Congo red positivity is seen.
These crystals and vacuoles can be subtle or striking on LM. In
some cases, there are no obvious changes on LM. On IF, there is
light chain restriction in rhomboid, rectilinear or needle-shaped
crystals in the crystalline variant (most often kappa light
chain), and in vacuoles in the non-crystalline form. The
demonstration of light chain restriction in crystalline tubulopathy
may require unmasking by protease digestion and can sometimes
only be demonstrated using IF on paraffin sections after protease
digestion.57
On electron microscopy, abnormalities within the proximal
tubular epithelial cells can take on a variety of appearances.
Crystals are electron dense and can be polygonal, rectilinear and/
or needle-shaped. When examined at high magnification, crystals
may show parallel lines, fibrils or a grid-like substructure.
Crystals and fibrils can lie freely in the cytoplasm and/or within
phagolysosomes. In non-crystalline tubulopathy, there is an in-
crease in cytoplasmic vacuoles, which can contain either finely
granular material, or have a mottled appearance with electron
densities within them. Intravacuolar fibrils of variable size can be
seen, which can be arranged in parallel bundles or randomly.58
Some of these fibrils, but not all, correspond to Congo red-
positive material (amyloid proximal tubulopathy).59 Whether

Figure 5 Crystalline podocytopathy. a. Light microscopy showing vacuolated podocytes and intracapillary foam cells in a segmental scar (H&E,
400x). b. Toluidine blue semi-thin section showing small needle-shaped crystals in a podocyte (600x). c. Immunofluorescence for kappa light chain
showing positive staining in needle-shaped crystals in podocytes (400x). d. Electron microscopy showing a needle-shaped crystal in a podocyte
(12,000x).

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 MINI-SYMPOSIUM: NEPHROUROLOGY

Differential diagnosis for tubular involvement in paraprotein-related diseases

Histopathology diagnostic LM IF EM
label

Light chain cast Intraluminal casts staining
nephropathy weakly with PAS, often with
a cracked or beaded
refractile appearance and/or
with a cellular reaction
around them; often
associated with an
interstitial reaction
(oedema/inflammation)
MIDD Ribbon-like PAS-positive
TBM thickening
Light chain proximal Intraepithelial crystals
tubulopathy, crystalline sometimes visible on LM
Light chain proximal Cytoplasmic vacuolation,
tubulopathy, non-crystalline sometimes striking
Light chain restriction in
intraluminal casts
Light chain restriction in a
linear pattern along TBM
Light chain restriction in
intraepithelial crystals;
almost exclusively kappa
Light chain restriction in
intraepithelial vacuoles;
kappa > lambda
Casts have homogeneous
appearance and/or may
contain crystals
Finely granular powdery
deposits in TBM
Intraepithelial crystals in
cytoplasm and/or lysosomes
Intraepithelial non-
crystalline inclusions in
lysosomes

LM: light microscopy; IF: immunofluorescence; EM: electron microscopy; TBM: tubular basement membrane; BM: basement membrane.

Table 4

Figure 6 Light chain cast nephropathy and tubular involvement in monoclonal immunoglobulin deposition disease (MIDD). a, b: Light chain cast
nephropathy; A. Light microscopy (H&E, 200x) showing angular intratubular casts with a cellular reaction around the edge (white arrows) and with
“cracks” (white arrowheads). B. Immunofluorescence for kappa light chain showing strong staining in the tubular casts; corresponding staining for
lambda was negative. c, d: tubular involvement in monoclonal immunoglobulin deposition disease (MIDD). C. Immunofluorescence staining (100x)
for kappa light chain high-lights strong linear staining in tubular basement membranes. D. Electron microscopy (7,000x) showing ill-defined
granular electron densities along the tubular basement membrane (white arrowheads).

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Figure 7 Light chain tubulopathy. aed: Non-crystalline tubulopathy. A: Light microscopy (H&E, 200x) showing marked fine vacuolation of tubular
epithelium. B. Toluidine blue stained semi-thin section (400x) showing vacuolation of tubular epithelium. ced: Electron microscopy. C. Large
cytoplasmic vacuoles in the tubular epithelium (8,000x). D. Some of the vacuoles contain fine parallel fibrils (50,000x). These were negative for
Congo red stain. eeh: Crystalline tubulopathy. E. Light microscopy (H&E, 400x) showing an irregular eosinophilic appearance of the tubular
epithelial cytoplasm. F. Toluidine blue stained semi-thin sections help to better appreciate some of the intracytoplasmic needle-shaped crystals in
the tubular epithelium. GeH: Electron microscopy. G. Rhomboid and needle-shaped crystals are noted in the tubular epithelium (5,000x). H. Some
of the rhomboid crystals show a grid-like appearance (200,000x).

these should be considered as crystalline, non-crystalline or a Any organized intraepithelial inclusions noted on EM should
third variant is not clear. prompt appropriate light chain testing on IF, including IF on
An important issue here is the distinction from the regular paraffin sections after protease digestion.55
physiological trafficking of light chains within proximal tubular The features of light chain tubulopathies are illustrated in
cells, which can be increased in patients with increased free light Figure 7.
chain excretion, and yet not cause injury. The presence of crys-
tals or fibrils is generally agreed to denote a pathological process. Interstitial and vascular lesions
For non-crystalline forms, the presence of excess free-light chains
The interstitium can be involved in AL amyloidosis. Lympho-
may be sufficient to cause injury to renal proximal tubular cells
matous involvement of the interstitium is not uncommon in low
even without crystals.55 Potential features to point towards
grade lymphomas. Figure 8 illustrates a case of renal involve-
pathogenicity are either the presence of a markedly increased
ment by follicular lymphoma.
number of lysosomes (“lysosomal constipation”),60 lysosomal
Interstitial histiocytes containing intracellular light chain
mottled inclusions, or features of epithelial injury such as
crystals can be seen in crystal-storing histiocytosis, which can
apoptosis, although this is disputed.61 This is an important
present as a localized or multisystem disorder. The multisystem
question to address as some cases of light chain tubulopathy do
disease can involve bone marrow, lungs, lymph nodes, liver,
well, even without treatment.62

Figure 8 Renal interstitial involvement by B cell follicular lymphoma. a. Light microscopy: H&E (200x) shows interstitial involvement by a uniform
population of small lymphoid cells. Lymphoid aggregates with germinal centre formation are noted (outlined by white arrows). b. Immunoperox-
idase for CD20 (400x) shows that the lymphoid cells are mostly B cells. c. Immunofluorescence for kappa light chain (400x) confirms monoclonality
of the lymphoid population.

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 MINI-SYMPOSIUM: NEPHROUROLOGY
Figure 9 PPRD can involve blood vessels. Light microscopy (PAS,
400x) image of an arteriole involved by intracapillary monoclonal IgM
deposits (same patient as Figure 4). This intraluminal material stained
positive with IgM and kappa.
spleen, gastrointestinal tract and kidney, and has a poor
prognosis.63
Arteries and arterioles can show deposits of AL amyloid,
powdery deposits in MIDD, intraluminal pseudo-thrombi in
(crystal)cryoglobulinaemia and intracapillary IgM deposits, and
fibrin thrombi in TMA. Intracapillary IgM is illustrated in
Figure 9.
Intravascular lymphoma can affect any vascular bed (arteries,
arterioles, venules and capillaries) and is most often large B cell
lymphoma.
Additional aspects
It is worth bearing in mind that a single biopsy can contain one
or more paraprotein-related pathologies. PPRD can also occur in
transplant biopsies, either as de novo disease, in a patient who
develops a paraprotein after transplantation, or as a recurrence.
PPRD in the transplant can be the first manifestation of a PPRD,
that upon investigation turns out to have been the unrecognized
cause of ESRD.
Most importantly, we advocate a multi-disciplinary review of
these cases by a team comprizing not only a renal pathologist
and renal physician, but also a haematologist. This will ensure
that the patient receives appropriate haematological work up
(including bone marrow biopsy, radiology with or without
lymph node biopsy, SPEP, SIFE/UIFE, serum FLC), a correct
classification of the haematological disease, a correct histo-
pathological label of the renal disease, and appropriate
management. A Jones proteins. N Engl J Med 1991; 324: 1845e51.
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Practice points
In summary, paraprotein involvement in the kidney can take on a
bewildering array of appearances. We supply here a list of recom-
mendations to assist in recognizing these lesions:
General
C Consider a renal biopsy in patients with “MGUS” and renal
dysfunction
C Have a low index of suspicion for PPRD in patients with renal
dysfunction of any presentation, especially beyond the age of 50
C This also applies in transplanted kidneys
C Be aware of the possibility of dual pathologies
C Final histological classification will depend on clinical picture and
serological findings (e.g. cryoglobulin or not)
Immunofluorescence
C Always do IF for light chains in native renal biopsies
C Have a low threshold for requesting IF on paraffin sections after
protease digestion
C Systematically examine tubules as well as glomeruli (casts,
epithelium and basement membranes)
C Commercially available antibodies to light chains may give false
negative results
C IgG subclasses may be useful to establish the monoclonal nature
of the IgG deposited and are essential in cases where only heavy
chain is deposited without light chain (HCDD, AH amyloidosis)
Electron microscopy
C Systematically examine tubules as well as glomeruli
C Examine more than one glomerulus to find deposits with sub-
structure e.g. cryoglobulin
REFERENCES
1 Cook L, Macdonald DHC. Management of paraproteinaemia.
Postgrad Med J 2007; 83: 217e23.
2 Batuman V, Verroust PJ, Navar GL, et al. Myeloma light chains are
ligands for cubilin (gp280). Am J Physiol 1998; 275: F246e54.
3 Klassen RB, Allen PL, Batuman V, Crenshaw K, Hammond TG.
Light chains are a ligand for megalin. J Appl Physiol (Bethesda,
Md : 1985) 2005; 98: 257e63.
4 Basnayake K, Stringer SJ, Hutchison CA, Cockwell P. The biology
of immunoglobulin free light chains and kidney injury. Kidney Int
2011; 79: 1289e301.
5 Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of bence
12 Ó 2019 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: NEPHROUROLOGY
6 Hutchison CA, Batuman V, Behrens J, et al. The pathogenesis and
diagnosis of acute kidney injury in multiple myeloma. Nat Rev
Nephrol 2011; 8: 43e51.
7 Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006;
108: 2520e30.
8 Leung N, Bridoux F, Hutchison CA, et al. Monoclonal gammop-
athy of renal significance: when MGUS is no longer undetermined
or insignificant. Blood 2012; 120: 4292e5.
9 Leung N, Bridoux F, Batuman V, et al. The evaluation of mono-
clonal gammopathy of renal significance: a consensus report of
the International Kidney and Monoclonal Gammopathy Research
Group. Nat Rev Nephrol 2019; 15: 45e59.
10 Kousios A, Duncan N, Charif R, Roufosse C. Smoldering myeloma
presenting with renal histopathology of monoclonal gammopathy
of renal significance: adding to the complexity. J Am Soc Nephrol
: JASN (J Am Soc Nephrol) 2018; 29: 2901.
11 Hogan JJ, Weiss BM. Bridging the divide: an onco-nephrologic
approach to the monoclonal gammopathies of renal significance.
Clin J Am Soc Nephrol : CJASN 2016; 11: 1681e91.
12 Fermand JP, Bridoux F, Kyle RA, et al. How I treat monoclonal
gammopathy of renal significance (MGRS). Blood 2013; 122:
3583e90.
13 Gumber R, Cohen JB, Palmer MB, et al. A clone-directed
approach may improve diagnosis and treatment of proliferative
glomerulonephritis with monoclonal immunoglobulin deposits.
Kidney Int 2018; 94: 199e205.
14 Joly F, Cohen C, Javaugue V, et al. Randall-type monoclonal
immunoglobulin deposition disease: novel insights from a
nationwide cohort study. Blood 2019; 133: 576e87.
15 Nasr SH, Valeri AM, Sethi S, et al. Clinicopathologic correlations in
multiple myeloma: a case series of 190 patients with kidney bi-
opsies. Am J Kidney Dis 2012; 59: 786e94.
16 Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of mono-
clonal gammopathy of undetermined significance. N Engl J Med
2006; 354: 1362e9.
17 Markowitz GS. Dysproteinemia and the kidney. Adv Anat Pathol
2004; 11: 49e63.
18 Motwani SS, Herlitz L, Monga D, Jhaveri KD, Lam AQ. Para-
protein-related kidney disease: glomerular diseases associated
with paraproteinemias. Clin J Am Soc Nephrol : CJASN 2016; 11:
2260e72.
19 Sethi S, Rajkumar SV, D’Agati VD. The complexity and hetero-
geneity of monoclonal immunoglobulin-associated renal dis-
eases. J Am Soc Nephrol : JASN (J Am Soc Nephrol) 2018; 29:
1810e23.
20 Alexander MP, Dasari S, Vrana JA, et al. Congophilic fibrillary
glomerulonephritis: a case series. Am J Kidney Dis 2018; 72:
325e36.
21 Said SM, Sethi S, Valeri AM, et al. Renal amyloidosis: origin and
clinicopathologic correlations of 474 recent cases. Clin J Am Soc
Nephrol : CJASN 2013; 8: 1515e23.
22 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and
laboratory features in 474 cases. Semin Hematol 1995; 32: 45e59.
23 Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis. Hematol Oncol
Clin N Am 1999; 13: 1211e33. ix.
24 Palladini G, Russo P, Bosoni T, et al. Identification of amyloido-
genic light chains requires the combination of serum-free light
chain assay with immunofixation of serum and urine. Clin Chem
2009; 55: 499e504.
DIAGNOSTIC HISTOPATHOLOGY xxx:xxx
Please cite this article as: Kousios A, Roufosse C, An update on paraprotein-related renal pathology, Diagnostic Histopathology, https://doi.org/
10.1016/j.mpdhp.2019.07.004
25 Nasr SH, Valeri AM, Cornell LD, et al. Renal monoclonal immu-
noglobulin deposition disease: a report of 64 patients from a
single institution. Clin J Am Soc Nephrol : CJASN 2012; 7: 231e9.
26 Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immu-
noglobulin deposition disease: the disease spectrum. J Am Soc
Nephrol : JASN (J Am Soc Nephrol) 2001; 12: 1482e92.
27 Pozzi C, D’Amico M, Fogazzi GB, et al. Light chain deposition
disease with renal involvement: clinical characteristics and prog-
nostic factors. Am J Kidney Dis 2003; 42: 1154e63.
28 Best Rocha A, Larsen CP. Membranous glomerulopathy with light
chain-restricted deposits: a clinicopathological analysis of 28
cases. Kidney Int Rep 2017; 2: 1141e8.
29 Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative glomeru-
lonephritis with monoclonal IgG deposits. J Am Soc Nephrol :
JASN (J Am Soc Nephrol) 2009; 20: 2055e64.
30 Bhutani G, Nasr SH, Said SM, et al. Hematologic characteristics
of proliferative glomerulonephritides with nonorganized mono-
clonal immunoglobulin deposits. Mayo Clin Proc 2015; 90:
587e96.
31 Kousios A, Duncan N, Tam FWK, et al. Proliferative glomerulo-
nephritis with monoclonal Ig deposits (PGNMID): diagnostic and
treatment challenges for the nephrologist!. Kidney Int 2019; 95:
467e8.
32 Higgins L, Nasr SH, Said SM, et al. Kidney involvement of patients
with waldenstrom macroglobulinemia and other IgM-producing B
cell lymphoproliferative disorders. Clin J Am Soc Nephrol :
CJASN. 2018; 13: 1037e46.
33 Muchtar E, Magen H, Gertz MA. How I treat cryoglobulinemia.
Blood 2017; 129: 289e98.
34 Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M. Biologic
and clinical significance of cryoglobulins. A report of 86 cases. Am
J Med 1974; 57: 775e88.
35 Terrier B, Karras A, Kahn JE, et al. The spectrum of type I cry-
oglobulinemia vasculitis: new insights based on 64 cases. Medi-
cine 2013; 92: 61e8.
36 Neel A, Perrin F, Decaux O, et al. Long-term outcome of
monoclonal (type 1) cryoglobulinemia. Am J Hematol 2014; 89:
156e61.
37 Harel S, Mohr M, Jahn I, et al. Clinico-biological characteristics
and treatment of type I monoclonal cryoglobulinaemia: a study of
64 cases. Br J Haematol 2015; 168: 671e8.
38 Sidana S, Rajkumar SV, Dispenzieri A, et al. Clinical presentation
and outcomes of patients with type 1 monoclonal cry-
oglobulinemia. Am J Hematol 2017; 92: 668e73.
39 Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cry-
oglobulinaemias. Lancet (London, England) 2012; 379: 348e60.
40 Gupta V, El Ters M, Kashani K, Leung N, Nasr SH. Crystalglo-
bulin-induced nephropathy. J Am Soc Nephrol : JASN (J Am Soc
Nephrol) 2015; 26: 525e9.
41 Tan SYS, Sibley RK, Belani S, et al. Thrombotic microangiopathy
with intraglomerular IgM pseudothrombi in Waldenstrom macro-
globulinemia and IgM monoclonal gammopathy. J Nephrol 2018;
31: 907e18.
42 Fogo A, Qureshi N, Horn RG. Morphologic and clinical features of
fibrillary glomerulonephritis versus immunotactoid glomerulop-
athy. Am J Kidney Dis 1993; 22: 367e77.
43 Alpers CE. Immunotactoid (microtubular) glomerulopathy: an en-
tity distinct from fibrillary glomerulonephritis? Am J Kidney Dis
1992; 19: 185e91.
13 Ó 2019 Published by Elsevier Ltd.
 MINI-SYMPOSIUM: NEPHROUROLOGY
44 Herrera GA, Ojemakinde KO, Turbat-Herrera EA, Gu X, Zeng X,
Iskandar SS. Immunotactoid glomerulopathy and cry-
oglobulinemic nephropathy: two entities with many similarities. A
unified conceptual approach. Ultrastruct Pathol 2015; 39: 270e80.
45 Nasr SH, Dasari S, Lieske JC, et al. Serum levels of DNAJB9 are
elevated in fibrillary glomerulonephritis patients. Kidney Int 2019;
95: 1269e72.
46 Dasari S, Alexander MP, Vrana JA, et al. DnaJ heat shock protein
family B member 9 is a novel biomarker for fibrillary GN. J Am Soc
Nephrol 2018; 29: 51e6.
47 Chauvet S, Roumenina LT, Aucouturier P, et al. Both monoclonal
and polyclonal immunoglobulin contingents mediate complement
activation in monoclonal gammopathy associated-C3 glomerul-
opathy. Front Immunol 2018; 9: 2260.
48 Ravindran A, Go RS, Fervenza FC, Sethi S. Thrombotic micro-
angiopathy associated with monoclonal gammopathy. Kidney Int
2017; 91: 691e8.
49 Larsen CP, Messias NC, Walker PD, et al. Membranoproliferative
glomerulonephritis with masked monotypic immunoglobulin de-
posits. Kidney Int 2015; 88: 867e73.
50 Larsen CP, Boils CL, Cossey LN, Sharma SG, Walker PD. Clini-
copathologic features of membranous-like glomerulopathy with
masked IgG kappa deposits. Kidney Int Rep 2016; 1: 299e305.
51 Akilesh S, Alem A, Nicosia RF. Combined crystalline podocytop-
athy and tubulopathy associated with multiple myeloma. Hum
Pathol 2014; 45: 875e9.
52 Lee EJ, Lee SY, Park SY, et al. Crystalline podocytopathy and
tubulopathy without overt glomerular proteinuria in a patient with
multiple myeloma. Kidney Res Clin Pract 2016; 35: 259e62.
53 Boudhabhay I, Titah C, Talbot A, et al. Multiple myeloma with
crystal-storing histiocytosis, crystalline podocytopathy, and light
chain proximal tubulopathy, revealed by retinal abnormalities: a
case report. Medicine 2018; 97: e13638.
54 Ito K, Hara S, Yamada K, et al. A case report of crystalline light
chain inclusion-associated kidney disease affecting podocytes
but without Fanconi syndrome: a clonal analysis of pathological
monoclonal light chain. Medicine 2019; 98: e13915.
55 Larsen CP, Bell JM, Harris AA, Messias NC, Wang YH, Walker PD.
The morphologic spectrum and clinical significance of light chain
proximal tubulopathy with and without crystal formation. Mod
Pathol 2011; 24: 1462e9.
56 Stokes MB, Valeri AM, Herlitz L, et al. Light chain proximal
tubulopathy: clinical and pathologic characteristics in the modern
treatment era. J Am Soc Nephrol 2016; 27: 1555e65.
DIAGNOSTIC HISTOPATHOLOGY xxx:xxx
Please cite this article as: Kousios A, Roufosse C, An update on paraprotein-related renal pathology, Diagnostic Histopathology, https://doi.org/
10.1016/j.mpdhp.2019.07.004
57 Nasr SH, Fidler ME, Said SM. Paraffin immunofluorescence: a
valuable ancillary technique in renal pathology. Kidney Int Rep
2018; 3: 1260e6.
58 Corbett RW, Cook HT, Duncan N, Moss J. Fibrillary inclusions in
light chain proximal tubulopathy associated with myeloma. Clin
Kidney J 2012; 5: 75e6.
59 Larsen CP, Borrelli GS, Walker PD. Amyloid proximal tubulopathy:
a novel form of light chain proximal tubulopathy. Clin Kidney J
2012; 5: 130e2.
60 Herrera GA. Proximal tubulopathies associated with monoclonal
light chains: the spectrum of clinicopathologic manifestations and
molecular pathogenesis. Arch Pathol Lab Med 2014; 138:
1365e80.
61 Brealey JK, Tran Y, Ninnes R, Abeyaratne A. Ultrastructural
identification of a proximal tubulopathy without crystals in a
relapsed multiple myeloma patient. Ultrastruct Pathol 2018; 42:
458e63.
62 Ryan M, Rovin B, Nadasdy T. Stable long-term renal function in a
patient with kappa-light chain renal tubular crystalline deposition.
Clin Nephrol 2015; 83: 189e95.
63 Galeano-Valle F, Diaz-Crespo FJ, Melero-Martin R, Apaza-
Chavez JE, Del-Toro-Cervera J, Demelo-Rodriguez P. Massive
generalized crystal-storing histiocytosis associated with extra-
cellular crystalline nephropathy: clinical, immunohistochemical,
and ultrastructural studies of a unique disorder and review of the
literature. CEN Case Rep 2019 Aug; 8(3): 166e72. https://doi.org/
10.1007/s13730-019-00385-5.
Acknowledgements
Dr Roufosse is supported by the NIHR Biomedical Research Centre
based at Imperial College Healthcare NHS Trust and Imperial College
London. The views expressed are those of the authors and not
necessarily those of the NHS, the NIHR or the Department of Health.
Dr Roufosse’s research activity is made possible with generous
support from Sidharth and Indira Burman. Infrastructure support for
this research was provided by the NIHR Imperial Biomedical Research
Centre. We acknowledge Dr Jill Moss and Dr Linda Moran from the
Electron Microscopy Unit at Charing Cross Hospital for technical and
diagnostic expertise.
14 Ó 2019 Published by Elsevier Ltd.