From MPGN to C3G. F Fakhouri, Nantes, France. «Membranoproliferative» is a pathological feature. Mesangial expansion «Doubles contours»

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1 From MPGN to C3G F Fakhouri, Nantes, France Conflits d intérêt: consultant auprès d Alexion Pharmaceuticals «Membranoproliferative» is a pathological feature Mesangial expansion «Doubles contours» Immune deposits 1

2 MPGN : classification MPGN I MPGN : classification MPGN II/DDD 2

3 MPGN : classification MPGN II/DDD MPGN : classification MPGN II/DDD C3 C9 3

4 MPGN : classification MPGN III MPGN : classification Secondary MPGN SLE HCV/Cryoglobulinemia TMA Chronic infections MPGN secondary to monoclonal gammapathy 4

5 Some MPGN do not have a «MPGN» pattern n=32 DDD cases MPGN 44% Mesangial GN 28% EndoC Proliferation 19% Crescentic GN 9% Nasr S, CJASN 2009 Is it «DDD versus the rest of MPGN»? n=27 DDD cases Outcome of DDD patients n=27 Mean followup: 5 years Complete response to TRT CKD ESRD Death 26% 48% 25% 11% Nasr S, CJASN

6 Do MPGN types differ? A Servais, VFB KI 2012 Do MPGN types differ? A Servais, VFB KI

7 Do MPGN types differ? A Servais, VFB KI

8 Is it «DDD versus the rest of MPGN»? Severity of primary MPGN, rather than MPGN type, determines renal survival and posttransplantation recurrence risk. Little MA, KI 2006 Isolated C3 deposits glomerulonephritis: a new entity. 8

9 Reclassifying MPGN: a mission impossible? MPGN I DDD C3GN IF C3 deposits Ig deposits EM Dense deposits + Reclassifying MPGN: a mission impossible? MPGN I DDD C3GN IF C3 deposits Ig deposits EM Dense deposits + 9

10 Reclassifying MPGN: a mission impossible? IF MPGN I DDD C3GN C3 deposits

11 Is C3 the culprit in MPGN? Uncontrolled C3 activation causes MPGN in mice deficient in FH. M Pickering, Nat Genet

12 Is C3 the culprit in MPGN? Noris, NEJM, How does a C3GN occur? C3 C3a FH 12

13 1 How does a C3GN occur? C3 C3a Intense classical pathway activation FH C3a 1 How does a C3GN occur? C3 FH 13

14 C3a 1 How does a C3GN occur? C3 FH 2 C3f FI i C3a 1 How does a C3GN occur? C3 FH C3f FI 2 i MCP CR1 Podocyte 14

15 C3a 1 How does a C3GN occur? C3 FH 2 3 C3f FI FI i i C3d C3a 1 How does a C3GN occur? C3 FH 2 3 C3f FI i Podocyte CR1 FI i C3d 15

16 C3a 1 How does a C3GN resolve? C3 FH Podocyte i C3d C3a 1 How does a C3GN resolve? C3 FI 2 Podocyte i C3d 16

17 C3a 1 How does a C3GN resolve? C3 FH 2 Podocyte C3d i C3a 1 How does a C3GN resolve? C3 FH 2 3 Podocyte C3d 17

18 C3a 1 How does a C3GN resolve? C3 FH 2 C3d 3 Podocyte C3a 1 How does a C3GN resolve? C3 FH 2 3 Podocyte 18

19 Complementdysregulation associated nephropathies Complementdysregulation associated nephropathies ahus C3 Glomerulopathy F Fakhouri Nature Rev Nephrology,

20 Complementdysregulation associated nephropathies ahus C3 Glomerulopathy DDD C3G F Fakhouri Nature Rev Nephrology, 201 Complementdysregulation associated nephropathies ahus C3 Glomerulopathy MPGN pattern DDD C3G F Fakhouri Nature Rev Nephrology,

21 Complementdysregulation associated nephropathies ahus C3 Glomerulopathy MPGN pattern C3G DDD Primary MPGN I Secondary MPGN F Fakhouri Nature Rev Nephrology, 201 Identification of a mutation in CFHRP5 in patients of Cypriot origin with GNitis. Gale D, de Jorge EG, Cook HT, Pickering MP, Lancet

22 Identification of a mutation in CFHRP5 in patients of Cypriot origin with GNitis. Gale D, de Jorge EG, Cook HT, Pickering MP, Lancet 2010 C3 DD Identification of a mutation in CFHRP5 in patients of Cypriot origin with GNitis. Gale D, de Jorge EG, Cook HT, Pickering MP, Lancet 2010 C3 DD Primary C3GN: a new entity which shares common genetic risk factors with HUS. A. Servais, F Fakhouri J Med Genet

23 Do MPGN types differ? AS, VFB KI 2012 Do MPGN types differ? AS, VFB KI

24 Do MPGN types differ? C3Nef Proliferative GNitis secondary to dysfunction of the alternative pathway of complement. 5 cases MPGN/C3GN Decreased AP functional assay C3Nef Increased soluble MAC H402 CFH atrisk allele CFH mutation AntiFH Ab 4/5 2/5 5/5 5/5 1/5 1/5 Sethi S, CJASN

25 Reclassifying MPGN: a mission impossible? IF MPGN I DDD C3GN C3 deposits

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27 10/23 patients had different IF patterns on repeat kidney biopsy 27

28 Conventional treatment of MPGN/C3G All patient MMF group RTX group CS group N=30 N=10 N=9 N=11 Response at 6 months n (%) 17/29 (59%) 6/10 (60%) 6/9 (66%) 5/10 (50%) Partial (n) 13 (45%) Complete (n) 4 (14%) Response at 12 months n (%) 18/28 (64%) 6/10 (60%) 6/8 (75%) 6/10 (60%) Partial(n) 12 (43%) Complete(n) 6 (21%) Response at last followup n (%) 14/30 (47%) 6/10 (60%) 4/9(44%) 4/11 (36%) Partial (n) 7 (23%) Sophie Chauvet, HEGP, Paris Complete(n) 7 (23%) Conventional treatment of MPGN/C3G Sophie Chauvet, HEGP, Paris 28

29 Eculizumab 29

30 6/10 improved 30

31 Three concepts 1. «MPGN» is a pathological feature «C3GN» relates to pathogenesis 2. Treatment of C3G should target AP dysregulation. 3. Eculzimaub and consort are promising therapies Anti C3/ Ab Eculizumab FH FH/CR1 31

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