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Monoclonal gammopathy of renal significance (MGRS) Kidney disease is a frequent complication of monoclonal
regroups all renal disorders caused by a monoclonal gammopathies that manifests with a wide range of renal
immunoglobulin (MIg) secreted by a nonmalignant B-cell lesions. These patterns are mostly determined by the physico-
clone. By definition, patients with MGRS do not meet the chemical characteristics of the pathogenic monoclonal
criteria for overt multiple myeloma/B-cell proliferation, and immunoglobulin (MIg).1 The renal disease may complicate
the hematologic disorder is generally consistent with a previously diagnosed clonal B-cell disorder or be the initial
monoclonal gammopathy of undetermined significance manifestation of the hematological disease. Two main
(MGUS). However, MGRS is associated with high morbidity categories of renal disorders associated with monoclonal
due to the severity of renal and sometimes systemic lesions gammopathies should be distinguished, depending on the
induced by the MIg. Early recognition is crucial, as burden of the underlying plasma cell or B-cell clone. The first
suppression of MIg secretion by chemotherapy often group of renal disorders requires the secretion of large
improves outcomes. The spectrum of renal diseases in MGRS amounts of all or part of the MIg and is only observed in the
is wide, including old entities such as AL amyloidosis and setting of a high tumor mass B-cell proliferation. This is
newly described lesions, particularly proliferative typically illustrated by the massive precipitation of light chain
glomerulonephritis with monoclonal Ig deposits and C3 (LC) in the lumen of distal tubules, which characterizes light-
glomerulopathy with monoclonal gammopathy. Kidney chain cast nephropathy, the most common cause of acute
biopsy is indicated in most cases to determine the exact kidney injury in multiple myeloma (MM). Light-chain cast
lesion associated with MGRS and evaluate its severity. nephropathy is considered as a MM defining event because it
Diagnosis requires integration of morphologic alterations by always forms as the result of high monoclonal LC production,
light microscopy, immunofluorescence (IF), electron indicating a high tumor burden, a situation that requires
microscopy, and in some cases by IF staining for Ig isotypes, urgent introduction of chemotherapy.2,3 Although rare,
immunoelectron microscopy, and proteomic analysis. another example is glomerular intracapillary deposition of
Complete hematologic workup with serum and urine protein MIgM to form thrombi in high tumor mass Waldenstroms
electrophoresis, immunofixation, and serum-free light-chain macroglobulinemia.4
assay is required. This review addresses the pathologic and The other group is renal diseases associated with low-
clinical features of MGRS lesions, indications of renal biopsy, grade lymphoproliferative disorders. Although they may
and a proposed algorithm for the hematologic workup. occur during symptomatic B-cell proliferations, these other
Kidney International advance online publication, 21 January 2015; MIg-related renal lesions are mainly encountered in patients
doi:10.1038/ki.2014.408 with a small B-cell clone and low malignant potential.5 Only
8% of patients with immunoglobulin light-chain (AL)
Correspondence: Nelson Leung, Division of Nephrology and Hypertension, amyloidosis6 and 20% of patients with Randall-type
Mayo Clinic, 200 First Street, Rochester, Minnesota 55905, USA. monoclonal Ig deposition disease (MIDD)7 have evidence
E-mail: leung.nelson@mayo.edu of a symptomatic MM at diagnosis. This clone can be
Received 28 February 2014; revised 17 July 2014; accepted 24 July 2014 expressed as any indolent B-cell lymphoid disorder, including
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the so-called smoldering asymptomatic MM and low-grade therapy including stem cell transplantation has been used in
lymphoplasmacytic lymphoma with Waldenstroms macro- AL amyloidosis in which the majority of patients do not meet
globulinemia, or a monoclonal gammopathy of undeter- the criteria for symptomatic MM.11 Hence, this is one of the
mined significance (MGUS). In this setting, structural first examples of successful treatment of a MGRS-related
peculiarities of the MIg, particularly the variable domain, kidney disease. The treatment strategy of MGRS is based on
and not the rate of production, are the main determinants of chemotherapy that should be adapted to the nature of the
renal lesions. The nonmalignant nature of these clones has underlying clone, either lymphocytic or plasmacytic, to
been a source of confusion for clinicians when it comes to renal function and to the presence or not of extrarenal
treatment. Because many of these clones are best classified as involvement.12 Rapid suppression of the secretion of
MGUS, defined as a plasma cell proliferative disorder that nephrotoxic MIg has been shown to favorably impact renal
manifests o3 g/dl of monoclonal protein and o10% bone and patient survival in most diseases associated with
marrow plasma cells, or smoldering MM, defined by 43 g/dl MGRS, including AL amyloidosis, light-chain deposition
of monoclonal protein and/or 410% bone marrow plasma disease (LCDD), immunotactoid glomerulopathy, and proli-
cells but without any end organ damage, chemotherapy is ferative glomerulonephritis with monoclonal Ig deposits
not indicated in patients with MGUS, smoldering MM, or (PGNMID).1316 In AL amyloidosis, renal response is closely
low-grade lymphomas.8 According to the current treatment associated with the magnitude of hematological response, as
guidelines, these patients require only clinical and biological renal response rate is significantly higher in patients who
surveillance as they may remain asymptomatic over a have achieved a serum-free light-chain (FLC) response of
prolonged period of time, and early therapy has not been more than 90%.17 Finally, in the absence of an efficient
shown to be beneficial in the majority of patients. suppression of the nephrotoxic MIg, MGRS-related renal
Chemotherapy is only introduced when symptoms related lesions recur in the allograft in most patients, usually within
to the underlying lymphocytic or plasmacytic proliferative the first year after renal transplantation.1822
process develop or are impending. Symptomatic MM is In addition to AL amyloidosis, the spectrum of MGRS
defined by evidence of end organ damage, characterized by includes various other renal lesions. Most are due to
CRAB (hyperCalcemia, Renal impairment, Anemia, Bone deposition of a MIg fragment with distinct localization and
disease). pattern of ultrastructural organization, usually resulting in
On the basis of the current guidelines, cytotoxic therapy is glomerular disorders but more rarely in tubular disorders
often withheld in patients with renal diseases associated with such as the Fanconi syndrome (FS). Glomerulopathies are
MIg who do not meet the criteria for MM or symptomatic featured either by organized deposits, fibrillar (AL and Ig
lymphoma.9 Such an approach is not appropriate for these heavy chains (AH) amyloidosis) or microtubular (type I
patients, as despite the absence of high tumor burden, they cryoglobulinemic glomerulonephritis, immunotactoid glo-
display high morbidity and even increased mortality. In an merulopathy), or by non-organized deposits (MIDD and
effort to address this need, the International Kidney and PGNMID). Importantly, our understanding of the spectrum
Monoclonal Gammopathy Research Group (IKMG) had of MGRS is evolving, and, in addition to kidney deposition of
their inaugural meeting in Bath, UK, in 2009. Members of a MIg, other mechanisms may be implicated, involving the
the IKMG come from the disciplines of nephrology, secretion of various biological factors and/or autoantibody
hematology, and nephropathology and from countries activity of the MIg. Examples include secretion of vascular
around the globe including Austria, Australia, Canada, endothelial growth factor in the POEMS syndrome (poly-
France, Italy, New Zealand, Spain, United Kingdom, and neuropathy, organomegaly, endocrinopathy, monoclonal
United States. Through a series of subsequent meetings, the gammopathy, and skin changes) that may trigger develop-
term monoclonal gammopathy of renal significance (MGRS) ment of renal endothelial cell injury and thrombotic
was refined and introduced in 2012 to distinguish these microangiopathy-like lesions,23 membranoproliferative
monoclonal gammopathies from MGUS.10 The main goal glomerulonephritis induced by dimeric monoclonal lambda
was to clearly delineate the benign hematological disorder LC acting as a mini-autoantibody against complement
MGUS, which cannot be associated with any end organ factor H,24,25 or membranous nephropathy caused by a
damage, from MGRS that is associated with severe monoclonal IgG3 kappa targeting the phospholipase A2
consequences related to MIg deposition in the kidneys (and receptor.26 Early recognition and prompt characterization of
sometimes in other organs) that considerably increase the type of MGRS is crucial, as it determines the therapeutic
morbidity and may even impair patient survival. It is strategy and strongly impacts renal prognosis.12 The purpose
important to recognize that like MGUS, the diagnosis of of this article is to provide keys for the diagnostic approach
MGRS does not exclude the possibility of future hematologic to recognize MGRS.
disease progression.
With its clear distinction from the benign term of INDICATIONS AND TIMING OF KIDNEY BIOPSY
MGUS, treatment strategies for MGRS-related kidney con- In a patient in whom MGRS is suspected, usually based on
ditions can be formulated without conflict with the current the coexistence of monoclonal gammopathy and renal
MM treatment guidelines. It should be noted that cytotoxic symptoms, it is essential to quickly and accurately assess
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the characteristics of the monoclonal gammopathy, the patients with glomerular involvement who display predomi-
underlying B-cell clone, the type of nephropathy, and its nant albuminuria (usually accompanied with secretion of the
impact on renal function. Baseline glomerular filtration rate MIg or a fragment of it) from those with tubulointerstitial
is a major determinant of renal outcome in most types of lesions.37 For instance, in patients with FS, proteinuria typically
MGRS, as shown in AL amyloidosis,17 MIDD,7 and contains a small amount of albumin but predominantly mono-
PGNMID.27 In addition, it is mandatory to carefully search clonal LC and low-molecular weight proteins. These findings
for extrarenal manifestations, which may influence prognosis should prompt search for symptoms of proximal tubule
and influence therapeutic decisions. Rapid diagnostic dysfunction, including normoglycemic glycosuria, uricosuria,
assessment is particularly critical in patients with AL phosphaturia, and proximal renal tubular acidosis.38,39 In those
amyloidosis, in whom concomitant heart, liver, or patients without urine abnormalities but impaired glomerular
peripheral nerve involvement is frequent, results in filtration rate and evidence of monoclonal gammopathy, a
decreased survival, and affects therapeutic strategy. Median kidney biopsy should be performed in the absence of an
survival is approximately 6 months in AL patients with obvious cause of renal disease. Indeed, small cohorts of AL
significant heart involvement.28 Efficient chemotherapy amyloidosis and LCDD patients with predominant vascular/
based on novel agents such as the cyclophosphamide tubulointerstitial deposits and 24 h urine protein excretion of
bortezomibdexamethasone regimen is currently recom- less than 0.5 g/day have been reported.40,41
mended in the presence of amyloid cardiomyopathy to
achieve rapid and deep hematological response, a key factor HEMATOLOGIC EVALUATION
for patient survival.29,30 Severe extrarenal manifestations are The finding of monoclonal Ig deposits in the kidney indicates
also not uncommon in MIDD and type I cryoglobulinemia, the presence of an underlying B-cell clone. Efforts should
and osteomalacia frequently reveals FS. In patients with be made to characterize this clone, which is a key point for
symptoms suggestive of systemic AL amyloidosis, minimally guiding the therapeutic strategy.12 Accordingly, in all cases,
invasive biopsies of abdominal fat and minor salivary glands a detailed hematologic evaluation should be performed
may be performed initially.31,32 (Figure 1). In patients with IgG, IgA, or LC only MGRS,
However, in most situations, a kidney biopsy with detailed bone marrow aspirate, and biopsy are usually sufficient to
immunofluorescence (IF) and electron microscopic (EM) identify the clone. Flow cytometry and/or immunohistolo-
studies to identify deposit composition and pattern of gical studies of bone marrow cells are often useful to detect
organization is needed. Because of the frequency of this clone as it may present without any morphologic
monoclonal gammopathies in patients aged over 50 years, abnormalities. Skeletal radiographs are mandatory to detect
it is important that the correct correlation of the renal lesions bone lesions and can be supplemented by a vertebral (and
with monoclonal gammopathy is performed, as the presence pelvic) magnetic resonance imaging.
of a monoclonal protein by itself is not equal to the causative Particularly, in patients with IgM MGRS, additional
agent. This is illustrated by the fact that up to 10% of patients imaging studies may be required, as the possibility of a
with hereditary amyloidosis were initially misdiagnosed as non-plasmacytic B-cell clone increases. A computer tomo-
AL amyloidosis because of the presence of a serum MIg33 and graphy scan of the chest, abdomen, and pelvis may help
that 10% of patients with amyloidosis derived from leukocyte identify lymph nodes that should undergo a biopsy.
cell-derived chemotaxin 2, which mainly affects the kidneys, The utility of positron emission tomography scan combined
have a serum MIg.34 Moreover, misdiagnosis of the amyloid with a computer tomography scan remains to be assessed.
subtype may occur, because of nonspecific trapping of the Phenotypic characterization of peripheral blood lympho-
MIg in the amyloid deposits.35 In addition, renal biopsy is cytes, including rearrangement of Ig genes, may be indicated.
indicated to assess the MGRS type and evaluate severity of In patients with MGRS, the likelihood of identifying the
renal disease. This remains important even in patients with B-cell clone significantly increases when a serum and/or urine
advanced chronic kidney disease in whom kidney monoclonal protein can be detected.
transplantation is planned, as the disease generally recurs
rapidly in the allograft in the absence of control of the Screening for MIg
underlying clone.1822 Kidney biopsy is a safe procedure in MGRS can present across a number of clinical scenarios,
patients with MGRS, as shown in a recent study of 148 from isolated proteinuria to end-stage kidney disease. It is
patients with monoclonal gammopathies in whom the rate of therefore imperative that the clinician considers the possibil-
hemorrhagic complications was 4.1%, similar to the control ity of underlying monoclonal gammopathy in patients with
population.36 various renal manifestations and performs appropriate tests.
The spectrum of renal manifestations in MGRS is wide and In many cases, the MIg can be identified in the serum or
varies according to disease type and molecular characteristics of urine by a conventional EP. However, in some cases, the MIg
the pathogenic MIg (Tables 13). Renal failure and proteinuria, levels are very small and may not be detected by EP, likely
with or without hematuria, are the most common presenting reflecting the small size of the underlying B-cell clone and/or
symptoms. Electrophoresis (EP) and immunofixation of a 24-h the affinity of the MIg for tissues and organs. In fact, in
urine specimen should be performed in all cases to distinguish several MGRS renal lesions, the MIg may seemingly be
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Abbreviations: CKD, chronic kidney disease; IF, immunofluorescence; LC, immunoglobulin light chains; LN, lymph nodes; LPL, lymphoplasmacytic lymphoma; MGRS, monoclonal gammopathy of renal significance; MM, multiple
demonstrated only in a kidney biopsy by IF or immuno-
Hematological disease
Symptomatic MM and
histochemistry.
Serum and urine immunofixation should be performed in
WM uncommon
all cases to identify the MIg isotype, even if the serum protein
EP is not informative, because it is more sensitive for
MGRS
MGRS
MGRS
detecting MIg than serum protein EP. Furthermore, it is more
MM
MM
LPL
sensitive than the FLC assay among patients with small clones
that produce mostly intact immunoglobulins.42,43 Analysis of
Most common symptoms: hypouricemia, hypophosphatemia, normoglycemic glycosuria, generalized aminoaciduria, low-molecular weight proteinuria, and proximal (type 2) renal tubular acidosis.
the serum and urine by western blotting further increases the
Bone marrow,
involvement
Crystals (needle-shaped)
Ultrastructural findings
PTC LC inclusions
Vk3 (rare)
or Vk3
Proximal tubule
CKD
Crystal-storing histio-
are exposed when the LCs are free but hidden when the LCs
are bound (Freelite, Binding Site, Birmingham, UK).47 These
syndrome
cytosis
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Abbreviations: AH, immunoglobulin heavy chain; AHL, immunoglobulin heavy and light chain; AL, immunoglobulin light chain; AKI, acute kidney injury; CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; CW,
glomerular capillary walls; EP, electrophoresis; FLC, serum-free light chain assay; GN, glomerulonephritis; GOMMID, glomerulonephritis with organized microtubular immunoglobulin deposits; HC, immunoglobulin heavy chains;
Hypocomp., hypocomplementemia; IF, immunofluorescence; Ig, immunoglobulin; ITGN, immunotactoid glomerulonephritis; LC, immunoglobulin light chains; MM, multiple myeloma; MPGN, membranoproliferative
Symptomatic MM uncommon
Hematological and immuno-
the serum. In the last few years, new FLC assays based on
monoclonal antibodies have become commercially available.
logical characteristics
Hypocomp. common
one epitope on a FLC.4851 In an attempt to overcome this
B-cell lymphoma
B-cell lymphoma
MM uncommon
CLL (common)
limitation, manufacturers frequently use multiple mono-
Hypocomp.
clonal antibodies within one assay batch. Significant work
B30%
now needs to be undertaken to determine the comparability
MGRS
MGRS
MGRS
WMa
WMa
MM
of these monoclonal assays to the original polyclonal FLC
assays. Preliminary studies suggest that they may be
67% in AL, 80% in AH/
Serum EP/immunofixa-
Serum EP/immunofixa-
Serum EP/immunofixa-
tion: 3567% Urine EP/
88% in AH/AHL -Urine
Urine EP/immunofixa-
complementary, although all international guidelines are
AHL -FLC: 76-88% in
Identification of an
tion: 76%
Frequent:
intracellular crys-
tals (crystal-cryo-
branched fibrils
globulinemia)
Randomly ar-
microtubules
hollow core
714 nm in
diameter
findings
Extra
glomerulonephritis; NS, nephrotic syndrome; Pred., predominantly; UN, unknown; WM, Waldenstroms macroglobulinemia.
(IgG14IgG24IgG3) (k4l)
in mesangium and CW
domain (CH1) deletion
(pred. subepithelial)
Glomerular thrombi
RENAL PATHOLOGY
(k4l)
MPGN
light)
Possible nephritic
Microhematuria
Microhematuria
Proteinuria, NS
Proteinuria, NS
Proteinuria, NS
Hypertension
CKD
CKD
uria
localization.56,57
GN
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Table 3 | Main clinical, pathological, and immunological characteristics of glomerular disorders with non-organized Ig deposits in MGRS
Glomerular Light microscopic Ultrastructural Extrarenal Identification of Hematological and immuno-
disease Renal symptoms pattern IF findings (Ig type) findings involvement an M-protein logical characteristics
review
MIDD Proteinuria, NS Nodular glomerulosclero- Linear deposits along TBM, Amorphous deposits Common, often Serum EP/immuno- MGRS
CKD sis (constant in HCDD) GBM and around arteriolar/ in TBM, GBM, mesan- asymptomatic: fixation: 2576% in Symptomatic MM
Microhematuria Thickened TBM and arterial myocytes gium and arteriolar/ heart, liver, lung LCDD, 80100% in WMa
Hypertension vascular walls LCDD: mostly kappa (Vk4) arterial walls LHCDD, 67100% in Hypocomp. common in g1
HCDD: truncated HC (g1, or HCDD and g3 HCDD
g3, or g4, or a), with CH1 Urine EP/immuno-
deletion. fixation: 4290% in
C3 deposits in g1 and g3 LCDD, 80100% in
HCDD LHCDD, 50100% in
LHCDD: LC truncated HC HCDD
deposits FLC: 100% in LCDD,
LHCDD, HCDD
PGNMID Proteinuria, NS MPGN Granular deposits in mesan- Non-organized gran- None Serum EP/immuno- Usually none
CKD Endocapillary GN gium, CW ular deposits in me- fixation: 30% MGRS
Microhematuria Membranous GN Monotypic IgG deposits: sangium, suben- Urine EP/immuno- MM, B-cell lymphoma, WM:
Hypertension Mesangial GN IgG3 most common, or IgG1, dothelial and/or fixation: 11% rare
or IgG2 (k4l) subepithelial zone FLC: UN Hypocomp. B30%
Rarley, monotypic IgM, IgA,
or LC deposits
C3 C1q deposits
C3 glomerulopathy Proteinuria, NS MPGN Granular C3 deposits in Sausage shaped in- None Serum EP/immuno- MGRS
with monoclonal CKD Mesangial GN mesangium and CW tramembranous and fixation: 100% MM
gammopathy Microhematuria Endocapillary No or paucity of Ig deposits large rounded me- Urine EP: 100% Hypocomp. common, with
Hypertension proliferative GN sangial electron FLC: 75100% low C3 and occasionally anti-
dense deposits in complement factor H auto-
DDD antibody
Ill-defined mesangial,
intramembranous
and subendothelial
electron dense de-
posits in C3GN
Humps common in
DDD and C3GN
Abbreviations: CKD, chronic kidney disease; CW, glomerular capillary walls; DDD, dense deposit disease; EP, electrophoresis; FLC, serum-free light chain assay; GBM, glomerular basement membrane; GN, glomerulonephritis; C3GN,
C3 glomerulonephritis; HCDD, heavy chain deposition disease; Hypocomp., hypocomplementemia; IF, immunofluorescence; Ig, immunoglobulin; LC, immunoglobulin light chains; LCDD, light chain deposition disease; LHCDD,
light and heavy chain deposition disease; MGRS, monoclonal gammopathy of renal significance; MIDD, monoclonal immunoglobulin deposition disease (Randall-type); MM, multiple myeloma; MPGN, membranoproliferative
glomerulonephritis; NS, nephrotic syndrome; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin deposits; TBM, tubular basement membrane; UN, unknown; WM, Waldenstroms macroglobulinemia.
a
In patients with IgM monoclonal gammopathy.
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Kidney biopsy a c
+ C3 predominant
No further
deposits hematologic
workup
Serum and urine +
monoclonal studies (protein
electrophoresis and Monoclonal
immunofixation, FLC) gammopathy b d
+
Bone marrow C3nef
aspirate and biopsy and anti-H
autoantibodies
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a b a b
c d c d
200 nm
within vascular lumens that may display a typical grid-like eosin and electron dense with occasional mottled
appearance.55 appearance on EM.77 LC proximal tubulopathy without
crystals can be of kappa or lambda types and is not usually
MGRS lesions with deposition of crystals associated with FS.77 A not uncommon diagnostic dilemma is
Light-chain proximal tubulopathy. (Figure 6): LC proximal distinguishing LC proximal tubulopathy without crystals
tubulopathy, previously referred to as the LC Fanconi from the physiologic intracellular proximal tubular
syndrome is characterized by the presence of rod- or trafficking of LC (without pathologic significance). We
rhomboid-shaped hypereosinophilic and PAS-negative crys- recommend that a diagnosis of LC proximal tubulopathy
tals within proximal tubular cells. Ultrastructurally, the without crystals should be reserved to cases associated with
crystals may appear granular or show lattice-like substruc- very large dysmorphic lysosomes, histologic evidence of acute
ture.72 Because of their intracellular localization and and/or chronic proximal tubular injury, marked swelling of
extensive crystallization, standard IF on frozen tissue may proximal tubular cells due to lysosomal indigestion, renal
fail to confirm their LC composition. IF on pronase-digested, insufficiency (not explained by other pathology), tubular
paraffin-embedded tissue, which has an antigen retrieval step, proteinuria (as opposed to pure overflow proteinuria), and/
and immunoEM are much more sensitive techniques, but the or clinical features of partial or complete FS.
latter is not widely used in renal pathology practice.73,74 Crystal-storing histiocytosis. (Figure 7): This is a rare
Patients with LC proximal tubulopathy with crystals may or complication of MM or MGRS, which typically involves the
may not have a complete or partial FS.38,39,75,76 The bone marrow but can also affect several extramedullary sites,
pathologic LC in this lesion is almost always kappa and including the kidney, peri-renal fat, lungs, and cornea.
restricted to the Vk1 subgroup. A more recently described Kidney biopsy reveals intracytoplasmic eosinophilic LC
pathologic variant of light-chain proximal tubulopathy called crystalline inclusions within interstitial histiocytes and
LC proximal tubulopathy without crystals manifests LC- occasionally within proximal tubular cells and podocytes.79
containing phagolysosomes within proximal tubular cells As in LC proximal tubulopathy with crystals, standard IF on
without crystal formation.72,77,78 The non-crystalline frozen tissue sometimes fails to demonstrate their LC
inclusions appear hypereosinophilic on hematoxylin and composition, which requires IF on pronase-digested
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2 m
Figure 9 | Pathology of proliferative glomerulonephritis with monoclonal IgG deposits. (a) Glomeruli exhibit marked global mesangial and
segmental endocapillary hypercellularity (H&E, X200). (b) On electron microscopy, there are large mesangial, intramembranous, and
subepithelial deposits, together with segmental duplication of the glomerular basement membrane. The electron dense deposits appear
granular (without substructure; X6000). (ce) Glomeruli in this case of PGNMID show bright global mesangial and glomerular capillary wall
staining for IgG3 (c) and kappa (d). Glomeruli are negative for lambda (e), IgA, IgM, IgG1, IgG2, and IgG4 (not shown). Note the lack of tubular
basement membrane deposits, which is quite different from monoclonal immunoglobulin deposition disease of the Randall type (X100 for ce).
H&E, hematoxylin and eosin; Ig, immunoglobulin; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin G deposits.
Figure 10 | Pathology of C3 glomerulopathy. ac are from a 69-year-old patient with IgG lambda MGRS and C3 glomerulonephritis.
Complement pathway workup showed CFH risk polymorphism (Y402H). On light microscopy, the glomerulus shows marked global mesangial
and segmental endocapillary hypercellularity with intracapillary infiltrating lymphocytes, monocytes, and some neutrophils (a; PAS, X200). On
immunofluorescence, there is global granular mesangial and glomerular capillary loop staining for C3 (b, X200). Glomeruli were negative for
IgG, IgA, IgM, kappa, and lambda in this case (not shown). Ultrastructurally, there are large electron dense mesangial deposits and scattered
subepithelial deposits (arrows; c, X7830). df are from a 59-year-old male with IgG kappa MGRS and dense deposit disease. Complement
pathway workup was positive for FH autoantibody. The glomerulus depicted shows global mesangial hypercellularity and segmental occlusion
of peripheral capillaries by endocapillary hypercellularity and influx of inflammatory cells (arrows). The glomerular basement membranes
appear segmentally thickened (d; H&E, X200). Immunofluorescence highlights global granular to semilinear glomerular capillary wall and
mesangial C3 deposits, with linear staining of Bowmans capsule (e; X200). The defining feature of dense deposit disease is sausage-like
thickening of the glomerular basement membranes by highly electron dense intramembranous deposits. Large rounded mesangial electron
dense deposits are also seen (f; X6000). CFH, complement factor H; H&E, hematoxylin and eosin; MGRS, monoclonal gammopathy of renal
significance; PAS, periodic acidSchiff.
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