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Recurrent Membranous Nephropathy in an Allograft


Caused by IgG3k Targeting the PLA2 Receptor
Hanna Debiec,* Melanie Hanoy, Arnaud Francois,| Dominique Guerrot, Sophie Ferlicot,**
Catherine Johanet, Pierre Aucouturier, Michel Godin, and Pierre Ronco*
*Institut National de la Sant et de la Recherche Mdicale UMR_S 702, Paris, France; Universit Pierre et Marie Curie
Univ-Paris 6, Paris, France; Department of Nephrology, Assistance Publique-Hpitaux de Paris, Tenon Hospital, Paris,
France; Department of Nephrology and |Department of Pathology, Rouen University Hospital, Rouen, France; Institut
National de la Sant et de la Recherche Mdicale U 1096, Rouen, France; **Department of Pathology, Assistance
Publique-Hpitaux de Paris Kremlin-Bictre Hospital, Paris, France; and Department of Immunology, Assistance
Publique-Hpitaux de Paris, and Institut National de la Sant et de la Recherche Mdicale UMR_S 938, Saint-Antoine
Hospital, Paris, France

ABSTRACT
Up to 80% of patients with idiopathic membranous nephropathy have non
complement-xing IgG4 autoantibodies to the phospholipase A2 receptor (PLA2R).
Membranous nephropathy recurs in approximately 40% of patients after kidney
transplantation, but the mechanism is unknown. Here, we describe a patient with
recurrent membranous nephropathy 13 days after kidney transplantation whose
graft biopsy specimen showed granular staining for C3, C5b-9, C1q, and IgG3k;
electron microscopy revealed subepithelial nonorganized deposits. A search for
hematologic disorders was negative. Retrospective evaluation of a biopsy sample
from the native kidney revealed a similar pattern: monotypic IgG3k deposits together with C3, C1q, and C5b-9. Glomerular deposits contained PLA2R in both
the graft and the native kidney, suggesting that the recurrence was the result of
circulating anti-PLA2R antibodies binding to PLA2R antigen expressed on donor
podocytes. Confocal analysis of anti-PLA2R and antihuman IgG3 showed colocalization, and the patient had IgG3k-restricted circulating anti-PLA2R antibodies.
Treatment with rituximab stabilized both proteinuria and serum creatinine, and circulating anti-PLA2R became undetectable. In summary, this case of recurrent membranous nephropathy in a graft suggests that circulating monoclonal anti-PLA2R
IgG3k caused the disease and activated complement by the classic pathway.
J Am Soc Nephrol 23: 19491954, 2012. doi: 10.1681/ASN.2012060577

Membranous nephropathy (MN) is one of


the more common causes of nephrotic
syndrome in the adult population, accounting for about 20% of cases. It can be
idiopathic, without identied cause
(70%80%), or secondary to various
clinical conditions, including infections
(hepatitis B, syphilis), systemic lupus erythematosus, cancers, and drug intoxications.1
MN is an immunologically mediated
disease dened by immune complex deposition in the subepithelial space that
J Am Soc Nephrol 23: 19491954, 2012

causes a membrane-like thickening. The


immune deposits consist of IgG, antigens
that have long eluded identication, and
the membrane attack complex of complement C5b-9. IgG4 is the most prominent deposited subclass in idiopathic
MN, although variable amounts of IgG1
are usually associated; in secondary MN,
IgG1, IgG2, and IgG3 exceed IgG4.2,3 The
formation of subepithelial immune deposits and complement activation are presumably responsible for functional

impairment of the glomerular capillary


wall, causing proteinuria. Evidence now
suggests that MN is triggered by antibodies directed against podocyte proteins.
Two major antigens, both membrane glycoproteins, have been identied. The rst
is neutral endopeptidase, the alloantigen
involved in rare neonatal cases of MN that
occur in newborns from neutral endopeptidasedecient mothers.4 The disease
could be transferred to rabbits injected
with immunoglobulin puried from the
infants mothers serum but not from the
fathers serum.5 The second antigen is the
M-type phospholipase A2 receptor
(PLA2R), the rst antigen identied in idiopathic MN in adults, which is considered
an autoimmune disease.6
Although anti-PLA2R antibodies are
found in about 70% of patients with
idiopathic MN69 and seem to correlate
with disease activity and proteinuria,6,10,11
there is no denitive proof that these

Received June 16, 2012. Accepted September 20,


2012.
Published online ahead of print. Publication date
available at www.jasn.org.
Correspondence: Dr. Pierre Ronco, INSERM Unit
702, Hpital Tenon, 4 rue de la Chine, 75020 Paris,
France. Email: pierreronco@yahoo.fr
Copyright 2012 by the American Society of
Nephrology

ISSN : 1046-6673/2312-1949

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antibodies are pathogenic. First, PLA2Rrelated MN could not be induced by


transfer of patients serum or IgG to
mouse, rat, or rabbit because these species do not express PLA2R antigen in
glomeruli. Second, as yet there is no animal model of PLA2R-related MN that
could phenocopy Heymann nephritis, a
reliable form of MN in the rat in which
the target antigen, megalin, is also located
at the podocyte surface.12,13 Third, antiPLA2R antibodies can occasionally be
found in patients with idiopathic MN
but without PLA2R antigen in subepithelial immune deposits, a nding suggesting that at least some anti-PLA2R
antibodies might not be pathogenic.14
Fourth, although PLA2R-related MN
can recur in the kidney graft, sometimes
after only a few days,1517 some patients
with high-titer anti-PLA2R antibodies at
the time of transplantation will not have
clinical or histologic recurrence.16 In
those cases, however, differences between
donor and recipient PLA2R sequence
variants might account for the lack of
recurrence.
Here we report an exceptional case of
recurrent PLA2R-related MN with monotypic IgG3k deposits and circulating antiPLA2R antibodies restricted to IgG3k,
which provides an argument favoring
the pathogenicity of anti-PLA2R antibodies, at least in this particular situation.
A kidney allograft biopsy was performed 13 days after transplantation
because of delayed graft function (plasma
creatinine, 2.82 mg/dl) and proteinuria
(1.85 g/d) in a 52-year-old man in whom
MN had been diagnosed 13 years earlier
and who has been receiving hemodialysis
for the last 6 years. Pretransplantation
assessment of the glomerulopathy failed
to identify a cause, thereby suggesting
idiopathic MN. The biopsy revealed early
recurrence of MN, characterized by abundant granular deposits of IgG on the outer
aspect of the glomerular basement membrane (Figure 1A). These deposits did not
show any organization by electron microscopy (Figure 1B). We performed a
subclass and light-chain isotype analysis
of deposited IgG, which exclusively
stained for IgG3k (Figure 1C). Biopsy
specimen also contained C3, C1q, and
1950

Figure 1. Characterization of immune deposits in kidney biopsy specimens from grafted


(AD) and native (E) kidneys. (A) Immunouorescence study showing early recurrence of
the MN (day 13) characterized by granular deposits of IgG. (B) Representative segment of
the capillary wall analyzed by electron microscopy. Electron-dense deposits seen on the
outer aspect of the glomerular basement membrane do not show any organization. (C)
Immunostaining for IgG subclasses and light-chain isotypes showing the presence of
monotypic IgG3k. (D) Complement components, including C3, C1q and C5b-9, detected
in the absence of MBL. (E) Kidney biopsy specimen from native kidney stained for IgG3
and light-chain isotype. The specimens shown in E are parafn sections, whereas those
shown in A, C, and D are cryostat sections. Original magnication for A, C, D, and E x400;
for B x40,000.

Journal of the American Society of Nephrology

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C5b-9 in deposits but no mannosebinding lectin (MBL) (Figure 1D). The


positive control for MBL staining is
shown in Supplemental Figure 1.
The nding of monotypic IgG3k deposits prompted an extensive search
for a hematologic disorder. Electrophoresis and immunoxation of serum proteins
did not disclose any qualitative anomaly.
Serum k and l free light-chain levels and
immunoglobulin classes were normal, except for IgG, which was moderately
decreased. Blood lymphocyte immunophenotyping was unremarkable. Positron
emission tomography did not reveal
hyperxation, and the bone marrow biopsy specimen was normal, revealing rare,
polytypic plasma cells.
We then asked whether deposits in
the native kidney biopsy specimen were
also monotypic. The pathologic report
described granular deposits of IgG, C3,
and C1q, but there was no information
on light-chain isotype. Because of the
lack of frozen kidney biopsy specimen,
we developed a new technique to perform subclass and isotype analysis in
parafn-embedded sections. The deposits stained for IgG3 and k but did not
stain for the l isotype (Figure 1E).
PLA2R antigen was detected in a granular pattern typical of subepithelial immune deposits in the native and kidney
graft biopsy specimens (Figure 2, A and B).
Co-localization with IgG3 was established
by confocal microscopy (Figure 2, CF).
Because both the native and kidney
graft biopsy specimens featured monotypic IgG3k deposits in the absence of
IgG4, we reasoned that the circulating
anti-PLA2R antibodies could also be
monotypic. Using the indirect immunouorescence test (Euroimmun AG, Lbeck, Germany), we rst showed that in
patients serum anti-PLA2R antibodies
were present at the time of transplantation
(Figure 3). Next, using subclass- and lightchain isotypespecic revealing antibodies, we found that anti-PLA2R antibodies
were restricted to IgG3k, which is the immunoglobulin isotype detected in glomerular deposits (Figure 2).
On the basis of these ndings, the patient received four injections of rituximab
(375 mg/m2) at 2-week intervals. Six
J Am Soc Nephrol 23: 19491954, 2012

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Figure 2. Detection of PLA2R in glomerular immune deposits. Immunouorescence


analysis of parafn kidney biopsy specimens shows PLA2R in (A) native and (B) grafted
kidney. (CE) Positively stained glomeruli in a biopsy specimen from grafted kidney that has
been double-labeled with anti-PLA2R (C) and anti-human IgG3 antibodies (D); E shows the
merged image of boxed areas in C and D. (F) Quantitative analysis of the uorescence
recorded across sections of a representative capillary loop (arrowheads). Note superimposition of the two signals, which indicates that subepithelial immune deposits are composed of PLA2R (red) and IgG3 (green). Original magnication for A, B, C, D, and E x400.

months later, proteinuria had decreased


dramatically (from 5.1 g/d before rituximab to 0.4 g/d), kidney graft function
had stabilized (serum creatinine, 2.72
mg/dl before rituximab versus 2.56 mg/
dl), and anti-PLA2R antibodies had disappeared (Figure 3).

DISCUSSION

To our knowledge, this is the rst report of


monotypic anti-PLA2R IgG3k associated
with MN, activation of the classic complement pathway, and very early recurrence
of the disease on the kidney graft. The
nding of IgG3k being co-localized with
PLA2R in both the native and the kidney

graft biopsy specimens, and of circulating


anti-PLA2R IgG3k, strongly suggests that
this antibody was responsible for the glomerular disease and its recurrence in this
patient.
Circulating monoclonal immunoglobulin may recognize self-antigens
as shown for IgM anti-IgG in type 2
cryoglobulins, perinuclear ANCA,18,19
and antiglomerular basement membrane antibodies. 20,21 In this patient,
the rate of synthesis of the antibody was
probably low because no monoclonal
component could be detected in the blood,
even by sensitive methods. A similar situation is observed in patients with proliferative GN with monoclonal IgG deposits,
which may also recur in the allograft;
IgG3k Anti-PLA2RRelated MN

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the MBL pathway.27 In addition, MBL was


identied in the glomeruli of patients
with idiopathic MN.3,28 The high C1qbinding ability of IgG3 probably explains
the discrepancy with most common
forms of idiopathic MN, in which IgG4
is the prevailing subclass.
Few reports have described very early
recurrence of PLA2R-related MN, and
all such cases were associated with polyclonal anti-PLA2R antibodies.1517 Recurrence occurred as early as 68 days
after transplantation,16, 17 suggesting that
anti-PLA2R antibodies brought by the recipients serum rapidly induced formation
of subepithelial deposits in the graft glomeruli, thus reproducing the passive Heymann nephritis model.29,30
Because of the monoclonal nature of
the antibody, our observation marks a
further step in the demonstration of
pathogenicity of anti-PLA2R antibodies.

CONCISE METHODS
Patient

Figure 3. Detection and isotyping of circulating anti-PLA2R antibodies in patients serum


using immunouorescence test (Euroimmun). The serum sample after transplantation
before rituximab treatment contains anti-PLA2R antibodies that are restricted to IgG3k.
Neg, negative; Rtx, rituximab; TX, transplantation.

however, no target antigen has yet been


identied in this entity.22,23 It is noteworthy that in the four patients with
recurrence, no serum monoclonal component could be detected at the time of
rst biopsy or at the time of recurrence,
although all four patients featured IgG3
deposits (three k, one l). IgG3 is the isoform identied in most cases of GN with
monoclonal IgG deposits.22,24 This subclass, which accounts for only 2%8% of
serum IgG in normal individuals, is especially prone to self-aggregability via
Fc-Fc interactions.25 In addition, compared with other IgG subclasses, it has a
slightly higher molecular weight, the
greatest complement-xing ability, and
globally more cationic charge, characteristics that may make it intrinsically
nephritogenic. 25,26 Although some
1952

patients with GN with monoclonal IgG


deposits have a history of autoimmune
disease, none had MN. In our patient,
development of MN was probably
caused by the anti-PLA2R activity of
the IgG3, although deposition of antiPLA2R antibody might also be enhanced
by the physicochemical properties of
IgG3.
Our case is unusual among idiopathic
MN cases because of signs of activation of
the classic complement pathway, such as
C1q deposits, associated with C3 and
C5b-9 in both native and graft biopsy
specimens. There was no evidence of lupus
disease. MBL was not found in immune
deposits, suggesting that in this case, the
MBL pathway was probably not activated,
in contrast with recent ndings which
indicate that anti-PLA2R IgG4 can activate

Journal of the American Society of Nephrology

The patient is a 56-year-old man in whom


nephrotic syndrome of rapid onset was diagnosed in 1993. Antinuclear antibodies were
absent, and serum complement C3 and C4
concentrations were normal. Diagnosis of
MN was established on a rst kidney biopsy
specimen. Light-chain isotype was not determined. At that time, no evidence indicated a
secondary cause, although the patient was a
heavy smoker (30 pack-years). His medical
history included childhood asthma, an acute
non-A, non-B, non-C viral hepatitis at age 10
years, and tonsillectomy. Family medical history was unremarkable. Because the serum
creatinine level increased to 1.36 mg/dl in July
1994, the patient was treated with steroids
and cyclophosphamide according to a revised
Ponticelli protocol.31 In May 1995, a second
kidney biopsy showed diffuse interstitial brosis. Immunosuppressive treatment was stopped. The patient was then lost to follow-up
until February 2002, when he was seen with
a major episode of volume expansion and
dilated cardiomyopathy. Hemodialysis was
started. Between 2002 and 2008, no additional
immunologic or hematologic disorder was
diagnosed. The patient received a kidney transplant in February 2008. Anti-HLA antibodies

J Am Soc Nephrol 23: 19491954, 2012

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were negative. Induction was achieved with


anti-IL2 receptor antibodies, and the immunosuppressive regimen included prednisone, tacrolimus, and mycophenolate mofetil. A biopsy of the graft was performed on day 13
because of delayed improvement of renal
function (serum creatinine, 2.71 mg/dl)
and proteinuria (1.85 g/d) in the absence of
urologic complication or off-target tacrolimus
concentrations. The donor presented no signicant medical history and had normal
kidney function and proteinuria. Informed
consent was obtained for further immunopathologic studies.

Analysis of Renal Biopsy Specimen


The patients biopsy specimen was prepared
for light, immunouorescence, and electron
microscopy by standard techniques. For detection of IgG subclasses, light-chain isotypes, and
complement components, cryosections of the
biopsy specimen were incubated with the following antibodies: FITC-conjugated, monoclonal antihuman IgG1 (Sigma-Aldrich), IgG2
(Sigma-Aldrich), IgG3 (Sigma-Aldrich), and
IgG4 (Sigma-Aldrich) antibodies; rabbit polyclonal antihuman k or l light chains (Dako);
antihuman C3 complement (Dako); antihuman C1q complement (Dako); nonconjugated
monoclonal antihuman C5b-9 (Dako);
and antimannan-binding lectin antibody 3B6
(abcam).

Detection of PLA2R Antigen, IgG3,


and Light-Chain Isotypes in ParafnEmbedded Kidney Biopsy
Specimens
PLA2R was assessed in glomerular deposits
by confocal microscopy with rabbit afnity
puried specic anti-PLA2R antibodies (Atlas Antibodies), followed by goat Alexa 488
conjugated antirabbit Fab IgG (Molecular
Probes). Co-localization of PLA2R and IgG3
was analyzed by confocal microscopy. The
biopsy specimens were rst incubated with
anti-PLA2R antibodies, then with goat Alexa
568conjugated antirabbit Fab IgG antibodies (Molecular Probes) and FITC-conjugated
monoclonal antihuman IgG3 from a mouse
(Sigma-Aldrich). Sections were examined
under a confocal microscope (Leica TCS-SP2)
and analyzed with Leica Confocal software, version 2.61. For PLA2R and IgG3 staining, the
antibodies were deposited on deparafnized
sections retrieved by heating in citric acid

J Am Soc Nephrol 23: 19491954, 2012

(pH, 6.0), followed by HistoReveal (abcam)


treatment. For detection of light-chain isotype,
FITC-conjugated rabbit polyclonal antihuman
k or l light-chain antibodies (Dako) were deposited on the deparafnized sections pretreated with HistoReveal (abcam).

Detection and Subclass Analysis of


Circulating Anti-PLA2R Antibodies
Circulating antibodies against PLA2R were
assessed by commercially available indirect
immunouorescence test (Euroimmun). For
detection of IgG subclass-specic antibodies,
FITC-conjugated monoclonal antihuman
IgG1 (Sigma-Aldrich),d IgG2 (SigmaAldrich), IgG3 (Sigma-Aldrich), and IgG4
(Sigma-Aldrich) antibodies from mouse were
used. For detection of light-chain isotypes,
FITC-conjugated rabbit polyclonal antihuman
k or l light chains were used (Dako).

ACKNOWLEDGMENTS
We thank Philippe Fontanges for assistance
with the confocal microscope.
The work was supported by grants from
Fondation pour la Recherche Mdicale (Equipe
FRM 2012) and by grant from Agence Nationale
pour la Recherche (ANR-07-Physio-016-01).

DISCLOSURES
None.

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This article contains supplemental material online


at http://jasn.asnjournals.org/lookup/suppl/doi:10.
1681/ASN.2012060577/-/DCSupplemental.
See related editorial, Monoclonal Anti-PLA2R
and Recurrent Membranous Nephropathy: Another
Piece of the Puzzle, on pages 19111913.

J Am Soc Nephrol 23: 19491954, 2012