IgA nephropathy: unusual forms

Transcription

1 IgA nephropathy: unusual forms Khalil EL KAROUI Service de néphrologie et transplantation rénale, INSERM U1151 Hôpital Henri Mondor, Créteil Actualités Néphrologiques J. Hamburger 23 Avril 2018

2 Introduction: IgA nephropathy «The most frequent primary glomerulonephritis» IgA + C3+ Mesangial proliferation: Until 1,6% of preimplantory biopsies in Japan Suzuki, KI, 2003

3 Several unusual forms! Clinical presentation Rapidly progressive GN, malignant hypertension/hypertensive emergency Histology Monotypic IgA deposits Associated diseases Inflammatory bowel diseases, Infections (staphylococcal) Unusual IgAN or other glomerulopathy?

4 Unusual clinical presentation: rapidly progressive GN

5 IgAN: Risk of evolutivity Very Low / Very High Very low risk No proteinuria, No HBP, no severe histological lesions: No disease? ESRD (10 y): 1% Annual Follow-up Berthoux, JASN, 2011 Very high risk of evolutivity Rapidly progressive glomerulonephritis >50%cellular+fibrocellular crescents ESRD (1y): 43%! Lv, JASN, 2013 KDIGO, 2012

6 Crescents/Necrosis and prognosis Crescents/Necrosis: up to 30% patients! But usually low proportion of glomeruli Crescents N (%) St Etienne + Necker Cohort <10% 892 (92%) 10-25% 43 (4%) 25-50% 19 (2%) >50% 10 (1%) <10% 10-25% 25-50% >50% P<0,001 Alamartine, personnal data Japanese Study, 702 patients deleterious role of crescents if inclusion of <30ml/mn or rapidly progressive Cut off: 6,8% Katafuchi, cjasn 2011

7 Crescents/Necrosis and prognosis 3096 patients, 4 cohorts, «Cellular or fibrocellular» Low rate Haas, JASN 2016

8 Rapidly progressive GN Few studies 113 chinese patients, 8 centers (Discovery + validation cohort) 66% crescent (cellular, fibrocellular, fibrous) Acute renal failure, proteinuria Lv, JASN, 2013

9 Rapidly progressive GN: pathology Severe pathology Acute/fibrous lesions Glomerular AND interstitial lesions Lv, JASN, 2013

10 Rapidly progressive GN: Treatment Follow-up 22m Treatment: steroids +/- immunosuppressive (mainly CYC) ESRD last FU 56% Lv, JASN, 2013

11 Rapidly progressive GN: Prognosis Similar prognosis than AASV? Lv, JASN, 2013

12 Unusual clinical presentation: hypertensive emergency

13 Malignant Hypertension/Hypertensive emergency Malignant hypertension: Definition? ( Malignant? OPH examination?) Severe BP elevation (180/120mmHg) with involvement of 3 targets organs (eye, kidney, heart, brain, microangiopathy) «Multi-organ damage» «Hypertensive emergency» Morbidity: 5y ESRD 25% (to 84%?!) Mortality: 5y: 15% Biological thrombotic microangiopathy during HE: 30% Shantsila, Am J Hypert, 2017 Cremer, J Hum Hypert, 2015 Amraoui, BMC nephrol, 2012 Gonzalez, NDT, 2010 Mancia, ESH/ESC guidelines, J Hypert, 2013

14 IgAN-Hypertensive emergency 45 chinese patients, , IgAN + MHT (BP and hypertensive retinopathy), 26 primary MHT, no IgAN control cohort 1,2% of IgAN Renal failure, Severe proteinuria, haematuria. Prognosis vs IgAN without MHT?? ESRD: 12% (3y) (?) Chen, KBPR, 2005

15 IgAN-Hypertensive emergency 45 chinese patients, , IgAN + MHT (BP and hypertensive retinopathy), 41 non-mht IgAN 19 primary MHT First manifestation of IgAN 62% Renal failure, Severe proteinuria, haematuria. Frequency?? Prognosis?? No specific associated histological lesions Jiang, NDT, 2008

16 IgAN-Hypertensive emergency El Karoui, Hill.. Nochy, JASN, 2012 French cohort, , 128 IgAN patients, 18 MHT (14%) FU 44mths Low egfr, and high proteinuria, biol thrombotic microangiopathy (27%) 99% RAS blockade, no steroids No C rare variant (n=11) 58% immediate RRT, 82% RRT/doubling screat last follow-up

17 IgAN-Hypertensive emergency: histology El Karoui, Hill, Nochy, JASN, 2012

18 But unusual cohort! El Karoui, Hill,.. Nochy, JASN, 2012

19 Prognosis Prognostic effect: egfr, biological TMA, +/- chronic histological lesions No effect of BP per se

20 IgAN-Hypertensive emergency: pathophysiology? Histological TMA may precede hypertension development No C rare variant in the french cohort (n=11) DelCFHR3-1 associates with IgAN protection (GWAS) Decreased Factor H activity and elevated FHR1/FH ratio in «progressive IgAN»? (but what is progressive IgAN? Large overlap ) malignant hypertension? IgAN-TMA Tortajada, Kidney Int, 2017 Medjerak-Thomas, Kidney Int, 2017

21 Unusual histology: monotypic IgA deposits

22 Monotypic IgA deposits Very rare published cases Mainly: heavy chain deposition disease (HCDD) alpha IgA-proliferative GN with Monoclonal Ig Deposits (IgA-PGNMID)? Boumedienne, NDT, 2011 Alexander, AJKD, 2011 Soares, AJKD, 2006 Setoguchi, Nephrology, 2014 Birchmore, Arth Rheum, 1996 Van Ginneken, Clin Nephrol, 1999 Dosa, Nephron, 1980 Monotypic IgA deposits: 6 of 65 IgAN cases (9%)? Lambda predominance in IgAN No difference in presentation and prognosis vs IgAN? Nagae, Clin Exp Nephrol, 2016

23 Monoclonal gammathy of renal significance Monotypic Ig deposits - Organized: fibrillar (amyloidosis++), microtubular (cryo, immunotactoid) - Non-organized : LHCDD (atteinte tubulaire), PGNMID (IgG) Nasr, JASN 2009 Guiard, cjasn 2011 Fermand, Blood 2013 Bridoux, KI 2015

24 Monotypic IgA deposits 19 patients, french centers + National reference center retrospective analysis Vignon, Kidney Int 2017

25 Monotypic IgA deposits: Histology Histological classification miga-gn n=14 MembranoProliferative GN: n=6 Mesangial GN: n=7 Membranous Nephropathy: n=1 Alpha-HCDD: n=5 Immunofluorescence Kappa n=7 Lambda n=7 Truncated alpha chain: n=5 (HCDD) Electronic microscopy N=11 Non-organized deposits n=10; paracristalline deposits n=1 (cryo?)

26 Histology: GN-mIgA Mesangial Membrano proliferative alpha lambda kappa Vignon, Kidney Int 2017

27 Eclectron microscopy IgA-PGNMID Alpha-HCDD Vignon, Kidney Int 2017

28 Haematological explorations in patients with GN-mIgA (n=14) Multiple myeloma n=1 (IgA kappa n=1) - Anemia and bone lytic lesion - BM: 12% plasma cells - IgA kappa = 18g/L Absence of monoclonal Ig n=9 - Negative serum and urine immunofixation - Normal serum free light chain - Normal BM exploration BUT - 2/2: positive immunoblot - 2/2: positive molecular analysis on BM n=9 n=1 n=4 Circulating mig n = 4 - positive serum immunofixation n=4/4 - Positive urine immunofixation n=3/4 - Monoclonal component 0,5-8g/L - Normal serum FLC - BM infiltration < 10% plasma cells Underlying clonal plasma cells Vignon, Kidney Int 2017

29 IgAN polytypic vs monotypic IgA deposits 25% miga cases: Initial diagnosis: IgA nephropathy monotypic n=19 polytypic n=49 p Age < Sex (H/F) 9/9 34/15 ns HBP (%) ns egfr (MDRD, ml/mn/1,73m 2 ) Proteinuria (g/g) Gammaglobulin (g/l) Albumin (g/l) Gamma/Albu (%)

30 IgA-PGNMID: Treatment No specific treatment n=4 ESRD n=1 Immunomodulatory treatment RAS blockade n=14 Chemotherapy regimen Steroid alone n = 3 Steroid + CYC n=3 Rituximab n=2 (2 nd line) Alkylating based n=2 Bortezomib based n=3 (3rd line n=2) Imid based n=1 Haematological response not evaluable Haematological response - VGPR n=4 - Not evaluable n=2 Major renal response n =1 RF stabilization n =3 RF degradation* n=2 ESRD n=1 *recurrence on renal transplant n=1 RF degradation n=2, ESRD n=1 Major Renal Response** n =6 ** Disapearance of renal deposits on repeat kidney biopsy n=1/1

31 Monotypic IgA deposits This is not an IgAN? Older patients Low egfr, High Proteinuria, Hypogammaglobulinemia Atypical histology Vignon, Kidney Int 2017 Alexander, AJKD, 2011 Setoguchi, Nephrology, 2014 But typical MGRS! Plasma cell disease, low tumoral proliferation, with renal expression (MGRS) Steroids, alkylating agents, bortezomib if evolutivity Risk of haematological evolutivity (myeloma) IgA Galactosylation abnormalities? Boumedienne, NDT, 2011

32 Unusual association

33 IgAN-associated diseases Cirrhosis Spondylarthropathies Inflammatory bowel diseases IgAN: most frequent GN in IBD «the gut-kidney axis» GWAS: loci associated both with IBD and IgAN Role of pathogens in mice IgAN (BAFF, CD89) LIGHT Tg mice: T cell mediated intestinal inflammation, seric piga elevation, IgA kidney deposits Diet effect on IgAN/ enteric steroids effect (NEFIGAN) Wang, JCI, 2004 Coppo, Pediatr nephrol, 2018 Fellstrom, Lancet, 2017

34 IBD-associated IgAN Hematuria: 50% of 29 UC patients? Wang, JCI, y, renal biopsies, 83 from IBD patients IgAN: 20/83 (24%), 4 IgA-vasculitis Ambrucz, cjasn, 2014

35 IBD-associated IgAN: french cohort Preliminary results 23 patients, 15males, 37y 18 Crohn s disease, 5 Ulcerative colitis IgAN diagnosed after IBD diagnosis Proteinuria 260mg/mmol Hu 52% egfr 70ml/mn/1,73m 2 18 patients: RAS blockade, 11 patients: steroids

36 IBD-associated IgAN: french cohort Preliminary results Comparison with primitive IgAN (124 patients) MICI + (n = 23) MICI (n = 124) AGE 37,9 (13-73) 39 (17-76) SEX HBP 43,5% 41,8% Initial edfg 70,9 (17-123) 66,7 (8-125) Proteinuria J0 (mg/mmol) 260 (12-900) 174 (0-940) Histological severity (MEST >1) 30,4% 54,9% Steroids 47,8% 34,9% FU (months) 60 (2,4-264) 63 (0-156) Final edfg 62,3 (5-150) 63,7 (5-133) Centralized histological evaluation: ongoing Final Protéinuria (mg/mmol) 124 (0-637) 88,16 (0-550) p = 0,56 t-test p = 0,39 X2 p = 1 X2 p = 0,54 t-test p = 0,03 t-test p = 0,03 X2 p = 0,26 X2 p = 0,59 Mann- Withney p = 0,85 t-test p = 0,24 t-test

37 R e n a l s u rv iv a l (% ) No obvious difference in renal survival Propensity score: ongoing IBD-associated IgAN: french cohort Preliminary results: renal survival Ig A N Ig A N - IB D M o n th s

38 Unusual association: IgA-dominant infection related GN

39 IgA-dominant infection related GN 5 diabetic patients, 4males, 65y ONGOING staphylococcal infection (foot ulcer) Nasr, Hum Pathol, 2003 Acute renal failure, hematuria, Proteinuria, Low C3 4/5 RRT (Follow-up 9 months) Histology diabetic nephropathy polynuclear neutrophils endocapillary proliferation, IgA+C3 deposits (mesangial/cap wall/subepithelial: humps)

40 IgA-dominant infection related GN 13 patients among 6334, 50y, 11 males, 5 diabetic, 4 RRT 6 staphyloccocal infection ARF, proteinuria, hematuria, low C3 (n=4/10) Histology diabetic nephropathy (n=3) polynuclear neutrophils endocapillary proliferation, IgA+C3 deposits (mesangial/cap wall/subepithelial: humps) One monotypic kappa?! Not only diabetic Not only staphylococcal infection Haas, Hum Pathol, 2008

41 Infection related GN Among infection related GN in adult >65y Clinico pathologic definition (infection, low C3, histology) 109 patients, 73% males, Diabetes, malignancy 61% Skin infection 28%, no infection 17%! 48% staphyloccocal infection 17% IgA-dominant (16 patients, 11/16 diabetic, 9/16 Staphyloccocal infection) Endocapillary++/mesangial proliferation (neutrophils) Frequent in older patients Specific histopathologic features Nasr, JASN, 2011

42 IgA-dominant infection related GN: Staphylococcal GN Among Saphylococcal GN Kidney biopsy + documented Staphylococcal infection 78 patients, 55y, 78% males, 41% Diabetes ARF, proteinuria, hematuria, Low C3 30% Skin infection (22%), endocarditis (21%) Histology IgA 75%, C3 86%, Crescents 35%; humps only 31%! Endocapillary++/mesangial proliferation (neutrophils) «pauci-immune pattern» 13% Diagnostic pitfall IgANephropathy/IgA vasculitis Statoskar, cjasn, 2015

43 Staphylococcal GN vs IgAN Age overlap Statoskar, cjasn, 2015

44 IgA-dominant infection related GN Infection-related is not post-infectious! Humps are not specific of postinfectious diseases No indication to immunosupressive therapy in ongoing staphylococcal infection! Glassock, AJKD, 2015

45 Conclusion (s) The most frequent GN, but also multiple unusual forms True IgAN with specific features, or other GN? Pathophysiological implications Hypertensive emergency/tma, IBD-associated IgAN Diagnostic pitfalls with therapeutic consequences monotypic IgA deposits, Infection-related GN

46 Thank you for your attention!