http://www.kidney-international.

org review
& 2015 International Society of Nephrology

Diagnosis of monoclonal gammopathy of renal

significance
Frank Bridoux1, Nelson Leung2,3, Colin A. Hutchison4, Guy Touchard1, Sanjeev Sethi5,
Jean-Paul Fermand6, Maria M. Picken7, Guillermo A. Herrera8, Efstathios Kastritis9, Giampaolo Merlini10,
Murielle Roussel11, Fernando C. Fervenza2, Angela Dispenzieri3, Robert A. Kyle3, Samih H. Nasr5
on behalf of the International Kidney and Monoclonal Gammopathy Research Group
1
Department of Nephrology and Transplantation, Centre Hospitalier Universitaire de Poitiers and Centre national de reference maladies
rares: amylose AL et autres maladies a depots dimmunoglobulines monoclonales; Universite de Poitiers, Poitiers, France; 2Division of
Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA; 3Division of Hematology, Department
of Medicine, Mayo Clinic, Rochester, Minnesota, USA; 4Department of Medicine, University of Otago, Wellington, New Zealand;
5
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA; 6Department of Hematology and
Immunology, Univerisity Hospital St Louis, Paris, France; 7Department of Pathology, Loyola University Medical Center, Maywood, Illinois,
USA; 8Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA; 9Department of Clinical
Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece; 10Department of Molecular Medicine,
University of Pavia, Pavia, Italy and 11Hematologie Clinique, Hopital Purpan, Toulouse, France

Monoclonal gammopathy of renal significance (MGRS)
regroups all renal disorders caused by a monoclonal
immunoglobulin (MIg) secreted by a nonmalignant B-cell
clone. By definition, patients with MGRS do not meet the
criteria for overt multiple myeloma/B-cell proliferation, and
the hematologic disorder is generally consistent with
monoclonal gammopathy of undetermined significance
(MGUS). However, MGRS is associated with high morbidity
due to the severity of renal and sometimes systemic lesions
induced by the MIg. Early recognition is crucial, as
suppression of MIg secretion by chemotherapy often
improves outcomes. The spectrum of renal diseases in MGRS
is wide, including old entities such as AL amyloidosis and
newly described lesions, particularly proliferative
glomerulonephritis with monoclonal Ig deposits and C3
glomerulopathy with monoclonal gammopathy. Kidney
biopsy is indicated in most cases to determine the exact
lesion associated with MGRS and evaluate its severity.
Diagnosis requires integration of morphologic alterations by
light microscopy, immunofluorescence (IF), electron
microscopy, and in some cases by IF staining for Ig isotypes,
immunoelectron microscopy, and proteomic analysis.
Complete hematologic workup with serum and urine protein
electrophoresis, immunofixation, and serum-free light-chain
assay is required. This review addresses the pathologic and
clinical features of MGRS lesions, indications of renal biopsy,
and a proposed algorithm for the hematologic workup.
Kidney International advance online publication, 21 January 2015;
doi:10.1038/ki.2014.408
Correspondence: Nelson Leung, Division of Nephrology and Hypertension,
Mayo Clinic, 200 First Street, Rochester, Minnesota 55905, USA.
E-mail: leung.nelson@mayo.edu
Received 28 February 2014; revised 17 July 2014; accepted 24 July 2014
Kidney disease is a frequent complication of monoclonal
gammopathies that manifests with a wide range of renal
lesions. These patterns are mostly determined by the physico-
chemical characteristics of the pathogenic monoclonal
immunoglobulin (MIg).1 The renal disease may complicate
a previously diagnosed clonal B-cell disorder or be the initial
manifestation of the hematological disease. Two main
categories of renal disorders associated with monoclonal
gammopathies should be distinguished, depending on the
burden of the underlying plasma cell or B-cell clone. The first
group of renal disorders requires the secretion of large
amounts of all or part of the MIg and is only observed in the
setting of a high tumor mass B-cell proliferation. This is
typically illustrated by the massive precipitation of light chain
(LC) in the lumen of distal tubules, which characterizes light-
chain cast nephropathy, the most common cause of acute
kidney injury in multiple myeloma (MM). Light-chain cast
nephropathy is considered as a MM defining event because it
always forms as the result of high monoclonal LC production,
indicating a high tumor burden, a situation that requires
urgent introduction of chemotherapy.2,3 Although rare,
another example is glomerular intracapillary deposition of
MIgM to form thrombi in high tumor mass Waldenstroms
macroglobulinemia.4
The other group is renal diseases associated with low-
grade lymphoproliferative disorders. Although they may
occur during symptomatic B-cell proliferations, these other
MIg-related renal lesions are mainly encountered in patients
with a small B-cell clone and low malignant potential.5 Only
8% of patients with immunoglobulin light-chain (AL)
amyloidosis6 and 20% of patients with Randall-type
monoclonal Ig deposition disease (MIDD)7 have evidence
of a symptomatic MM at diagnosis. This clone can be
expressed as any indolent B-cell lymphoid disorder, including

Kidney International 1
review
the so-called smoldering asymptomatic MM and low-grade
lymphoplasmacytic lymphoma with Waldenstroms macro-
globulinemia, or a monoclonal gammopathy of undeter-
mined significance (MGUS). In this setting, structural
peculiarities of the MIg, particularly the variable domain,
and not the rate of production, are the main determinants of
renal lesions. The nonmalignant nature of these clones has
been a source of confusion for clinicians when it comes to
treatment. Because many of these clones are best classified as
MGUS, defined as a plasma cell proliferative disorder that
manifests o3 g/dl of monoclonal protein and o10% bone
marrow plasma cells, or smoldering MM, defined by 43 g/dl
of monoclonal protein and/or 410% bone marrow plasma
cells but without any end organ damage, chemotherapy is
not indicated in patients with MGUS, smoldering MM, or
low-grade lymphomas.8 According to the current treatment
guidelines, these patients require only clinical and biological
surveillance as they may remain asymptomatic over a
prolonged period of time, and early therapy has not been
shown to be beneficial in the majority of patients.
Chemotherapy is only introduced when symptoms related
to the underlying lymphocytic or plasmacytic proliferative
process develop or are impending. Symptomatic MM is
defined by evidence of end organ damage, characterized by
CRAB (hyperCalcemia, Renal impairment, Anemia, Bone
disease).
On the basis of the current guidelines, cytotoxic therapy is
often withheld in patients with renal diseases associated with
MIg who do not meet the criteria for MM or symptomatic
lymphoma.9 Such an approach is not appropriate for these
patients, as despite the absence of high tumor burden, they
display high morbidity and even increased mortality. In an
effort to address this need, the International Kidney and
Monoclonal Gammopathy Research Group (IKMG) had
their inaugural meeting in Bath, UK, in 2009. Members of
the IKMG come from the disciplines of nephrology,
hematology, and nephropathology and from countries
around the globe including Austria, Australia, Canada,
France, Italy, New Zealand, Spain, United Kingdom, and
United States. Through a series of subsequent meetings, the
term monoclonal gammopathy of renal significance (MGRS)
was refined and introduced in 2012 to distinguish these
monoclonal gammopathies from MGUS.10 The main goal
was to clearly delineate the benign hematological disorder
MGUS, which cannot be associated with any end organ
damage, from MGRS that is associated with severe
consequences related to MIg deposition in the kidneys (and
sometimes in other organs) that considerably increase
morbidity and may even impair patient survival. It is
important to recognize that like MGUS, the diagnosis of
MGRS does not exclude the possibility of future hematologic
disease progression.
With its clear distinction from the benign term of
MGUS, treatment strategies for MGRS-related kidney con-
ditions can be formulated without conflict with the current
MM treatment guidelines. It should be noted that cytotoxic
2 Kidney International
F Bridoux et al.: MGRS
therapy including stem cell transplantation has been used in
AL amyloidosis in which the majority of patients do not meet
the criteria for symptomatic MM.11 Hence, this is one of the
first examples of successful treatment of a MGRS-related
kidney disease. The treatment strategy of MGRS is based on
chemotherapy that should be adapted to the nature of the
underlying clone, either lymphocytic or plasmacytic, to
renal function and to the presence or not of extrarenal
involvement.12 Rapid suppression of the secretion of
nephrotoxic MIg has been shown to favorably impact renal
and patient survival in most diseases associated with
MGRS, including AL amyloidosis, light-chain deposition
disease (LCDD), immunotactoid glomerulopathy, and proli-
ferative glomerulonephritis with monoclonal Ig deposits
(PGNMID).1316 In AL amyloidosis, renal response is closely
associated with the magnitude of hematological response, as
renal response rate is significantly higher in patients who
have achieved a serum-free light-chain (FLC) response of
more than 90%.17 Finally, in the absence of an efficient
suppression of the nephrotoxic MIg, MGRS-related renal
lesions recur in the allograft in most patients, usually within
the first year after renal transplantation.1822
In addition to AL amyloidosis, the spectrum of MGRS
includes various other renal lesions. Most are due to
deposition of a MIg fragment with distinct localization and
pattern of ultrastructural organization, usually resulting in
glomerular disorders but more rarely in tubular disorders
such as the Fanconi syndrome (FS). Glomerulopathies are
featured either by organized deposits, fibrillar (AL and Ig
heavy chains (AH) amyloidosis) or microtubular (type I
cryoglobulinemic glomerulonephritis, immunotactoid glo-
merulopathy), or by non-organized deposits (MIDD and
PGNMID). Importantly, our understanding of the spectrum
of MGRS is evolving, and, in addition to kidney deposition of
a MIg, other mechanisms may be implicated, involving the
secretion of various biological factors and/or autoantibody
activity of the MIg. Examples include secretion of vascular
endothelial growth factor in the POEMS syndrome (poly-
neuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy, and skin changes) that may trigger develop-
ment of renal endothelial cell injury and thrombotic
microangiopathy-like lesions,23 membranoproliferative
glomerulonephritis induced by dimeric monoclonal lambda
LC acting as a mini-autoantibody against complement
factor H,24,25 or membranous nephropathy caused by a
monoclonal IgG3 kappa targeting the phospholipase A2
receptor.26 Early recognition and prompt characterization of
the type of MGRS is crucial, as it determines the therapeutic
strategy and strongly impacts renal prognosis.12 The purpose
of this article is to provide keys for the diagnostic approach
to recognize MGRS.
INDICATIONS AND TIMING OF KIDNEY BIOPSY
In a patient in whom MGRS is suspected, usually based on
the coexistence of monoclonal gammopathy and renal
symptoms, it is essential to quickly and accurately assess
F Bridoux et al.: MGRS
the characteristics of the monoclonal gammopathy, the
underlying B-cell clone, the type of nephropathy, and its
impact on renal function. Baseline glomerular filtration rate
is a major determinant of renal outcome in most types of
MGRS, as shown in AL amyloidosis,17 MIDD,7 and
PGNMID.27 In addition, it is mandatory to carefully search
for extrarenal manifestations, which may influence prognosis
and influence therapeutic decisions. Rapid diagnostic
assessment is particularly critical in patients with AL
amyloidosis, in whom concomitant heart, liver, or
peripheral nerve involvement is frequent, results in
decreased survival, and affects therapeutic strategy. Median
survival is approximately 6 months in AL patients with
significant heart involvement.28 Efficient chemotherapy
based on novel agents such as the cyclophosphamide
bortezomibdexamethasone regimen is currently recom-
mended in the presence of amyloid cardiomyopathy to
achieve rapid and deep hematological response, a key factor
for patient survival.29,30 Severe extrarenal manifestations are
also not uncommon in MIDD and type I cryoglobulinemia,
and osteomalacia frequently reveals FS. In patients with
symptoms suggestive of systemic AL amyloidosis, minimally
invasive biopsies of abdominal fat and minor salivary glands
may be performed initially.31,32
However, in most situations, a kidney biopsy with detailed
immunofluorescence (IF) and electron microscopic (EM)
studies to identify deposit composition and pattern of
organization is needed. Because of the frequency of
monoclonal gammopathies in patients aged over 50 years,
it is important that the correct correlation of the renal lesions
with monoclonal gammopathy is performed, as the presence
of a monoclonal protein by itself is not equal to the causative
agent. This is illustrated by the fact that up to 10% of patients
with hereditary amyloidosis were initially misdiagnosed as
AL amyloidosis because of the presence of a serum MIg33 and
that 10% of patients with amyloidosis derived from leukocyte
cell-derived chemotaxin 2, which mainly affects the kidneys,
have a serum MIg.34 Moreover, misdiagnosis of the amyloid
subtype may occur, because of nonspecific trapping of the
MIg in the amyloid deposits.35 In addition, renal biopsy is
indicated to assess the MGRS type and evaluate severity of
renal disease. This remains important even in patients with
advanced chronic kidney disease in whom kidney
transplantation is planned, as the disease generally recurs
rapidly in the allograft in the absence of control of the
underlying clone.1822 Kidney biopsy is a safe procedure in
patients with MGRS, as shown in a recent study of 148
patients with monoclonal gammopathies in whom the rate of
hemorrhagic complications was 4.1%, similar to the control
population.36
The spectrum of renal manifestations in MGRS is wide and
varies according to disease type and molecular characteristics of
the pathogenic MIg (Tables 13). Renal failure and proteinuria,
with or without hematuria, are the most common presenting
symptoms. Electrophoresis (EP) and immunofixation of a 24-h
urine specimen should be performed in all cases to distinguish
Kidney International
review
patients with glomerular involvement who display predomi-
nant albuminuria (usually accompanied with secretion of the
MIg or a fragment of it) from those with tubulointerstitial
lesions.37 For instance, in patients with FS, proteinuria typically
contains a small amount of albumin but predominantly mono-
clonal LC and low-molecular weight proteins. These findings
should prompt search for symptoms of proximal tubule
dysfunction, including normoglycemic glycosuria, uricosuria,
phosphaturia, and proximal renal tubular acidosis.38,39 In those
patients without urine abnormalities but impaired glomerular
filtration rate and evidence of monoclonal gammopathy, a
kidney biopsy should be performed in the absence of an
obvious cause of renal disease. Indeed, small cohorts of AL
amyloidosis and LCDD patients with predominant vascular/
tubulointerstitial deposits and 24 h urine protein excretion of
less than 0.5 g/day have been reported.40,41
HEMATOLOGIC EVALUATION
The finding of monoclonal Ig deposits in the kidney indicates
the presence of an underlying B-cell clone. Efforts should
be made to characterize this clone, which is a key point for
guiding the therapeutic strategy.12 Accordingly, in all cases,
a detailed hematologic evaluation should be performed
(Figure 1). In patients with IgG, IgA, or LC only MGRS,
bone marrow aspirate, and biopsy are usually sufficient to
identify the clone. Flow cytometry and/or immunohistolo-
gical studies of bone marrow cells are often useful to detect
this clone as it may present without any morphologic
abnormalities. Skeletal radiographs are mandatory to detect
bone lesions and can be supplemented by a vertebral (and
pelvic) magnetic resonance imaging.
Particularly, in patients with IgM MGRS, additional
imaging studies may be required, as the possibility of a
non-plasmacytic B-cell clone increases. A computer tomo-
graphy scan of the chest, abdomen, and pelvis may help
identify lymph nodes that should undergo a biopsy.
The utility of positron emission tomography scan combined
with a computer tomography scan remains to be assessed.
Phenotypic characterization of peripheral blood lympho-
cytes, including rearrangement of Ig genes, may be indicated.
In patients with MGRS, the likelihood of identifying the
B-cell clone significantly increases when a serum and/or urine
monoclonal protein can be detected.
Screening for MIg
MGRS can present across a number of clinical scenarios,
from isolated proteinuria to end-stage kidney disease. It is
therefore imperative that the clinician considers the possibil-
ity of underlying monoclonal gammopathy in patients with
various renal manifestations and performs appropriate tests.
In many cases, the MIg can be identified in the serum or
urine by a conventional EP. However, in some cases, the MIg
levels are very small and may not be detected by EP, likely
reflecting the small size of the underlying B-cell clone and/or
the affinity of the MIg for tissues and organs. In fact, in
several MGRS renal lesions, the MIg may seemingly be
3
review F Bridoux et al.: MGRS

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

lung, skin, cornea

liver, spleen, LN, sensitivity for detecting very low amounts of MIg15 but is not
(osteomalacia)

Bone marrow,
involvement

routinely available. The latter technique allows identification

Extrarenal

of IgG subclass and may detect circulating truncated

None
Bone

monoclonal heavy chain.15

The issue whether serum only screening is a valuable
alternative to assessing both serum and urine was recently
PTC lysosomes or free in the

occasionally in PTC and glo-

Crystals (rhomboid) within

challenged again through the routine use of the FLC assay. In

Increased lysosomes with

Crystals (needle-shaped)
Ultrastructural findings

an assessment of 1877 patients with monoclonal gammopa-

a mottled appearance

within histiocytes and

accumulations of LCs
Amorphous granular

thies, Katzmann et al. found that serum protein EP and a

quantitative serum FLC assay identified 100% of patients with
merular cells

symptomatic MM and Waldenstroms macroglobulinemia,

cytoplasm

99.5% of patients with smoldering MM, 96.5% of patients

with AL amyloidosis, 79% of patients with LCDD, and 89% of
Table 1 | Main clinical, pathological, and immunological characteristics of tubular disorders in MGRS

patients with MGUS.42 The authors concluded that for

optimal sensitivity in AL amyloidosis and LCDD serum and
Mostly kappa :Vk1
Lambda or kappa
PTC LC inclusions

PTC LC inclusions

urine immunofixation was recommended. Similar

PTC LC staining
kappa: Vk1, or
Almost always

conclusions were reached in a study dedicated to the

IF findings

Vk3 (rare)

detection of the monoclonal protein in patients with

(Ig type)

or Vk3

AL amyloidosis, confirming the necessity to perform both

serum and urine immunofixation.43 Although some
international guidelines recommend the combination of
sions (pseudo-pseudo Gaucher cells)

serum EP and FLC measurement alone for the screening of

in the interstitium and perirenal fat
PTC atrophy and dedifferentiation

PTC atrophy and dedifferentiation

PTC atrophy and dedifferentiation

monoclonal gammopathies,44,45 the applicability of this

Histiocytes with crystalline inclu-

strategy must be weighed with considerable caution. As

Intra-cytoplasmic inclusions
Light microscopic findings

PTC cytoplasmic swelling

already discussed, MGRS is frequently associated with a small

clone, which may be difficult to identify, and it may not be
driven by free LC. In addition, the value of urine protein study
varies with the specific MGRS pathology under consideration.
myeloma; PTC, proximal tubular cells; WM, Waldenstroms macroglobulinemia.

Thus, in a case series of 51 individuals with MIDD, Nasr et al.

demonstrated that all had an abnormal serum FLC ratio;
however, only 81% of these had abnormal urinary assessment
using EP and immunofixation.7 In contrast, only 50% of
patients with MPGN secondary to a monoclonal protein had
Proximal tubule dysfunc-

Slowly progressive CKD

an abnormal FLC, whereas 78% and 96% had an abnormal

Tubular proteinuria
Renal symptoms

urine or serum immunofixation, respectively.46 Until robust

progressive CKD

Proximal tubule

data based on large repositories including all types of MGRS

suggest otherwise, we recommend assessment of both serum
dysfunction

and urine in patients suspected to have MGRS.

tiona

CKD

Interpretation of serum FLC assay

To date, the clinical evaluation of FLC assays has been almost
Proximal tubulopathy

Crystal-storing histio-

entirely based on nephelometric immunoassays using poly-

Tubular disorder
Light chain Fanconi

clonal antibodies raised in sheep against LC epitopes, which

without crystals

are exposed when the LCs are free but hidden when the LCs
are bound (Freelite, Binding Site, Birmingham, UK).47 These
syndrome

cytosis

assays, which have high sensitivity, suggest clonality by

comparing the concentration and ratio of kappa to lambda in
a

4 Kidney International
F Bridoux et al.: MGRS review

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

They are by definition limited because of the identification of

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

AL, 82% in AH/AHL

EP/immunofixation:
tion: 66-80% in AL,

2153% -FLC: 20%

still based on the original FLC assays.

immunofixation:
Table 2 | Main clinical, pathological, and immunological characteristics of glomerular disorders with organized Ig deposits in MGRS

Use of FLC assays in patients with renal impairment

M-protein

tion: 76%

tion: UN requires a degree of diagnostic sensitivity in their interpreta-

FLC: UN tion by either the reporting laboratory or the clinician. This is
a consequence of the close relationship of serum concentra-
tions of FLCs to underlying renal function.52 As renal
Uncommon (peripheral

skin, peripheral nerve,

Extra-renal involve-

impairment progresses, there is a polyclonal elevation in both

peripheral nerve

kappa and lambda FLCs. In addition, in patients with normal

renal function, the physiologically greater production of
nerve, skin)
heart, liver,
Frequent:

Frequent:

polyclonal kappa LC is masked by the more rapid clearance

joints
ment

of monomeric (kappa) LC as compared with larger dimeric

(lambda) LC. In case of renal impairment, there is a subtle
Microtubules 10 to

shift in the FLC ratio. Adoption of the renal-range for the

Parallely arranged

intracellular crys-
tals (crystal-cryo-
branched fibrils

FLC ratio of 0.373.17 (normal range in patients with

1060 nm, with
Ultrastructural

globulinemia)
Randomly ar-

microtubules

hollow core

preserved renal function: 0.261.65) has been shown to

ranged un-

714 nm in
diameter
findings

Extra

increase the reliability of the assays in patients with kidney

90 nm

glomerulonephritis; NS, nephrotic syndrome; Pred., predominantly; UN, unknown; WM, Waldenstroms macroglobulinemia.

impairment.53 Importantly, the delta between the involved

and uninvolved LC is often useful at diagnosis and should be
AH: HC deposits (g1, or g4,

(IgG14IgG24IgG3) (k4l)

Monotypic IgG, IgM, or IgA

endothelial), vascular walls
Granular/smudgy deposits

monitored regularly as it is likely to be the best indicator of

AHL: LC and HC deposits,

Granular deposits in me-

sangium, CW (pred. sub-
or a), with first constant

Monotypic IgG deposits

AL: LC deposits, mostly

in mesangium and CW
domain (CH1) deletion

response to treatment, as validated in AL amyloidosis54 and

- C3, C4, C1q deposits
mostly g l or a k

C3, C4, C1q deposits

IF findings (Ig type)

(pred. subepithelial)

Glomerular thrombi

suggested in most MGRS.12

lambda

RENAL PATHOLOGY
(k4l)

The pathologic diagnosis of renal lesions in MGRS requires

integration of morphologic alterations seen on light micro-
Vascular and tubulo interstitial
and CW deposits (dichroism

Intrarenal vasculitis occasional

Congo-red-positive mesangial

birefringence under polarized

Glomerular thrombi common

scopy (LM), IF, and EM, as well as correlation with the

Mesangial GN with membra-

Interstitial tumoral infiltrate

Light microscopic findings

clinical parameters. IF should be performed using a panel of

involvement common

antibodies specific for the different LC and Ig isotypes. In

glomerular disorders related to deposition of an entire
Endocapillary GN
common (CLL)

monoclonal IgG (immunotactoid glomerulopathy, type I

nous features

cryoglobulinemic glomerulonephritis, PGNMID), or of a

truncated monoclonal heavy chain (heavy chain deposition
MPGN

MPGN
light)

disease (HCDD), AH amyloidosis), IF studies with antibodies

In patients with IgM monoclonal gammopathy.

against IgG subclasses are useful to clearly assess composition

syndrome, AKI, an-
hematuria uncom-
Hypertension and

Possible nephritic

and clonality of deposits. IF and EM are essential to

Renal symptoms

Microhematuria

Microhematuria
Proteinuria, NS

Proteinuria, NS

Proteinuria, NS

determine the specific MGRS lesion, which is crucial for

Hypertension

Hypertension

assessing prognosis and to initiate proper therapy. MGRS

lesions can be divided into two large categories on the basis
mon
CKD

CKD

CKD

uria

of their ultrastructural appearance: those with organized

deposits and those with mostly granular deposits (i.e.,
Type I cryoglobuline-
Glomerular disease

without substructure)55 (Tables 13, Figure 2). In difficult

AHL amyloidosis
AH amyloidosis
AL amyloidosis

cases, sensitive techniques such as immunoEM and laser

ITGN/GOMMID

microdissection/mass spectrometry analyses may be required

to confirm the composition of renal deposits and their
mic

localization.56,57
GN

Kidney International 5
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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.

Kidney International
F Bridoux et al.: MGRS
F Bridoux et al.: MGRS review

Kidney biopsy a c

Ig or light chain restriction

on immunofluorescence

+ 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

Lymph node biopsy* *If bone marrow is negative and

high suspicion for lymphoma

Figure 1 | Proposed algorithm for hematologic workup in

patients with MGRS. MGRS, monoclonal gammopathy of renal
significance; FLC, serum-free light chain assay. Figure 3 | Pathology of renal Igrelated amyloidosis. (a) There is
global marked mesangial and segmental glomerular capillary wall
deposition of acellular non-argyrophilic amyloid deposits (silver stain,
X200). (b) By definition, amyloid deposits should be Congo-red
positive. The figure shows extensive glomerular and vascular and
focal interstitial Congo-red positive amyloid deposits, which produce
MGRS-associated renal lesions anomalous colors (yellow/orange/green) when viewed under
polarized light (X200). (c) On high magnification at the ultrastructural
level, amyloid fibrils appear haphazardly oriented and measure
Organized deposits Non-organized
or inclusions deposits/inclusions
between 7 and 14 nm in diameter (electron microscopy, X46,000).
(d) On immunofluorescence, amyloid deposits appear smudgy and
show light chain restriction. The figure shows global mesangial and
Fibrils Microtubules Crystals or Monoclonal segmental glomerular capillary wall staining for lambda (X400).
inclusions immunoglobulin
deposition disease Staining for kappa was negative (not shown). Ig, immunoglobulin.
(LCDD, LHCDD,
LIght chain proximal HCDD)
Ig-related
Immunotactoid tubulopathy (with or
amyloidosis
(AL, AHL, AH)
GN/GOMMID without Fanconi amyloid is Congo-red positive and produces anomalous
syndrome) Proliferative
GN with mono- colors (yellow/orange/green) under polarized light.60 Small
clonal Ig deposits
Type 1
Crystal-storing (PGNMID) deposits of amyloid may be inconspicuous in hematoxylin
Fibrillary GN cryoglobulinemic
histiocytosis
GN and eosin, PAS, trichrome, and silver stains; hence, a Congo-
C3 glomerulopathy
associated with
red stain should be performed, not only to confirm the
monoclonal
gammopathy
presence of amyloid, but also to rule it out.59 The screening
of Congo-red stained slides under fluorescent light will also
increase the sensitivity of detection of amyloid.59 Renal AIg
Figure 2 | Diagram of MGRS-associated renal lesions.
affects glomeruli and vessels in the vast majority of cases and
AH, immunoglobulin heavy chain amyloidosis; AHL, immunoglobulin
heavy and light chain amyloidosis; AL, immunoglobulin light chain the interstitium in roughly half of the cases, but vascular-
amyloidosis; GN, glomerulonephritis; GOMMID, glomerulonephritis limited AL may rarely occur.40 Ultrastructurally, amyloid
with organized microtubular monoclonal immunoglobulin deposits; deposits appear as randomly arranged, nonbranching fibrils,
HCDD, heavy chain deposition disease; LCDD, light chain deposition
disease; LHCDD, light and heavy chain deposition disease; MGRS,
ranging in thickness between 7 and 14 nm, which can be seen
monoclonal gammopathy of renal significance; PGNMID, proliferative within the mesangium, glomerular basement membranes,
glomerulonephritis with monoclonal immunoglobulin G deposits. vessels, interstitium, and/or tubular basement membranes. A
departure from the haphazard orientation of fibrils is the
formation of amyloid spicules, which result from parallel
MGRS lesions with fibrillar deposits alignment of fibrils in the subepithelial zone perpendicular to
Igrelated amyloidosis. (Figure 3): Igrelated amyloidosis the glomerular basement membrane. The latter is more
(AIg) accounts for 4 80% of cases of renal amyloidosis in common in AIg than other forms of renal amyloidosis.35,61
the US.35 AIg in most cases is derived from fragments of On IF, amyloid deposits appear smudgy with fuzzy borders.
monoclonal AL and rarely from fragments of Ig heavy chains The IF finding of an intense staining for a single AL with
and light chains (AHL) or Ig heavy chains only (AH).58,59 negativity for Ig heavy chains is diagnostic of AL, with
Amyloid has a characteristic appearance on LM: acellular roughly three quarters of renal AL cases expressing lambda
deposits that stain pale eosinophilic on hematoxylin and LC. The diagnosis of AH is based on the presence of intense
eosin, periodic acidSchiff (PAS)-negative or weak, staining for a single Ig heavy chain (most commonly gamma)
trichrome-blue or gray, and silver-negative. By definition with negativity for kappa and lambda LCs, whereas the
and in contrast to the deposits of all other MGRS lesions, diagnosis of AHL is reserved for intense staining for a single

Kidney International 7
review
Ig heavy chain and a single AL (most commonly IgGl).58 In
early renal AL, the deposits can be inconspicuous by LM and
easily missed by EM but unequivocally identified by IF. IF has
a sensitivity of 82% and a specificity of 100% for diagnosing
AL but has lower sensitivity and specificity for diagnosing Ig
AHL and AH, and therefore a negative or equivocal IF
staining for Ig heavy and/or light chain does not exclude
AIg.35,62 Amyloid typing by laser microdissection followed by
mass spectrometry has a higher sensitivity and specificity
compared with IF and immunoperoxidase and should be
performed when there is no frozen tissue available for IF,
negative staining for kappa and lambda, equal staining for
kappa and lambda, or bright staining for IgG, IgA, or
IgM.35,63 Laser microdissection/mass spectrometry may also
assist in the distinction between AIg and fibrillary
glomerulonephritis (FGN).64 ImmunoEM may be also
helpful to assess the composition of amyloid fibrils to
highlight the association of amyloid fibrils with monoclonal
Ig deposition and thereby eliminate nonspecific binding of Ig
fragments.65
Non-amyloid FGN. The majority of cases of non-amyloid
FGN show polyclonal glomerular Ig deposits, staining
for IgG (predominantly IgG4 and IgG1), kappa, and lambda
on IF and are not associated with a circulating serum
paraprotein.15,66,67 These cases should not be considered a
manifestation of MGRS. However, a minority of cases are
associated with monotypic glomerular deposits and should
be considered a manifestation of MGRS. In a recent
series of 66 cases of FGN, 7 (11%) stained for IgG and a
single LC on IF and 3 (5%) stained for IgG without LCs.
Serum IF performed in 9 of the above 10 cases detected
a MIg in 8 (89%).66 LM in FGN typically shows
mesangial hypercellularity, duplication of the glomerular
basement membranes, and glomerular non-congophilic
deposits. Ultrastructurally, the deposits are composed
of randomly oriented fibrils ranging from 9 to 26 nm in
diameter. In contrast to amyloid fibrils, they rarely form
spicules or affect vessels but can involve tubular basement
membranes.
MGRS lesions with microtubular substructure
Immunotactoid glomerulopathy. (Figure 4): Immunotac-
toid glomerulopathy, also referred to as glomerulonephritis
with organized microtubular monoclonal Ig deposits, is
defined by glomerular deposition of microtubules that have
distinct hollow centers at magnification of o30,000, ar-
ranged at least focally in parallel arrays, and stain for Igs by
IF, in the absence of clinicopathologic diagnosis of cryoglo-
bulinemic glomerulonephritis or lupus nephritis.15,67,68 The
microtubules are usually thicker compared with the fibrils of
amyloid and FGN, ranging in size from 10 to 90 nm. The two
most common morphologic patterns of glomerular injury on
LM and EM are membranous glomerulonephritis in which
the deposits are primarily present in the subepithelial space
and membranoproliferative glomerulonephritis in which the
deposits are preferentially located in the subendothelial
8 Kidney International
F Bridoux et al.: MGRS
a c
b
Figure 4 | Pathology of immunotactoid glomerulopathy. (a) The
glomerulus shows global glomerular capillary wall thickening and
mesangial expansion by red-staining immune deposits (trichrome
stain, X400). (b) In this case of immunotactoid glomerulopathy with a
predominantly membranous pattern of injury, there is coarsely
granular global glomerular capillary wall and segmental mesangial
staining for IgG (X400). Similar glomerular staining for lambda was
seen, with negative staining for kappa (not shown). (c) Electron
microscopy in a different case exhibits large subendothelial and
mesangial deposits composed of large microtubules (mean 52 nm)
with hollow centers, which are organized in parallel arrays (X9700).
zone.15,67,68 On IF, the glomerular deposits generally but
not always stain for IgG (most commonly IgG1) and C3 and
exhibit LC restriction.
Type I cryoglobulinemic glomerulonephritis. (Figure 5):
Glomerular involvement occurs in 30% of patients with
type I cryoglobulinemia.69 On LM, type I cryoglobulinemic
glomerulonephritis shows membranoproliferative or endo-
capillary proliferative glomerulonephritis with numerous
intracapillary infiltrating monocytes and large PAS-positive
intraluminal immune deposits protein (hyaline)
thrombi.69,70 On EM, the deposits are seen mainly in the
subendothelial zone and intracapillary lumen and in over half
of cases appear organized (with fibrillar, microtubular, or
fingerprint substructure).70 The organized substructure is
more commonly seen in the intraluminal deposits. On IF, the
glomerular deposits are composed of monoclonal light and
heavy chains (most commonly IgG kappa) and comple-
ment.71 IF is useful to determine the type of cryoglobulin-
emia present: the glomerular deposits in type II cryoglobulin-
emic glomerulonephritis typically exhibit brighter staining
for IgM than IgG and for kappa than lambda (consistent with
monoclonal IgM kappa against polyclonal IgG), whereas they
stain similarly for IgG, IgM, kappa, and lambda in type III
cryoglobulinemic glomerulonephritis (consistent with
polyclonal IgGs and IgMs).
In crystalcryoglobulinemia, monoclonal Ig deposits are
highly organized into intracellular and/or extracellular
crystals in the cytoplasm of glomerular endothelial, mesan-
gial cells, and/or in glomerular subendothelial spaces and
F Bridoux et al.: MGRS
a b
c d
200 nm
Figure 5 | Pathology of type I cryoglobulinemic
glomerulonephritis. Kidney biopsy from a 65-year-old male
patient with IgA lambda type I cryoglobulinemia. (a) Global
endocapillary hypercellularity with numerous hyaline thrombi in
glomerular capillary lumens (green light trichrome stain, X312). (b)
The toluidine blue-stained semithin sections revealed crystalline
inclusions within glomerular capillary lumens (X312, and insert
X1000). (c) By electron microscopy (X2500), subendothelial deposits
and hyaline thrombi were highly organized with a remarkable grid-
like appearance on higher magnification (insert, X100,000). (d)
Immunoelectron microscopy, anti-human lambda light-chain gold
conjugate (X60,000). Numerous gold particles specifically decorated
crystalline glomerular thrombi. Similar staining was observed with
the anti-alpha conjugate, whereas no significant staining was seen
with anti-gamma, anti-m, and anti-kappa conjugates (not shown).
within vascular lumens that may display a typical grid-like
appearance.55
MGRS lesions with deposition of crystals
Light-chain proximal tubulopathy. (Figure 6): LC proximal
tubulopathy, previously referred to as the LC Fanconi
syndrome is characterized by the presence of rod- or
rhomboid-shaped hypereosinophilic and PAS-negative crys-
tals within proximal tubular cells. Ultrastructurally, the
crystals may appear granular or show lattice-like substruc-
ture.72 Because of their intracellular localization and
extensive crystallization, standard IF on frozen tissue may
fail to confirm their LC composition. IF on pronase-digested,
paraffin-embedded tissue, which has an antigen retrieval step,
and immunoEM are much more sensitive techniques, but the
latter is not widely used in renal pathology practice.73,74
Patients with LC proximal tubulopathy with crystals may or
may not have a complete or partial FS.38,39,75,76 The
pathologic LC in this lesion is almost always kappa and
restricted to the Vk1 subgroup. A more recently described
pathologic variant of light-chain proximal tubulopathy called
LC proximal tubulopathy without crystals manifests LC-
containing phagolysosomes within proximal tubular cells
without crystal formation.72,77,78 The non-crystalline
inclusions appear hypereosinophilic on hematoxylin and
Kidney International
review
a b
c d
Figure 6 | Pathology of light-chain proximal tubulopathy.
(a) Large rod-shaped hypereosinophilic crystals are seen within the
cytoplasm of some proximal tubular cells. (H&E, X600). (b) By
immunofluorescence performed on pronase-digested, paraffin-
embedded tissue, proximal tubular crystals stain strongly for kappa
(as shown) with negative lambda (not shown). The intracellular
crystals failed to stain for kappa or lambda on standard
immunofluorescence on frozen tissue (not shown). (c)
Ultrastructurally, the proximal tubular cells are loaded with electron
dense light-chain crystals with rod, rhomboid, or rectangular shapes.
The crystals are present predominantly free within the cytoplasm (not
membrane-bound). The proximal tubular brush borders appear intact
(X1850). (d) In this case of light-chain proximal tubulopathy, the
proximal tubular cells are filled with large election dense
phagolysosomes, without crystals (electron microscopy, X9700). H&E,
hematoxylin and eosin.
eosin and electron dense with occasional mottled
appearance on EM.77 LC proximal tubulopathy without
crystals can be of kappa or lambda types and is not usually
associated with FS.77 A not uncommon diagnostic dilemma is
distinguishing LC proximal tubulopathy without crystals
from the physiologic intracellular proximal tubular
trafficking of LC (without pathologic significance). We
recommend that a diagnosis of LC proximal tubulopathy
without crystals should be reserved to cases associated with
very large dysmorphic lysosomes, histologic evidence of acute
and/or chronic proximal tubular injury, marked swelling of
proximal tubular cells due to lysosomal indigestion, renal
insufficiency (not explained by other pathology), tubular
proteinuria (as opposed to pure overflow proteinuria), and/
or clinical features of partial or complete FS.
Crystal-storing histiocytosis. (Figure 7): This is a rare
complication of MM or MGRS, which typically involves the
bone marrow but can also affect several extramedullary sites,
including the kidney, peri-renal fat, lungs, and cornea.
Kidney biopsy reveals intracytoplasmic eosinophilic LC
crystalline inclusions within interstitial histiocytes and
occasionally within proximal tubular cells and podocytes.79
As in LC proximal tubulopathy with crystals, standard IF on
frozen tissue sometimes fails to demonstrate their LC
composition, which requires IF on pronase-digested
9
review
Figure 7 | Pathology of crystal-storing histiocytosis. The figure
shows numerous light-chain crystals with rod, needle, or rhomboid
shapes, within the cytoplasm of interstitial infiltrating histiocytes. The
tubule depicted in the upper portion of the image does not exhibit
intracytoplasmic or intraluminal crystals (electron microscopy,
X1850).
a b
c d
Figure 8 | Pathology of renal monoclonal immunoglobulin
deposition disease. (a) The glomerulus shows nodular mesangial
sclerosis, which is seen in most but not all cases of MIDD. The nodules
are PAS-positive similar to the nodules of diabetic glomerulosclerosis
(PAS, X400). (b) The diagnostic ultrastructural finding in MIDD is finely
granular electron dense deposits involving the outer aspect of the
tubular basement membranes (as seen in this figure) and the inner
aspect of the glomerular basement membranes (not shown) (electron
microscopy, X2400). (c and d) In this case of LCDD kappa type,
immunofluorescence reveals diffuse linear glomerular and tubular
basement membranes staining for kappa (c) with negative staining
for lambda (d; X100 for c and d). LCDD, light chain deposition
disease; MIDD, monoclonal immunoglobulin deposition disease. PAS,
periodic acidSchiff.
paraffin tissue or evaluation by the immunoperoxidase
method. Crystal-storing histiocytosis may coexist with LC
proximal tubulopathy and/or cast nephropathy.80
MGRS lesions with granular (non-organized) deposits
MIg deposition disease of the Randall type (MIDD).
(Figure 8): MIDD includes three subtypes, depending on
the composition of deposits: LCDD, the most common
10
F Bridoux et al.: MGRS
subtype, in which the deposits contain monoclonal LC only
(kappa in most cases), light and heavy chain deposition
disease (LHCDD), in which the deposits are composed of
monoclonal light and heavy chains (most commonly IgG
kappa), and HCDD, in which the deposits are derived from
monoclonal heavy chains only (most frequently gamma),
which always lack the first constant (CH1) domain. LM
shows thickening of tubular basement membranes in most
cases and nodular mesangial sclerosis in 2/3 of cases,
accompanied by variable degrees of tubular atrophy, inter-
stitial fibrosis, and inflammation.7,9,81 It has a very distinctive
appearance on IF: diffuse linear staining along basement
membranes of glomeruli, tubules, and vascular myocytes for
kappa or lambda only in LCDD, for a single Ig heavy chain
with LC restriction in LHCDD, or for a single class of Ig with
CH1 domain deletion and no corresponding LC in HCDD.
The IF deposits correspond to punctate powdery electron-
dense deposits along the inner aspect of glomerular basement
membranes and outer aspect of tubular basement
membranes on EM. Glomerular crescents may be seen,
particularly in alpha HCDD.82
Proliferative glomerulonephritis with monoclonal IgG depos-
its. (Figure 9): LM in PGNMID generally shows membra-
noproliferative or endocapillary proliferative glomerulo-
nephritis, with or without membranous features, and less
commonly pure mesangial proliferative glomerulo-
nephritis.27,83 EM exhibits granular, non-organized
deposits, typically in a subendothelial and mesangial
distribution, with or without subepithelial deposits. By
definition, and in contrast to immune complex type
glomerulonephritis, the glomerular deposits on IF appear
monoclonal, staining for a single LC isotype and a single IgG
heavy chain subtype (most commonly IgG3).27 PGNMID
patients with monoclonal IgG3 deposits are less likely
to have a detectable circulating paraprotein compared
with those with monoclonal IgG1 or IgG2 deposits.27
Contrary to Randall-type HCDD and LHCDD, the deposits
in PGNMID are restricted to glomeruli (without
extraglomerular or extrarenal involvement) and contain an
intact MIg. Of note, there have been rare reported cases
of glomerulonephritis in which the glomerular deposits are
composed of MIg components other than IgG, including
IgM, IgA, or LCs only.46,8486
C3 glomerulopathy with monoclonal gammopathy. (Fig-
ure 10): C3 glomerulopathy encompasses two pathologic
entities, C3 glomerulonephritis and dense deposit disease,
both of which are due to dysregulation of the complement
alternative pathway (CAP; e.g., mutations or functional inhi-
bition of complement-regulating proteins) and are charac-
terized by glomerular C3 deposition with absent or scanty Ig
deposition.87 LM in C3 glomerulopathy shows mesangial
proliferative, membranoproliferative, or endocapillary pro-
liferative glomerulonephritis. Dense deposit disease is
distinguished from C3 glomerulonephritis on the ultrastruc-
tural level: the former shows highly electron dense sausage-
like deposits that segmentally infiltrate the glomerular
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F Bridoux et al.: MGRS review

2 m

lgG3 Kappa Lambda

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.

Kidney International 11
review
basement membrane lamina densa, whereas the latter shows
less electron dense, ill-defined granular deposits in the
subendothelial space, subepithelial space, and/or
mesangium. A subset of patients with dense deposit disease
or C3 glomerulonephritis have a demonstrable circulating
MIg in the blood and evidence of a plasma cell dyscrasia in
the bone marrow.8890 In contrast to all other MGRS lesions,
the MIg in C3 glomerulopathy is not deposited in the kidney.
In these patients, the MIg likely causes glomerulonephritis
indirectly through continuous CAP activation, such as by
inhibiting the complement-regulating proteins.24,89,91 Several
arguments strongly suggest a causal relationship between
monoclonal gammopathy and C3 glomerulopathy. First,
3050% of patients 450 years of age with C3 glomerulopathy
have a detectable monoclonal Ig,89 a frequency that largely
exceeds that of MGUS in the general population (3.2% in
patients aged over 50 years).92 Second, as mentioned above,
monoclonal Igs may induce CAP through autoantibody
activity against factor H. In a patient with MPGN Meri24 and
Jokiranta25 isolated and characterized a dimeric monoclonal
Vl3 LC, which behaved as a mini autoantibody to factor H.
By binding to the short consensus repeat domain 3 at the
N-terminal end of factor H, this dimer blocked the
interaction between factor H and C3b, thereby inhibiting
the activity of factor H and inducing uncontrolled CAP
activation.24,25 Third, disappearance of anti-factor H auto-
antibodies with hematological response after chemotherapy
has been described in some patients with C3
glomerulopathy.90 However, the role of MIg in CAP
activation in C3 glomerulopathy remains to be formally
demonstrated by the few reference laboratories capable of
performing appropriate functional assays.
SUMMARY
The pathologic spectrum of renal diseases in MGRS is wide
and kidney biopsy is required to determine the exact nature
of the lesion and to evaluate the severity of renal disease. The
monoclonal protein may cause kidney damage directly
through deposition or precipitation, as in AL amyloidosis,
MIDD, and light-chain proximal tubulopathy, or indirectly
through an autoantibody activity, as in C3 glomerulopathy
with monoclonal gammopathy. Because of the small amount
and/or rapid deposition in the kidney, the paraprotein may
be undetectable in the blood by serum EP/immunofixation
or FLC and therefore may require more sensitive techniques.
Early recognition of MGRS is crucial, as it strongly impacts
renal prognosis. A common problem in clinical nephro-
logy practice is to convince hematologists to initiate swift
and efficient chemotherapy for patients with MGRS,
who by definition do not fulfill the criteria for MM. Hence,
there is a need to increase clinicians awareness of MGRS,
as more widespread acceptance of this concept should
result in less delay in appropriate therapy. A consensus on
the pathological definition of the MGRS spectrum is needed
in order to design future collaborative studies in these
disorders.
12
F Bridoux et al.: MGRS
DISCLOSURE
All the authors declared no competing interests.
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