IgA Nephropathy - «Maladie de Berger»

Transcription

1 IgA Nephropathy - «Maladie de Berger» B. Vogt, Division de Néphrologie/Consultation d Hypertension CHUV, Lausanne 2011 Montreux CME SGN-SSN

2 IgA Nephropathy 1. Introduction 2. Etiology and Pathogenesis 3. Epidemiology 4. Clinical Manifestations of IgA Nephropathy and of Schoenlein-Henoch Purpura 5. Natural History 6. Transplantation 7. Treatment

3 Néphropathie à IgA IgA nephropathy GN à dépôts mésangiaux d IgA Maladie de Berger Les dépôts intercapillaire d IgA-IgG. Par J. Berger et N. Hinglais. J Urol Nephrol (Paris) 74: , 1968 Purpura rhumatoide de Schönlein-Henoch

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6 JEAN BERGER Les dépôts intercapillaire d IgA-IgG Par MM. J. Berger et N. Hinglais J. Urol. Nephrol. (Paris) 74: , 1968 Résumé

7 Renée Habib ( )

8 IgA Nephropathy IgA nephropathy is a mesangial proliferative glomerulonephritis characterized by diffuse mesangial deposition of IgA. IgA is unique among glomerular diseases in being defined by the presence of an immune reactant rather than by any other morphological feature found on renal biopsy, and the light microscopic changes are variable.

9 A classification of disorders associated with glomerular IgA deposits Primary : - IgA Nephropathy (Berger s disease) Multi-system : - Schoenlein-Henoch purpura (children and adults) -> drug side effect in adults Secondary : - Coeliac disease - Crohn s disease - Dermatitis herpetiformis - Chronic liver disease - Seronegative spondylarthropathies - Psoriasis - Sicca syndrome, etc. Glassock et al. 1995

10 Henoch-Schoenlein Purpura Schoenlein-Henoch Purpura Schoenlein 1837 Henoch 1874 Schoenlein-Henoch purpura is a small-vessel vasculitis affecting the skin, joints, gut, and kidneys. Affects predominantly children, usually mild disease, and can occurs in adults as life threatening vascultis. Histology: mesangial IgA deposition

11 Schoenlein-Henoch Purpura Complication of therapy with a non-steroidal antiinflammatory drug

12 Schoenlein-Henoch Purpura

13 Schoenlein-Henoch Purpura Complication of therapy with allopurinol

14 Schoenlein-Henoch Purpura with vasculitis of the gut Complication of antibiotic therapy

15 IgA Nephropathy 1. Introduction and Definition, Pathology 2. Etiology and Pathogenesis 3. Epidemiology 4. Clinical Manifestations of IgA Nephropathy and of Schoenlein-Henoch Purpura 5. Natural History 6. Transplantation 7. Treatment

16 Human IgA Systems MUCOSAL Secretory component SYSTEMIC T cells T cells IgA IgA IgA1 = IgA2 BLOOD 95% IgA1 IgA1 >> IgA2 J. Feehally

17 IgA nephropathy MUCOSAL Secretory component SYSTEMIC T cells T cells IgA IgA IgA1 = IgA2 Poorly galactosylated IgA1 O-glycoforms BLOOD 95% IgA1 IgA1 >> IgA2 Anti-IgA IgG auto-antibodies J. Feehally

18 Human IgA subclasses Hinge region IgA1 IgA2 J. Feehally

19 Human IgA subclasses A plausible site for a pathogenic abnormality Hinge region Hinge has unusual O-glycosylation IgA1 J. Feehally

20 Potential diagnostic tests for IgA Nephropathy in the future Measurements of serum levels of: - Poorly galactosylated IgA1 O-glycoforms - Anti-IgA1 IgG auto-antibodies - Susceptibility loci: - MHC on chromosome 6p21 - complement factor H locus on chromosome 1q32 - cluster of genes on chromosome 22q22

21 IgA Nephropathy 1. Introduction and Definition, Pathology 2. Etiology and Pathogenesis 3. Epidemiology 4. Clinical Manifestations of IgA Nephropathy and of Schoenlein-Henoch Purpura 5. Natural History 6. Transplantation 7. Treatment

22 IgA nephropathy is the most prevalent pattern of glomerular disease seen in most Western and Asian countries where renal biopsy is widely practiced.

23 15-21% 4.7% <5% J. Feehally

24 15-21% North Italian kindreds 4.7% <5% Kentucky kindreds J. Feehally

25 IgA Nephropathy 1. Introduction and Definition, Pathology 2. Etiology and Pathogenesis 3. Epidemiology 4. Clinical Manifestations of IgA Nephropathy and of Schoenlein-Henoch Purpura 5. Natural History 6. Transplantation 7. Treatment

26 IgA nephropathy can have different clinical presentations influencing treatment decisions Microscopic haematuria Macroscopic haematuria Acute renal failure Crescentic IgA nephropathy Proteinuria > 1g/day Nephrotic syndrome Progressive renal insufficiency

27 RENAL BIOPSY LM IF The renal biopsy gives the precise histologic diagnosis of renal disease! EM

28 IgA Nephropathy 1. Introduction and Definition, Pathology 2. Etiology and Pathogenesis 3. Epidemiology 4. Clinical Manifestations of IgA Nephropathy and of Schoenlein-Henoch Purpura 5. Natural History 6. Transplantation 7. Treatment

29 NATURAL HISTORY OF IgA NEPHROPATHY By 20 years, 25% of patients will have end-stage renal disease, and 20% will have progressive impairment of renal function. The risk of renal failre is not uniform. As in any chronic gomerular disease, the presence of hypertension, proteinuria, and renal impairment at presentation, as well as histologic evidence of glumerular and interstitial fibrosis, identifies at the time of diagnosis those with a poor prognosis. Crescentic IgA nephropathy has very poor renal prognosis.

30 LEAD TIME BIAS IN DIAGNOSIS OF IgA NEPHROPATHY Geddes CC et al. NDT 2003; 18: 1541

31 NATURAL HISTORY OF SCHOENLEIN- HENOCH PURPURA Observations are restricted to those referred to renal biopsy. Children: majority of patients have minor transient renal involvement and have excellent prognosis. Adults: Renal prognosis is not so good. 40% of patients will have chronic renal failure or ESRD 15y after diagnosis. Prognosis depends on early diagnosis and treatment.

32 IgA NEPHROPATHY PROGNOSTIC MARKERS AT PRESENTATION CLINICAL POOR PROGNOSIS Increasing age Duration of preceding symptoms Severity of proteinuria Hypertension HISTOPATHOLOGICAL POOR PROGNOSIS Glomerular sclerosis Tubular atrophy Interstitial fibrosis Vascular wall thickening Renal impairment Capillary wall IgA deposits [?] GOOD PROGNOSIS Recurrent macroscopic haematuria NO IMPACT ON PROGNOSIS Gender Serum IgA level NO IMPACT ON PROGNOSIS Intensity of IgA deposits J. Feehally, 2010

33 The Oxford Classification of IgA nephropathy KEY FEATURES IgA HISTOLOGY FEATURE Mesangial hypercellularity Present in 50% of the glomeruli Present in >50% of the glomeruli Segmental glomerulosclerosis Absent Present Endocapillary hypercellularity Absent Present Tubular atrophy/interstitial fibrosis CLASSIFICATION M0 M1 S0 S1 E0 E1 0-25% of cortical area T % of cortical area T1 >50% of cortical area T Kidney Int 76;

34 IgA Nephropathy 1. Introduction and Definition, Pathology 2. Etiology and Pathogenesis 3. Epidemiology 4. Clinical Manifestations of IgA Nephropathy and of Schoenlein-Henoch Purpura 5. Natural History 6. Transplantation 7. Treatment

35 RECURRENT IgA NEPHROPATHY Pooled published data 5 year follow up Recurrence 38-61% Graft dysfunction due to recurrence 15% Graft loss due to recurrence 7%

36 Proportion with a Surviving Allograft GRAFT LOSS DUE TO RECURRENT GLOMERULONEPHRITIS ANZDATA (Slide from J. Feehally) Number at Risk Pauci-immune crescentic GN IgA Nephropathy Membranous Nephropathy FSGS MCGN type Years after Transplantation

37 RECURRENT IgA NEPHROPATHY Retrospective study from Birmingham, Alabama 152 patients transplanted for IgAN in cyclosporin era + Azathioprine [61] or Mycophenolate [91] IgAN recurrence rate not different: Aza 10% vs MMF 8% Graft survival with recurrence not different Switching azathioprine to mycophenolate had no effect Chandrakantan A et al. NDT 2005; 20: 1214

38 IgA Nephropathy 1. Introduction and Definition, Pathology 2. Etiology and Pathogenesis 3. Epidemiology 4. Clinical Manifestations of IgA Nephropathy and of Schoenlein-Henoch Purpura 5. Natural History 6. Transplantation 7. Treatment

39 TREATMENT OF GLOMERULONEPHRITIS Non-Immunological TREATMENT Immunological TREATMENT

40 Treatment of IgA Nephropathy Most IgA nephropathies goes unnoticed, is very benign, and does not need treatment. Proteinuria, hypertension, and GFR are key determinants of the type of treatment.

41 Treatment of glomerulonephritis 1. Nephropathy: diagnosis and therapy 2. Control blood pressure: < 125/85 mm Hg 3. Target proteinuria: < 0.3 g/24 h 4. Control renal anemia: Hb (13) g/dl 5. Control Ph x Ca, ipth, consider bicarbonate 6. Control lipids, control HbA1c in diabetes: < Stop smoking 8. Decrease salt intake, exercise and weight loss if indicated Perico N. et al., KI 2005;68:S95, modified

42 Specific Non-Immunological TREATMENT Fish oil : randomized controlled trial over 2 y offers renal protection but does not lower proteinuria. Donadio JV et al NEJM 331;1194 Other studies negative. Tonsillectomy : Prospective randomized study in Japan ongoing Diet : No evidence for beneficial effect of gluten free diet

43 Treatment of biopsy proven, primary IgA Nephropathy LOW RISK Minor urinary abnormalities, GFR normal, no hypertension MODERATE TO HIGH RISK Proteinuria > g/d and/or GFR reduced and/or hypertension ACUTE OR RAPID GFR LOSS Nephrotic syndrome or RPGN J Am Soc Nephrol 22: , 2011

44 Treatment of biopsy proven, primary IgA Nephropathy LOW RISK minor urinary abnormalities, GFR normal, no hypertension -> Monitor annually or 6-monthly for at least 10 years

45 Treatment of biopsy proven, primary IgA Nephropathy MODERATE TO HIGH RISK If proteinuria > g/d and/or GFR reduced and/or hypertension -> First optimize supportive therapy If proteinuria >0.5 1 g/day GFR normal or slowly, but > ml/min -> Continue supportive therapy for at least 3 6 months -> Continue supportive therapy alone, if proteinuria < 1g/day and GFR decline < 30%/6 months (?) -> Add corticosteroid, if proteinuria > 1g/day or progressive GFR-loss despite blood pressure control

46 Treatment of biopsy proven, primary IgA Nephropathy MODERATE TO HIGH RISK If GFR < ml/min: -> Add corticosteroid, if proteinuria > 1g/day or progressive GFR loss despite blood pressure control

47 Treatment of biopsy proven, primary IgA Nephropathy ACUTE OR RAPID GFR LOSS Exclude acute kidney injury (AKI) due to macro-haematuria or other common cause -> if the case: Supportive therapy If presence of nephrotic syndrome or RPGN -> Add immunosuppression

48 Immunological TREATMENT - Steroids, steroids, steroids??? - Azathioprine - Mycophenlate mofetil - Cyclosporine - Cyclophosphamide - Rituximab, etc.

49 Corticosteroid treatment in IgA nephropathy Randomized controlled trial N = 86 Creatinine < 133 M proteinuria 1-3.5g/24h Regimen Methylprednisolone 1g iv x3 at 1,3,5 months plus Prednisolone 0.5 mg/kg/alt days for 6 months No important side effects no study drop outs (???) Pozzi C et al Lancet 1999;353:883 JASN 2004;15:157

50 Corticosteroid treatment in IgA nephropathy After 5 years follow-up: primary end-point: 50% increase in creatinine Steroid group: 9 of 43 patients Control group: 14 of 43 patients Proteinuria: decreased only in steroid group: from 1.9 to 0.7 g/24h Folluw-up 5 years: same tendency for renal survival Pozzi C et al Lancet 1999;353:883 JASN 2004;15:157

51 Survival without endpoint Corticosteroid treatment in IgA nephropathy 50% creatinine increase years Patients at risk Steroids Control Pozzi C et al Lancet 1999;353:883 JASN 2004;15:157

52 Addition of Azathioprine to Corticosteroids Does Not Benefit Patients with IgA Nephropathy C Pozzi, S Andrulli, A Pani, P Scaini, L Del Vecchio, G Fogazzi, B Vogt, V De Cristofaro, L Allegri, L Cirami, A Deni Procaccini, and F Locatelli J Am Soc Nephrol 21: , 2010 N=207, 5-year follow-up Primary endpoint: 50% increase in plasma creatinine levels from baseline Steroids vs steroids + AZA: 12.9% vs 11.3%, p=ns In patients with IgAN, six months treatment with azathioprine does not increase the benefit of treatment with steroids alone, but does increase the occurence of adverse events.

53 Immunologic treatment of IgA nephropathy Proteinuria > 1 g/day hypertension ACE or ARB If BP < 125/75 and persistent proteinuria of >1g/day after 3-6 months of RAAS blockade: -> Discuss steroids according to Pozzi C., et al. Lancet 1999

54 Immunologic treatment of IgA nephropathy Proteinuria > 1 g/day hypertension ACE or ARB If BP < 125/75 and persistent proteinuria of >1g/day after 3-6 months of RAAS blockade: -> Discuss steroids according to Pozzi C., et al. Lancet 1999 If aggressive form of IgA nephropathy / vasculitis steroides + cyclophosphamide 3 months followed by AZA and steroids (PDN 10mg) 2 years

55 Immunosuppressive treatment in IgA nephropathy with crescenting glomerulonephritis N = 38 Randomized controlled trial Creatinine M ESRD predicted in 5 years Regimen at least 2 years Prednisolone 40 mg/day tapering to 10 mg/day Plus Cyclophosphamide 1.5 mg/kg/day for 3 months Followed by Azathioprine 1.5 mg/kg/day Versus control : supportive therapy Ballardie & Roberts JASN 2002; 13:142

56 CONTROLLED PROSPECTIVE TRIAL OF STEROIDS AND CYTOTOXICS IN PROGRESSIVE IgA NEPHROPATHY % Kidney Survival Treatment N=19 Control N=19 Years Ballardie & Roberts JASN 2002; 13: 142

57 KEY POINTS IgA Nephropathy (1) - IgA nephropathy is a chronic/acute kidney disease defined by deposition of IgA in the glomeruli. - An abnormality in the glycosylation of the hinge region of the IgA1 isotype of IgA is fundamental to the origins of this very common form of glomerulonephritis.

58 KEY POINTS IgA Nephropathy (2) - Incomplete understanding of the pathogenesis of IgA nephropathy has hampered development of targeted therapies - Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers slows progression of IgA nephropathy to end-stage renal disease - No immunosuppressive treatment can be unequivocally recommended until large randomized, controlled trials are performed

59 IgA nephropathy maladie de Berger Current Therapy for IgA Nephropathy J Floege, and F Eitner. J Am Soc Nephrol 22: , 2011 The Pathophysiology of IgA Nephropathy H Suzuki, et al. (B. Julien group) J Am Soc Nephrol 22: , 2011