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Glomerulonephritis With Isolated C3 Deposits and
Monoclonal Gammopathy: A Fortuitous Association?
Frank Bridoux,*
†¶
Estelle Desport,*
¶
Ve´ronique Fre´ meaux-Bacchi,
‡
Christine Fen Chong,* Jean-Marc Gombert,
§¶
Corinne Lacombe,
§¶
Nathalie Quellard, and Guy Touchard*
¶
Summary
Background and objectives Glomerular deposition of monoclonal Ig has been exceptionally described as the
cause of membranoproliferative glomerulonephritis, through activation of the complement alternative path-
way (CAP).
Design, setting, participants, & measurements We retrospectively studied six adults with monoclonal gam-
mopathy and glomerulonephritis (GN) characterized by isolated C3 deposits.
Results All patients presented with hematuria, associated with chronic renal failure and proteinuria in five
patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undeter-
mined significance and one had smoldering myeloma. The serum monoclonal IgG (
four of six,
two of
six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3
and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none
had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH,CFI, and MCP
genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesan-
gial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but
negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed
to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In
one patient, monoclonal
LC deposits were observed on a follow-up kidney biopsy after 4 years.
Conclusions GN with isolated glomerular C3 deposits might represent an unusual complication of plasma
cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig
against a CAP regulator protein.
Clin J Am Soc Nephrol 6: 2165–2174, 2011. doi: 10.2215/CJN.06180710
Introduction
A wide variety of glomerular diseases may occur
during the course of plasma cell disorders, resulting
from deposition of a monoclonal Ig. Based on light
microscopy (LM), immunofluorescence (IF), and elec-
tron microscopic (EM) studies of kidney biopsy, these
disorders may be classified according to the nature,
localization, and ultrastructural appearance of mono-
clonal Ig deposits (1,2). Organized glomerular mono-
clonal Ig deposits include immunoglobulinic amyloid-
osis (2), microtubular/immunotactoid glomerulopathy
(3,4), and type I cryoglobulinemic glomerulonephritis
(GN) (5,6), whereas granular amorphous deposits are
mostly represented by Randall-type monoclonal Ig
deposition disease (MIDD). MIDD is characterized by
peritubular, glomerular, and vascular deposition of
either a single monoclonal light chain (LC) or a trun-
cated heavy chain (HC) lacking the first constant do-
main, or of both monoclonal Ig LC and HC (1,7).
Recently, a novel type of proliferative GN or mem-
branoproliferative GN (MPGN) with monoclonal Ig
deposits was described (8–12). This entity mimics
immune-complex GN and differs from classic MIDD
by the absence of Ig deposition on tubular and vas-
cular basement membranes, and by the nonlinear,
granular appearance of glomerular deposits (8,9).
Like other monoclonal Ig-related glomerulopathies,
it is prone to recurrence after kidney transplanta-
tion (11).
Although hypocomplementemia and glomerular
deposition of C3 or other complement components
are common findings in most types of glomerular
disorders related to monoclonal Ig deposition (3,4,8–
10,13,14), little attention has been paid to the role of
the complement system in the pathogenesis of renal
lesions. Evidence of the nephrotoxic property of a
monoclonal Ig, through activation of the complement
alternative pathway (CAP) involving anticomplement
factor H (CFH) antibody activity, was first demon-
strated in a patient with MPGN, dense deposits of C3,
and monoclonal lambda LC (15,16). Rare cases of
dense deposit disease (DDD), also referred to as
*Department of
Nephrology, CHU
Poitiers, Universite´de
Poitiers, Poitiers,
France;
†
CNRS UMR
6101, Universite´de
Limoges, Limoges,
France;
‡
Assistance
Publique-Hoˆ pitaux de
Paris, Laboratory of
Immunology, Hoˆ pital
Europe´ en Georges
Pompidou, Paris,
France;
§
Laboratory of
Immunology,
储
Department of
Pathology, CHU
Poitiers, Universite´de
Poitiers, Poitiers, France;
¶
Centre national de re´-
fe´ rence maladies rares
amylose AL et autres
maladies a`de´poˆts
d’immunoglobulines
monoclonales.
Correspondence: Pr
Frank Bridoux,
Department of
Nephrology and Renal
Transplantation, Hoˆ pital
Jean Bernard, 2, rue de
la Mile´ trie, CHU
Poitiers, 86021 Poitiers,
France. Phone: 33 5 49
44 41 59; Fax: 33 5 49
44 42 36; E-mail:
f.bridoux@chu-poitiers.fr
www.cjasn.org Vol 6 September, 2011 Copyright © 2011 by the American Society of Nephrology 2165
Article
MPGN type II, have been reported in association with
plasma cell disorders (17–19). We studied six patients with
monoclonal gammopathy and glomerular disease distinct
from DDD, characterized by glomerular C3 deposits with-
out monoclonal Ig deposits at presentation. Our data sug-
gest that this entity might represent an unusual renal com-
plication of plasma cell dyscrasia not related to monoclonal
Ig deposition but to local glomerular CAP activation by the
monoclonal Ig, with or without hypocomplementemia.
Study Population and Methods
Patients
Six patients referred to five nephrology departments
between 1990 and 2009 were retrospectively studied. In-
clusion criteria were as follows: (1) isolated diffuse granu-
lar glomerular C3 deposits, without evidence of Ig LC or
HC deposits on IF study of kidney biopsy; (2) presence of
serum and/or urine monoclonal Ig; and (3) absence of
detectable serum cryoglobulin.
Demographics and clinical and biologic data were re-
corded at the time of the first kidney biopsy and at the last
follow-up visit. Estimated GFR (eGFR) was calculated us-
ing the modified MDRD (Modification of Diet in Renal
Disease) equation (20).
Pathologic Studies
All kidney biopsy samples were processed for light and
IF microscopy, as described previously (3). Sections were
systematically stained with Congo red and examined un-
der polarized light. The extent of tubular atrophy, intersti-
tial fibrosis, arteriosclerosis, and the abundance of glomer-
ular deposits were graded on a scale from 0 to 3⫹. For
direct IF, 3-
m cryostat sections were stained using poly-
clonal FITC conjugates specific for
␣
,
␥
, and
Ig HC;
and
LC (Dakopatts, Glostrup, Denmark); and C3, C4, C1q,
and albumin (Morphosys AbD, Du¨sseldorf, Germany). In
two patients, indirect IF was performed using monoclonal
antibodies to C5b-C9 membrane-attack complex, CFH and
properdin (Morphosys AbD), and a fluorochrome-conju-
gated rabbit anti-mouse as secondary antibody (Dako-
patts). In five patients, ultrathin sections were processed
for EM studies and examined under a JEOL JEM-1010
electron microscope (JEOL, Tokyo, Japan) (3).
Hematologic and Immunologic Studies
Bone marrow smears or biopsy (with IF studies in one
case) were performed in all patients. CH50 and plasma
concentrations of C3, C4, factor B, CFH, and I were mea-
sured, as described previously (21). CD46 surface expres-
sion was determined on granulocytes using flow cytom-
etry (22). C3 nephritic factor (C3NeF) was assessed by the
ability of tested plasma IgG to stabilize a preformed cell-
bound C3bBb convertase, and anti-CFH Ab by ELISA
(23,24). Complement genetic screening was performed in
four patients, using direct sequencing of all CFH,IF, and
MCP exons. The CFH H402 haplotype was tagged by
genotyping the single nucleotide polymorphism rs1061170
(c.1204T⬎C; p. Tyr402His), as reported elsewhere (25).
Serum samples were collected, processed at 37°C, and
tested for cryoglobulins. Serum and urine monoclonal Ig
were detected by conventional electrophoretic and immu-
noelectrophoretic (IEL) analysis. In two patients, Western
blots were performed to determine serum monoclonal Ig
subclasses, using the same specific monoclonal antibodies
as for IF studies (26).
Results
Clinical Data at Diagnosis
Six Caucasian patients—three women and three men
(median age 67.5 years, range 40 to 74)—were included in
the study. At the time of kidney biopsy, five patients had
hypertension with significant proteinuria (median 3.3 g/d,
range 2 to 5.1), and nephrotic syndrome in three patients.
Hematuria was found in all patients, two of whom had
experienced episodes of gross hematuria. Median serum
creatinine level was 150
mol/L (range 70 to 298
mol/L).
Three patients had stage 3 chronic kidney disease
(CKD), two had stage 4 CKD, and one had stage 5 CKD.
Fundoscopic examination, performed in two patients,
did not show Drusen or macular degeneration. None
had lipodistrophy or other extrarenal manifestations,
and none had experienced any infectious episode before
admission (Table 1).
Hematologic and Immunologic Findings
At the time of diagnosis, all patients had a serum mono-
clonal IgG (kappa four patients, lambda two patients), with
LC proteinuria in five patients. Western blot showed that
the IgG subclass was
␥
1 in patients 1 and 2. Three patients
had abnormal serum free kappa (two patients) or lambda
(one patient) LC levels. In patients 1, 3, and 5, monoclonal
gammopathy had been diagnosed 2 to 10 years before
admission.
Bone marrow examination showed a 3% infiltration by
dystrophic plasma cells, consistent with stage I multiple
myeloma, in patient 3. IgG1
-positive plasma cells (1.5%)
were found by IF in patient 1. None of the patients had
lytic bone lesions, lymphadenopathy, or spleen or liver
enlargement (Table 1).
Tests for serum cryoglobulins, rheumatoid factor, hepa-
titis B and C, and HIV infection were negative in all pa-
tients. Antinuclear, anti-dsDNA, and M2 antimitochon-
drial antibodies were detected in patient 4, without any
symptom of systemic autoimmune disease.
Complement Studies
Patients 2 and 3 had low serum C3 and factor B levels,
which suggested CAP activation. Patient 5 showed de-
creased levels of factor B, with normal C3 levels. In patient
1, low levels of C3 with normal C4 were observed, but
further tests were not available. In the five other patients,
serum levels of C4, CFH, and I proteins were normal.
CD 46 surface expression on granulocytes was normal in
the three patients tested. None of the patients presented
with a C3NeF. Anti-CFH IgG antibodies were detected
before treatment in patient 2. No genetic abnormality was
found in CFH,CFI, and MCP genes in patients 2 to 4 and 6.
Patients 3 and 6 carried at least one copy of CFH H402
allele (Table 2).
Pathologic Findings
In all patients, the light microscopic appearance of glo-
merular lesions was characterized by mesangial prolifera-
2166 Clinical Journal of the American Society of Nephrology
tion, neutrophilic leukocyte afflux in glomerular tufts, and
deposits in the mesangium and glomerular capillary walls
(CW; Figure 1). Patients 2 and 6 had mild extracapillary
proliferation (Figure 1C), and microthrombi within capil-
lary loops were present in patient 3. Few subepithelial
deposits (humps) were observed in five patients (Figure
1D). Five patients had degenerative lesions, including
global glomerular sclerosis, tubular atrophy, interstitial
fibrosis, and arteriosclerosis, of variable severity.
The main feature by direct IF was diffuse and bright
granular glomerular deposits of C3 in all patients (Figure
2A, C, D). No significant staining was observed with anti-
kappa, lambda,
␣
,
␥
,
, C4, and C1q conjugates. Indirect IF
studies, available in patients 2 and 3, did not show signif-
icant C5b-C9 deposits; however, positive staining was ob-
served with anti-CFH and antiproperdin antibodies (Fig-
ure 2B). By EM, performed in five patients, nonextensive
amorphous electron-dense deposits, or deposits of inter-
mediate density, with a “sausage-shaped” appearance,
were observed within the lamina densa, which appeared to
be interrupted on the subendothelial surface (Figure 3).
Deposits of lesser density were found in the subepithelial
space (humps) or in paramesangial areas (nodular pseu-
dohumps) in most patients (Figure 3A, B).
In patient 1, two follow-up biopsies showed persistence
of glomerular C3 deposits with progression of interstitial
fibrosis and glomerular sclerosis. In patient 2, a control
biopsy at 4 years showed significant amounts of granular
monoclonal lambda LC deposits that colocalized with C3
in the mesangium and glomerular CW (Figure 2D, inset;
Table 3).
Treatment and Follow-Up
Four patients were given chemotherapy with high-dose
dexamethasone, either alone (patient 2) or combined with
melphalan (patient 3) or cyclophosphamide (patient 4).
Patient 5, who progressed to stage III multiple myeloma
after 11 years of follow-up, received three courses of bort-
ezomib plus dexamethasone, relayed by melphalan plus
Table 1. Renal presentation at baseline and clinical outcome
Patient No. 1 2 3 4 5 6
Baseline characteristics
age (years)/gender
(M/F)
40/F 59/M 74/M 71/F 73/F 64/M
hypertension No Yes Yes Yes Yes Yes
serum creatinine
(
mol/L)
70 150 150 298 130 280
GFR ml/min per 1.73 m
2
85 44 42 14 37 21
protids/albumin (g/L) 75/32 60/34 66/28 69/35 57/24 64/29
proteinuria (g/24 h)/
Nephrotic syndrome
0.5/No 2/No 3.3/Yes 2.5/No 5.1/Yes 3.5/Yes
haematuria Yes
a
Yes Yes Yes Yes
a
Yes
serum monoclonal Ig IgG1
IgG1
IgG
IgG
IgG
IgG
MIg concentration (g/L) 30 7 16 18.9 21.3 4
serum FLC (mg/L) NA 988 (
) NA 525 (
) 102 (
)NA
kappa/lambda ratio NA 0.03 NA 53.2 5.0 NA
LC proteinuria
(U ⫹S)
(U ⫹S)
(U)
(U)
(U ⫹S) No
bone marrow PC (%) 4 ⬍5 3 (dystrophic) 7.5 5 3
Treatment
time from diagnosis
(months)
47 36 7 20
serum creatinine
(
mol/L)
450 180 500 250
GFR (ml/min per 1.73 m
2
)at
the onset of treatment
12 34 8 17
chemotherapy regimen No treatment Dex Mel ⫹Dex CYC ⫹Dex Bortezomib ⫹Dex No treatment
Outcome
ESRD (months from
diagnosis)
Yes (90) Yes (55) Yes (48) Yes (12) Yes (23) No
serum Cr (
mol/L) 290
serum monoclonal
IgG (g/l)
23 17 27 14 NA 6
serum FLC (mg/L) 8800 (
) NA NA 653 (
) 559 (
)NA
kappa/lambda ratio 1392.4 NA NA 31.4 36.3 NA
death Yes No No No No No
follow-up time (months) 162 94 60 25 36 4
a
macroscopic hematuria.
S, serum; U, urine; NA, not available; ESRD, end stage renal disease; FLC, free light chains; GFR, glomerular filtration rate; LC, light
chains; MIg, monoclonal immunoglobulin, Dex, high-dose dexamethasone; Mel, melphalan; CYC, cyclophosphamide.
Clin J Am Soc Nephrol 6: 2165–2174, September, 2011 Glomerular C3 Deposits and Monoclonal Gammopathy, Bridoux et al. 2167
thalidomide and dexamethasone. Treatment was intro-
duced less than 1 years after diagnosis in only one patient,
and three had at least stage 4 CKD at the onset of therapy.
None achieved hematologic response; however, in patient
2, serum titers of IgG anti-CFH autoantibodies decreased
and became undetectable after 11 courses of dexametha-
sone. Post-treatment kidney biopsies were not performed
in any patient.
After a median follow-up of 47 months (range 4 to 162
months), five patients had progressed to (ESRD) over a
median time of 48 months (range 12 to 90 months). Patient
1 died from sepsis 14 years after diagnosis and 6 years after
the onset of hemodialysis.
Discussion
The association of proliferative glomerular disease with
isolated C3 deposits is an extremely rare condition in
adults (27). Isolated intramembranous diffuse C3 deposits
is characteristic of DDD (27,28), but disseminated granular
glomerular CW and mesangial C3 deposits, without IgG
deposits, are sometimes observed in late stages of post-
streptococcal GN. These two conditions result from CAP
activation. C3NeF, an autoantibody with anti-CAP C3 con-
vertase activity, is found in more than 80% of DDD cases
and in some cases of poststreptococcal GN (23,27). Re-
cently, Servais et al. (29) introduced the term glomerulone-
phritis C3 (GNC3) to describe glomerular disease in a
series of 19 patients, mostly adults, with isolated glomer-
ular C3 deposits distinct from classical DDD and poststrep-
tococcal GN. Thirteen patients displayed features of type I
MPGN, whereas five patients had mesangial and epimem-
branous deposits without mesangial proliferation and sub-
endothelial deposits. Circulating C3NeF and low serum C3
levels, indicative of systemic CAP activation, were fre-
quent in patients with MPGN features. By contrast, C3
levels were normal in most patients without MPGN
features who displayed mutations in CFH or factor I in
two thirds of cases. Mutations in the C3 gene have been
described in DDD (30), whereas mutations in CFH gene,
or in complement factor H-related protein 5 gene, have
been identified in DDD and GNC3 (21,31,32). These data
suggest that different mechanisms of CAP activation
might result in various patterns of glomerular damage.
In the present series, all six patients had similar glomer-
ular lesions, with isolated glomerular C3 deposits and
overlapping features of type III MPGN and DDD. Clinical
manifestations were homogeneous, including heavy pro-
teinuria, with nephrotic syndrome and progressive renal
failure in most cases. Three patients had low serum C3
levels (with low factor B levels in two), and one showed
low factor B levels with normal C3 levels. Serum levels of
CFH and I proteins were normal in five of five patients, as
was CD46 expression in three of three patients, and no
mutations in CFH,CFI, and MCP genes were identified in
four of four patients. Strikingly, all had evidence of mono-
clonal gammopathy. None of the patients had circulating
C3NeF, indicating that an autoantibody activity against the
CAP C3 convertase was not involved in the pathogenesis
of glomerular lesions.
The prevalence of monoclonal gammopathy in adults
with isolated glomerular C3 deposits appears to largely
exceed that of the general population, which is around
Table 2. Complement studies
Patient No. 1
2
3456
Before
Chemo During
Chemo After
Chemo
Complement
components
CH50 (%) NA 55 86 NA 91 82 68 106
C3 antigen (mg/L) 550 433 433 539 583 915 672 901
C4 antigen (mg/L) 109 239 218 168 117 224 186 319
CAP proteins
Factor B antigen
(mg/L)
NA 55 48 43 66 94 82 142
H protein (%) NA 88 73 89 138 177 117 165
I protein (%) NA 131 117 125 111 130 88 148
CD46 (MFI) NA 714 NA 791 584 NA 879 NA
C3 NeF NA Negative NA NA Negative Negative Negative Negative
anti-factor H IgG NA Positive Positive Negative Negative Negative Negative Negative
Genetic testing
CFH NA No
mutation
2 copies of
H402
No
mutation
NA 1 copy of
H402
CFI NA No
mutation
No
mutation
No
mutation
NA No
mutation
MCP NA No
mutation
No
mutation
No
mutation
NA No
mutation
Chemo, chemotherapy; MFI, mean fluorescence index; C3Nef, C3 nephritic factor; NA, not available.
Normal values: CH50, 70% to 130%; C3 antigen, 660 to 1250 mg/L; C4 antigen, 93 to 380 mg/L; Factor B, 90 to 320 mg/L; H protein, 65%
to 140%; I protein, 70% to 130%; MCP, 600 to 1400 MFI.
2168 Clinical Journal of the American Society of Nephrology
1% to 2% in adults and increases from 3.2% to 7.5% in
patients aged over 50 years and over 85 years, respec-
tively (33,34). Since the first description of MPGN and
isolated C3 deposits with monoclonal gammopathy (17),
few similar cases have been described. Nasr et al. (18)
reported that four adults (22%) out of a series of 32 DDD
cases had a history of plasma cell disorder. All had
typical ultrastructural features of DDD and sole or dom-
inant C3 deposition without LC restriction. The type of
the circulating monoclonal component was not detailed.
In a recent series of 81 hepatitis-negative MPGN pa-
tients, 28 had evidence of monoclonal gammopathy,
three of whom had isolated C3 deposits (12). Recently,
Sethi et al. found that among 14 patients with DDD, 10
(71.4%) had a serum monoclonal IgG (19). By IF, only C3
deposits were observed. Two patients with monoclonal
gammopathy and either DDD (19) or GNC3 (35) carried
one or two copies of the CFH H402 allele variant, which
has been found to be associated with increased risk of
DDD (36). However, as the frequency of the H402 allele
is high in the general population, and as it was not
present in two patients from the present series, it is
unclear whether a genetic permissive background is re-
quired for the development of DDD or GNC3 in patients
with monoclonal gammopathy.
In the present series, the diagnosis of DDD was unlikely,
as characteristic glomerular patterns (“tram tracks,” mes-
angial rings, continuous glomerular intramembranous
dense deposits) were not observed, and because circulating
C3NeF, a common finding in DDD, was absent. Whereas,
in previous reports, typical ultrastructural features of DDD
were mostly observed in patients with monoclonal gam-
mopathy (17–19), C3GN has been also described as in the
present patients (35).
Figure 1. |Light microscopic findings. (A) Patient 2, toluidine blue staining (original magnification: ⫻400): diffuse membrano proliferative
glomerulonephritis with mesangial and glomerular capillary wall deposits, and numerous neutrophils within capillary lumens. (B) Patient 3,
Marinozzi’s silver staining (original magnification: ⫻400): atypical segmental membranoproliferative lesions with nodular appearance of the
mesangium and duplication of glomerular basement membranes. (C) Patient 6, light green trichrome (original magnification: ⫻400):
glomerular crescentic proliferation with ribbon-like basement membrane thickening of the underlying tuft. (D) Patient 6, light green trichrome
(original magnification: ⫻400): numerous round mesangial (pseudohumps) (arrowhead), associated with fibrinoid deposits in glomerular
capillary walls, and some voluminous humps (arrow).
Clin J Am Soc Nephrol 6: 2165–2174, September, 2011 Glomerular C3 Deposits and Monoclonal Gammopathy, Bridoux et al. 2169
The frequency of complement activation in patients with
plasma cell disorders is likely to be underestimated. Defi-
cient alternative and terminal complement pathways have
been reported in 30% of patients with multiple myeloma
(37). In the present series, a role of monoclonal Ig in the
local or systemic activation of CAP, leading to subse-
quent glomerular proliferative lesions and C3 deposits,
is questionable. Such a hypothesis is strongly suggested
in patient 2, in whom MPGN with C3 deposits, but no
evidence of monoclonal Ig deposition, was diagnosed
simultaneously with IgG1
monoclonal gammopathy
and circulating anti-CFH IgG autoantibody. A control
biopsy at 4 years, before treatment, revealed colocaliza-
tion of glomerular C3 and lambda LC deposits, suggest-
ing that isolated C3 deposits might be an initial step
before subsequent monoclonal Ig deposition. This case is
reminiscent of the MPGN case LOI, in which a dimeric
monoclonal V
3 LC was shown to behave as a mini
autoantibody to CFH. By binding to the short consensus
repeat domain 3 at the N-terminal end of CFH, the LOI
dimer blocked the interaction between CFH and C3b,
thereby inhibiting the activity of CFH and inducing
uncontrolled CAP activation (15,16). We later reported a
similar case (LOP) with MPGN and lambda LC, C3,
CFH, and C5b-C9 deposits, without evidence of C3NeF.
A serum fraction enriched in monoclonal lambda LC
induced C3 conversion by the AP, with cleavage of
factor B and increased Bb level, while the C4 level re-
mained normal (2). The association of isolated glomer-
ular C3 deposits with MGUS, rather than with high-
mass myeloma (12,18,19,35), might suggest that
prolonged CAP activation by the monoclonal Ig is re-
quired for the development of glomerular lesions.
In the present case, and in previously reported cases, of
glomerular C3 deposits with monoclonal gammopathy,
renal outcome was poor, with progression to ESRD in most
Figure 2. |Immunofluorescence findings. (A) Patient 3, anti-C3 FITC-conjugate (original magnification: ⫻400): bright disseminated granular
and semilinear glomerular deposits, without ring forms in mesangium or dual tonality. (B) Patient 3, anticomplement factor H FITC-conjugate
(original magnification: ⫻400): similar, although weaker, fluorescence pattern of glomerular capillary walls. (C) Patient 6, anti-C3 FITC
conjugate (original magnification: ⫻400): monotonal diffuse granular capillary wall and mesangial bright deposits. (D) Patient 2, first kidney
biopsy, anti C3-FITC conjugate (original magnification: ⫻400): similar staining pattern as in Fig. 2A. Inset, second kidney biopsy, anti-
FITC
conjugate: few mesangial and capillary wall deposits associated with persistent colocalized bright C3 deposits (not shown).
2170 Clinical Journal of the American Society of Nephrology
Figure 3. |Electron microscopic findings. (A) Patient 2, second kidney biopsy (original magnification: ⫻4000): electron-dense voluminous
subepithelial deposits (humps) (asterisks). (B) Patient 2, second kidney biopsy (original magnification: ⫻6000): round, nodular (pseudohumps)
electron-dense mesangial deposits (asterisk) and interrupted intramembranous dense deposits (arrow). (C) Patient 1, third kidney biopsy
(original magnification: ⫻3300): glomerular basement membrane thickened by highly electron-dense interrupted intramembranous deposits
displaying a sausage-shaped (arrow) or bead-like (arrowhead) pattern. (D) Patient 1, third kidney biopsy, original magnification: ⫻3000):
intramembranous interrupted electron dense deposits (asterisks). Note the disruption of glomerular basement membrane, with protrusion of
podocyte epithelium (between short arrows) into the capillary lumen (white arrow) and neoproduction of basement membrane-like material
(arrowheads). US, urinary space; CL, capillary lumen.
Clin J Am Soc Nephrol 6: 2165–2174, September, 2011 Glomerular C3 Deposits and Monoclonal Gammopathy, Bridoux et al. 2171
patients (12,18,19). The demonstration of improvement of
renal function with reduction in proteinuria following che-
motherapy would reinforce the role of monoclonal gam-
mopathy in the pathogenesis of isolated glomerular C3
deposits. In our series, treatment was introduced too late in
the course of the disease to draw any valid conclusion on
its potential benefit. However, as the anti-CFH autoanti-
body disappeared after dexamethasone therapy in patient
2, early chemotherapy aimed at controlling the underlying
clonal disorder should be discussed with regard to pre-
venting progression toward ESRD (12). Eculizumab ther-
apy, which may improve renal symptoms in DDD (38),
also represents an interesting alternative (39).
Conclusions
Monoclonal gammopathy should be considered in adult
patients with MPGN. Isolated C3 deposits might represent
an unusual complication of plasma cell dyscrasia related to
CAP activation by the monoclonal Ig. Further studies,
based on testing the ability of purified monoclonal Igs to
activate CAP through an autoantibody activity against
CFH or another complement regulator protein, are needed
to confirm this hypothesis.
Acknowledgments
Portions of this work were previously presented in abstract
form at the 2007 World Congress of Nephrology, Rio de Janeiro,
Brazil, and at the 9th Re´union Commune de la Socie´te´deNe´ph-
rologie et de la Socie´te´ Francophone de Dialyze, 2007, Lyon,
France.
This work was supported by a grant from AREN Poitou-Char-
entes.
We gratefully acknowledge the colleagues who participated
in this study: R. Makdassi; C. H. U. Amiens; D. Le Chapois and
A. Nony; C. H. Bourges; J. L. Mahe; C. H. Abbeville; L. Mer-
cadal, Hoˆpital La Pitie´-Salpeˆ trie`re, Paris; P. Siohan; C. H. Quim-
per; S. Le Coz; and C. H. Saint Nazaire. We are indebted to Dr.
Winston Hutchinson, who carefully reviewed the manuscript.
Disclosures
None.
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Table 3. Renal biopsy findings
Patient No. 1 2
3456
Kidney Biopsy No. 12312
Light microscopy
no. of glomeruli 13 8 15 32 12 12 32 23 10
sclerotic glomeruli (%) 0 0 20 9 83 16 62 26 20
crescents (%) 0 0 0 10 0 0 0 10
tubular atrophy ⫹ ⫹⫹ ⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹
interstitial
inflammation
0⫹
a
⫹⫹ ⫹⫹ ⫹
b
⫹ ⫹ ⫹⫹ ⫹⫹
a
interstitial fibrosis ⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹ ⫹⫹
arteriosclerosis 0 ⫹ ⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹
Immunofluorescence
Ig heavy chain ⫺⫺⫺⫺⫺⫺⫺⫺⫺
Ig light chain ⫺⫺⫺⫺⫹⫹(
)⫺⫺⫺⫺
complement C3⫹⫹⫹ C3⫹⫹⫹ C3⫹⫹⫹ C3⫹⫹⫹ C3⫹⫹⫹ C3⫹⫹⫹ C3⫹⫹⫹ C3⫹⫹⫹ C3⫹⫹⫹
electron microscopy A NA A A NA NA A A A
Topography of deposits
mesangial deposits ⫹ ⫹ ⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹
subepithelial deposits ⫺⫺⫺⫹⫹⫹⫹⫹⫹⫹
subendothelial deposits ⫹⫹⫹⫹⫹⫹⫹⫹⫹⫹⫹⫹
GBM ⫹⫹⫹⫹⫹ ⫹ ⫹⫹
a
Infiltrate containing numerous plasma cells;
b
infiltrate containing predominant
-positive lympho plasmacytoid cells. ⫺: absent, ⫹:
mild, ⫹⫹ : moderate, ⫹⫹⫹ : diffuse.
A, available; NA, not available; GBM, glomerular basement membrane.
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Received: July 19, 2010 Accepted: May 27, 2011
The first two authors contributed equally to the work.
Published online ahead of print. Publication date available at
www.cjasn.org.
2174 Clinical Journal of the American Society of Nephrology
