Membranous nephropathy and antiPLA2:
an update
16 May 2013
Patrick Peeters, M.D.
Dept Nephrology
Ghent University Hospital
© 2008 Universitair Ziekenhuis Gent
Plan of presentation
Membranous nephropathy MN: what is it?
Epidemiology
Clinical features
Pathogenesis – e.g. antiPLA2R
antiPLA2R usefulness
Treatment
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Case
Male, 56-y
03/2009 nephrotic syndrome with anasarca
03/2009 biopsy: MN
-> 03/2009 Screat 1,1 mg/dl (eGFR 80 ml/min/1,73m²) +
proteinuria 17 g/24h
R/ 6 m wait and see
-> 08/2009 proteinuria 18 g/24h: R/ CellCept because no
spontaneous response
-> 01/2010 Screat 1,2 mg/dl en proteinuria 8 g/24h.
-> 05/2010 proteinuria 13-17 g/24h: R/ CellCept + Medrol
32mg.
-> 07/2010: R/ Switch to Neoral + tapering Medrol: partial
response proteinuria 16 g/24h -> 6 g/24h.
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Case
-> 10/2010 Screat 1,86 mg/dl + proteinuria 6 g/24h: R/
Stop Neoral nephrotoxic + Medrol -> 32mg : Screat down
to 1,19 mg/dl.
-> 02/2011 Screat 1,4 mg/dl + proteinuria 9 g/g creat: R/
Rituximab 1 g x 2.
-> 02/2012 Screat 2 mg/dl (eGFR 35 ml/min/1,73m²) +
proteinuria 9,9 g/g creat with RAAS blockade: start
cyclophosphamide PO + CS
-> 05/2012 antiPLA2R pos
->02/2013 Screat 1.2 mg/dl (eGFR 64) + proteinuria down
to 1.8 g/d gradually
-> antiPLA2R neg
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Epidemiology
Most common cause of nephrotic syndrome in adults:
+/- 25 %
Not common in children
Peak incidence 5th-6th decade
Predominance males 2:1
10-20% of patients have proteinuria < 2 g/day and no
nephritic syndrome (MN frequency is thus likely
underestimated)
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Idiopathic vs. Secundary disease (25%)
Autoimmune disease (SLE 20%, thyroiditis, …)
Malignancies (colon ca, lung ca, …)
Infection (HBV, HCV, …)
Drugs (penicillamine, gold, NSAID, …)
IgG4 related disease
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Cancer-associated MN
Lefaucheur, Kidney Int 2006 (N= 240 patients)
incidence ratio 9.8 (5.5-16.2) men and 12.3 (4.5-26.9) women
48% tumor asymptomatic
Most common malignacies: lung & prostate (GI, CLL)
Risk factors: smoking & older age
Strong relation between reduction of proteinuria and clinical
remission cancer
Bjorneklett Am J Kidney Dis 2007
incidence ratio 2.25
Median time from MN diagnosis to cancer : 60 months
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Clinical features MN
+/- 80% in nephrotic syndrome
Onset NOT associated with prodromal process or
antecedent infections
Normotension at onset in 70%
Hyperlipidemia/hypoalb
Most patients present with normal or slightly decreased
renal function
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Clinical features MN
If occurs, progressive renal failure is mostly indolent
An abrupt change in renal function should prompt
investigation of superimposed incident
Crescentic GN: 1/3 have anti-GBM or/and ANCA
Acute bilateral renal vein thrombosis and hypovolemia; assoc
with sudden macroscopic hematuria and flank pain or may be
insidious
Drugs: NSAID, diuretics, antimicrobials
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Disease course MN
Estimate of renal survival (pooled analysis of n = 1189):
86% in 5y –> 65% in 10y –> 59% in 15y
>25% of patients may have a complete spontaneous
remission of proteinuria over 5 y
In study of 100 untreated patients followed 10 y:
30% had progressive renal impairment after 8 y
Of the 62% who presented with nephrotic proteinuria, 50%
underwent spontaneous remission in 5 y
Schieppati NEJM 1993
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Untreated course MN 1993
10% of non-treated patients
are in complete remission at
12 m -> 16% at 24m -> 22%
at 36 months
Spontaneous remission
may take up to 36-48 m
Schieppati NEJM 1993
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Natural History anno 2010
Retrospective study n= 328
71% with eGFR>60 ml/min/1.73m²
67% on ACEi/ARB
Spontaneous remission in 31.7%
Partial remission PR in 14.7+/-11.4 m of whom 50%
remained in remission
Time to CR: 38+/-25 m (4-120 m)
26% of patients with baseline proteinuria 8-12 g/d and
21% of patients with baseline proteinuria > 12g/d
developed a spontaneous remission
© 2008 Universitair Ziekenhuis Gent
Polanko et al, J Am Soc Nephrol 2010;21:697-704
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Predictors of outcome
Overtly decling GFR
Persistent proteinuria
>8g/d for > 6m assoc with 66% probability of CRI
>6g/d for > 9m assoc with 55% probability of CRI
>4g/d for > 18m assoc with increased risk of CRI
Amount of proteinuria at presentation
Non-nephrotic proteinuria have a better 10-y survival rate
>10 g proteinuria have 60% probability of ESRD at 8 y
Male gender, age > 50 y, poorly controlled AHT, reduced GFR
at onset
Stage III or IV on histology
FSGS superimposed on MN (at 5 y, CRI in 52% of patients with
FSGS + MN vs. 12% MN alone)
Crescents
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Nachman ASN 2012
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Pathogenesis MN
Animal models
Antigen-Antibody immune complex
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From Immune Complex to Nephrotic Syndrome
© 2008 Universitair Ziekenhuis Gent
Cybulsky A V et al. Am J Physiol Renal Physiol
2005;289:F660-F671
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Podocyte antigens
A/Heymann nephritis - megalin: 1959 experimental rat model
B/ Neutral endopeptidase in newborns from neutral
endopeptidase-deficients mothers
C/ Type-M phospholipase A2 receptor Beck NEJM 2009
D/
Alpha-enolase
Superoxide dismutase 2
Aldose reductase
E/ cationic Bovine serum albumin - Debiec NEJM 2011
F/ dsDNA, thyroglobulin, CEA, PSA, HBeAg, Treponema Ag
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In situ
formation of
immune
deposits in
three forms of
membranous
nephropathy.
Ronco
P , and Ziekenhuis
Debiec H
JASN 2010;21:564-569
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Gent
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NEP neutral endopeptidase
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Debiec NEJM 2002
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SOD – aldose reductase
Serum antibodies against cytoplasmic antigens of podocytes are increased in a significant
portion of MN patients.
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CJASN, 2012: 7; pg 1394-1400
SOD – aldose reductase
AR and SOD2 are expressed in renal
biopsies of MN patients.
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Prunotto M et al. JASN 2010;21:507-519
MN due to
cationic
BSA
Debiec NEJM 2011
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Phospholipase A2 receptor as the target antigen
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The Netherlands Journal of Medicine, 2012
Phospholipase A2 receptor as the target antigen
The majority of
antiPLA2R is IgG4
PLA2R is present in
podocytes as detected
by IF on normal human
kidney
Beck NEJM 2009
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The presence of anti-PLA2R antibodies in MN
sera parallels clinical course of disease
Beck
NEJM Ziekenhuis
2009 Gent
© 2008 Universitair
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Serum levels of circulating anti-PLA2r and anti-NEP IgG4.
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CJASN, 2012: 7; pg 1394-1400
Genome-wide association study MN
© 2008 Universitair Ziekenhuis Gent
N Engl J Med 2011;364:616-626
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Genome-wide association study MN
Chromosome 6 containing
HLA-DQA1
Chromosome 2 containing
PLA2R1
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N Engl J Med 2011;364:616-626
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© 2008 Universitair Ziekenhuis Gent
N Engl J Med 2011;364:616-626
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© 2008 Universitair
Gent 2012
The Netherlands
JournalZiekenhuis
of Medicine,
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The Netherlands Journal of Medicine, 2012; 70; 3: 109-113
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The Netherlands Journal of Medicine, 2012; 70; 3: 109-113
Relationship between clinical disease (proteinuria)
and immunological activity (circulating anti-PLA2R)
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Correlation between the anti-PLA2R antibody
level and proteinuria (baseline samples, n = 14).
© 2008 Universitair Ziekenhuis Gent
Hofstra J M et al. CJASN 2011;6:1286-1291
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Anti-PLA2R-autoantibody levels during the
clinical course of 13 anti-PLA2R-positive patients
with remission of proteinuria during follow-up.
© 2008 Universitair Ziekenhuis Gent
Hofstra J M et al. CJASN 2011;6:1286-1291
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Anti-PLA2R ab by ELISA predict long-term outcome
in prevalent population with idiopathic MN
Active disease
Number
Partial remission
Complete remission
P
40
27
23
55 (44–64)
61 (51–72)
58 (45–63)
0.24
Male
30
19
15
0.73
Female
10
8
8
170.8 (39–502)
28.2(13–49)
23.7 (17–30)
<0.001
8(2–27)
51 (18–93)
55 (37–111)
<0.001
DQA1*05:01 (1–2 vs. 0)
34 (84%)
22 (81%)
15 (65%)
0.18
DQB1*02:01 (1–2 vs. 0)
29 (73%)
18 (67%)
13 (57%)
0.45
8.6 (7.1–11.7)
10.6 (6.4–13.1)
6.8 (4.7–9.1)
0.14
7.8 (5.9–12.8)b
1.6 (0.9–2.2)
0.17 (0.10–0.22)
95 (76–121)
102 (72–131)
88 (82–102)
0.26
Treatment before a-PLA2R assay
12 (30%)
12 (44%)
10 (43%)
0.38
ESRD
10 (25%)
0 (0%)
0 (0%)
0.001
DSC
18 (45%)
1 (4%)
1 (4%)
0.0001
Total follow-up (months)
82 (36–149)
92 (60–143)
92 (47–145)
0.83
Follow-up from assay (months)
51 (10–114)
37 (14–52)
25 (8–49)
0.15
Age (years)
A-PLA2R (µ/ml)
A-PLA2R assay from onset (months)
Proteinuria at onset (g/day)
Proteinuria at a-PLA2R assay (g/day)
Creatinine at onset (µmol/l)
© 2008 Universitair Ziekenhuis Gent
Kanigicherla Kidney Int 2013
<0.001
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Longitudinal a-PLA2R levels and proteinuria
plotted over time in two patients
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Kanigicherla Kidney Int 2013
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Survival analysis of time to doubling of Screatinine
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Kanigicherla Kidney Int 2013
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Representative immunoblots
demonstrate four patterns of
response of IgG4 anti-PLA2R
signal at sequential time
points after rituximab
treatment (0 to 30 months; all
patients are missing data from
one or more time points).
© 2008 Universitair Ziekenhuis Gent
Beck L H et al. JASN 2011;22:1543-1550
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Anti-PLA2R (left box plot) declines in advance of a more gradual decline of
proteinuria (right) in those patients who cleared anti-PLA2R.
© 2008 Universitair Ziekenhuis Gent
Beck L H et al. JASN 2011;22:1543-1550
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Correlation between anti-PLA2R antibody levels measured with IIFT (titers: 1/10
to 1/3200) and ELISA (units per milliliter) techniques.
significant correlation (r=0.868, P<0.01)
© 2008 Universitair Ziekenhuis Gent
Hofstra J M et al. JASN 2012;23:1735-1743
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Correlation between anti-PLA2R levels measured with an ELISA
technique and proteinuria in patients of the Dutch cohort.
© 2008 Universitair Ziekenhuis Gent
Hofstra J M et al. JASN 2012;23:1735-174347
Outcome in aPLA2R antibody-positive patients (n=79): outcome in
different tertiles of antibody titer (ELISA)
Outcome
aPLA2R=41–175
U/ml (n=26)
aPLA2R=176–610
U/ml (n=26)
aPLA2R>610 U/ml
(n=27)
P Value
Partial remission
11 (42%)
8 (31%)
11 (41%)
NS
Complete
remission
7 (27%)
9 (35%)
8 (30%)
NS
Renal failure
1 (4%)
3 (12%)
5 (19%)
NS
Persistent
proteinuria
7 (27%)
6 (23%)
3 (11%)
NS
Spontaneous
remissiona
10 (38%)
8 (31%)
1 (4%)
<0.01
© 2008 Universitair Ziekenhuis Gent
Hofstra J M et al. JASN 2012;23:1735-174348
+ antiPLA2R ab
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Treatment
Steroids alone ineffective
MMF alone probably ineffective; moderately effective in
combination with CS
Cyclophosphamide/chlorambucil effective in
combination with CS (Ponticelli regimen)
Cyclosporin/tacrolimus effective, but high relapse rate
Synthetic ACTH probably effective
Rituximab probably effective
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Conclusion - Membranous Nephropathy
Most common cause of NS in nondiabetic adults
Typical histopathology – subepithelial deposits
1/3 spontaneous remission – 1/3 renal decay
Immune deposits in situ directed against endogenous
antigens on podocytes or circulating LMW Ag crossing
BM
Ab against phospholipase A2 PLA2 Receptor in 70% of
idiopathic MN
Correlation with clinical status
– Lower antiPLA2R associated with remission
– Decline predicts clinical response to immunusuppression
– Higher levels predicts greater GFR regression
–
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The future?
Idiopathic …
-> Autoimmune
Anti-phospholipase A2 receptor (70%)
Antigen still unknown or simply inactive (30%)
Secondary (causative antigen still unknown)
Systemic lupus erythematosus
Hepatitis B
Malignancy
Other causes …
Alloimmune
Fetomaternal alloimmunization to neutral endopeptidase
De novo MN post-renal transplantation (?)
MN post-allogeneic stem cell transplantation (?)
Beck Kidney Int 2010
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Anticipated role of antiPLA2R antibody assay
in the diagnosis and
treatment of patients with
nephrotic
syndrome and membranous
nephropathy
© 2008 Universitair Ziekenhuis Gent
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The Netherlands Journal of Medicine, 2012
© 2008 Universitair Ziekenhuis Gent
N Engl J Med 2011;364:616-626
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