ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY John Feehally IgA NEPHROPATHY The commonest pattern of glomerulonephritis in the world CLASSIFICATION OF GLOMERULONEPHRITIS Histopathology Clinical Immune mechanisms CLASSIFICATION OF GLOMERULONEPHRITIS Histopathology Clinical Immune mechanisms Patterns established on light microscopy Membranous Membranoproliferative Focal segmental glomerulosclerosis etc…… CLASSIFICATION OF GLOMERULONEPHRITIS Histopathology Clinical Immune mechanisms Patterns established on light microscopy Membranous Membranoproliferative Focal segmental glomerulosclerosis ‘Patterns’ not ‘diseases’ etc…… IgA1 deposition In the glomerular mesangium IgA NEPHROPATHY ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY Is IgA nephropathy a single ‘disease’ ? IgA NEPHROPATHY A pattern of glomerulonephritis with many variations Recurrent visible haematuria Coincides with mucosal infection Nephrotic syndrome Asymptomatic Haematuria / proteinuria CKD Proteinuria Hypertension Renal impairment HENOCH-SCHȌNLEIN NEPHRITIS Henoch-Schőnlein purpura ‘SECONDARY’ IgA NEPHROPATHY COMMONLY REPORTED ASSOCIATIONS Alcoholic liver disease Celiac disease Ankylosing spondylitis Reiter’s syndrome Uveitis Dermatitis herpetiformis RECURRENT IgA NEPHROPATHY RECURRENT IgA NEPHROPATHY Pooled published data – 5 year follow up Recurrence 38-60% Graft dysfunction due to recurrence Graft loss due to recurrence 15% 7% RECURRENT IgA NEPHROPATHY Pooled published data – 5 year follow up Recurrence 38-60% Graft dysfunction due to recurrence Graft loss due to recurrence 15% 7% Why does IgA nephropathy NOT always recur ? 15-21% 4.7% <5% Percentage of patients with primary glomerular disease 15-21% Male > Female 4.7% <5% Male = Female IgA NEPHROPATHY Variations in: Pathological pattern Clinical pattern Transplant recurrence Epidemiological pattern Pathogenesis IgA NEPHROPATHY No proof that IgAN is a single Not expect ‘disease’ a single pathogenic mechanism to lead to mesangial IgA deposition No proof that IgAN and injuryis the same ‘disease’ in all parts of the world ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY Can you predict which patients with IgA nephropathy will get kidney failure? ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY Can you predict which patients with IgA nephropathy will get kidney failure? CLINICAL evidence PROGNOSIS IN IgA NEPHROPATHY Rodicio 1982 PROGNOSIS IN IgA NEPHROPATHY 20% ESRD @ 20 years Rodicio 1982 IgA NEPHROPATHY IN INDIA CMC Vellore 1994-2003 Chacko B et al. Nephrology 2005; 10: 496 IgA NEPHROPATHY IN INDIA CMC Vellore 1994-2003 478 adults 55% - Nephrotic syndrome at presentation 56% - Serum creatinine > 123 μmol/L at presentation Chacko B et al. Nephrology 2005; 10: 496 MACROSCOPIC HAEMATURIA AND PROGNOSIS IN IgA NEPHROPATHY Beukhof 1983 LEAD TIME BIAS IN DIAGNOSIS OF IgA NEPHROPATHY Geddes CC et al. NDT 2003; 18: 1541 ISOLATED NON-VISIBLE HAEMATURIA IN IgA NEPHROPATHY How benign is it ? Cohort study – Toronto – 286 patients Non-visible haematuria Proteinuria < 0.2 g/24hr plus Normal BP Bartosik et al. AJKD 2001; 38: 728 ISOLATED MICROSCOPIC HAEMATURIA IN IgA NEPHROPATHY How benign is it ? Cohort study – Toronto – 286 patients Microscopic haematuria Proteinuria < 0.2 g/24hr plus Normal BP 10 year risk of deterioration in renal function = ZERO Bartosik et al. AJKD 2001; 38: 728 ISOLATED NON-VISIBLE HAEMATURIA IN IgA NEPHROPATHY How benign is it ? Cohort study – Hong Kong Non-visible haematuria plus Proteinuria < 0.4 g/24hr During 7 years follow up, 44% had a ‘clinical event’ 33% proteinuria 26% hypertension 7% renal impairment Szeto C et al Am J Med 2001; 110:434 OUTCOME AND AVERAGE FOLLOW-UP PROTEINURIA IN IgA NEPHROPATHY REMISSION OF PROTEINURIA IMPROVES PROGNOSIS IN IgA NEPHROPATHY Time-average proteinuria 1 - < 1g/24h 2 – 1-2 g/24h 3 – 2-3g/24h 4 - >3g/24h Reich H et al. JASN 2007; 18: 3177 ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY Can you predict which patients with IgA nephropathy will get kidney failure? PATHOLOGICAL evidence A CLINICO-PATHOLOGICAL CLASSIFICATION FOR IgA NEPHROPATHY Does pathology add prognostic information .. to clinical data at time of biopsy ? .. to clinical data during follow up ? A CLINICO-PATHOLOGICAL CLASSIFICATION FOR IgA NEPHROPATHY Does pathology add prognostic information .. to clinical data at time of biopsy ? Perhaps the biopsy is only useful diagnosis IgAN up ? ? .. to toestablish clinical the data during of follow PATHOLOGICAL CLASSIFICATIONS IN RENAL DISEASE Are usually based on expert opinion ... and pre-conceived ideas of what lesions are important OXFORD CLASSIFICATION OF IgA NEPHROPATHY A different way Approach the problem with an open mind With an international consensus group • Study all histological lesions • Test reproducibility & independence • Then test correlations with outcome SCORING OF SELECTED PATHOLOGY FEATURES Mesangial hypercellularity - in > or <50% of glomeruli M0 or M1 Endocapillary hypercellularity – present/absent E0 or E1 Segmental sclerosis/adhesions – present/absent S0 or S1 Tubular atrophy/interstitial fibrosis – 0-25%, 26-50%, >50% T0 or T1 or T2 Each can be scored easily in routine clinical practice PREDICTIVE SIGNIFICANCE OF PATHOLOGY FEATURES IN IgA NEPHROPATHY MEST Each adds predictive value to …. Initial clinical features Follow up clinical features In all ages and races studied VALIDATION STUDIES FOR THE OXFORD CLASSIFICATION OF IgAN M E S T Macedonia 2010 98 + + + + USA 2011 54 + + - + Japan 2011 161 children + + - + France 2011 183 - + + + USA, Canada 2011 187 adults & children + + + + China 2011 410 - + + + Japan 2011 702 - - + + Sweden 2012 99 + + - + Korea 2012 197 + - + + 6/10 7/10 6/10 10/10 WHAT NEXT ? Validation studies Work towards combining pathology and clinical elements – to produce a single ‘risk score’ There is now the opportunity to design smaller, shorter RCTs ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY How good is the evidence to guide the treatment of IgA nephropathy ? KI Supplements 2012 2(2): 1-274 CLINICAL PRACTICE GUIDELINE FOR GLOMERULONEPHRITIS Examples of Rating Guideline Recommendations QUALITY of Supporting Evidence is shown as A, B, C or D Level 1 Level 2 We recommend…. 1A Most patients should receive the recommended course of action Supported by evidence from high quality RCTs We suggest … 2D Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision appropriate for them No RCTs Supported by limited observational data Examples of Rating Guideline Recommendations QUALITY of Supporting Evidence is shown as A, B, C or D Level 1 We recommend…. 1A Most patients should receive the recommended course of action Supported by evidence from high quality RCTs Of 10 recommendations or suggestions in the IgA Nephropathy guideline Level 2 We suggest … Only 2 (20%) are 1A or2D 1B Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision appropriate for them No RCTs Supported by limited observational data Clinical Practice Guideline for Glomerulonephritis …. will not tell you what to do for every difficult patient in every situation Clinical Practice Guideline for Glomerulonephritis …. will not tell you what to do for every difficult patient in every situation The Guideline is not there to give you expert advice about an individual problem case Clinical Practice Guideline for Glomerulonephritis …. will not tell us what to do for every difficult patient in every situation ….will remind us what we know Clinical Practice Guideline for Glomerulonephritis …. will not tell us what to do for every difficult patient in every situation ….will remind us what we know ….will remind us what we do not know ASSESSMENT AND MANAGEMENT OF IgA NEPHROPATHY “Should I treat this patient with IgA nephropathy ?” TREATMENT DECISIONS IN IgA NEPHROPATHY Non-visible haematuria Visible haematuria Acute kidney injury Crescentic IgA nephropathy Proteinuria > 1g/day Nephrotic syndrome Hypertension Progressive fall in GFR TREATMENT DECISIONS IN IgA NEPHROPATHY Microscopic haematuria Macroscopic haematuria Acute kidney injury Crescentic IgA nephropathy Proteinuria > 1g/day Nephrotic syndrome Hypertension Progressive fall in GFR TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY Recurrent Macroscopic Haematuria No role for antibiotics No role for tonsillectomy TREATMENT DECISIONS IN IgA NEPHROPATHY Microscopic haematuria Macroscopic haematuria Acute kidney injury Proteinuria > 1g/day Nephrotic syndrome Hypertension Progressive renal insufficiency TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY Macroscopic Haematuria with acute renal failure Renal biopsy is mandatory if not improve in 2-3 days with supportive measures AKI WITH VISIBLE HAEMATURIA IN IgA NEPHROPATHY 9 published reports – 84 patients How common ? AKI in 38% (4/11) of visible haematuria episodes (Praga 1985) Much less common in most other reports How important are crescents ? Crescents often seen, but in <20% of glomeruli and usually not the cause of AKI Moreno J et al. CJASN 2012; 7: 175 AKI WITH VISIBLE HAEMATURIA IN IgA NEPHROPATHY 9 published reports – 84 patients Recovery of renal function ? Most reports (29 patients) … 100% have complete recovery of renal function Two reports (55 patients) – only 73% full recovery Moreno J et al. CJASN 2012; 7: 175 AKI WITH VISIBLE HAEMATURIA IN IgA NEPHROPATHY Recovery of renal function ? One centreFull in Spain recov(52 patients) Full recovery less likely: Older age Duration of visible haematuria (mean 15 vs 36 days) Peak sCr (7.1 vs 309 mg/dL) Tubular necrosis Tubular red cell casts Interstitial; fibrosis Moreno J et al. CJASN 2012; 7: 175 TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY Macroscopic Haematuria with acute renal failure Renal biopsy is mandatory if not improve in 2-3 days with supportive measures Acute Tubular Necrosis Crescentic IgA nephropathy Supportive measures only Immunosuppression may be appropriate TREATMENT DECISIONS IN IgA NEPHROPATHY Microscopic haematuria Macroscopic haematuria Acute renal failure Crescentic IgA nephropathy Proteinuria > 1g/day Nephrotic syndrome Hypertension Progressive renal insufficiency CRESCENTIC GLOMERULONEPHRITIS Renal outcome with best known treatment Renal survival 1 year 5 years Systemic vasculitis 80% 75% Goodpasture’s 70% 50% Crescentic IgA nephropathy 50% 20% TREATMENT FOR CRESCENTIC IgA NEPHROPATHY A number of recent optimistic reports Corticosteroids + Cyclophosphamide Small : < 20 patients Selection criteria variable All are anecdotal TREATMENT FOR CRESCENTIC IgA NEPHROPATHY Definition? More than just a few crescents Rapidly progressive renal failure TREATMENT FOR CRESCENTIC IgA NEPHROPATHY Definition? More than just a few crescents Rapidly progressive renal failure Which patients respond ? Treat if crescents + other active glomerular damage AND no chronic or irreversible changes TREATMENT FOR CRESCENTIC IgA NEPHROPATHY If immunosuppression is indicated… INDUCTION: Prednisolone 0.5-1mg/kg/day Cyclophosphamide 2mg/kg/day MAINTENANCE: Prednisolone in reducing dosage Azathioprine 2mg/kg/day [plasma exchange unproven] TREATMENT FOR CRESCENTIC IgA NEPHROPATHY If immunosuppression is indicated… INDUCTION: Prednisolone 0.5-1mg/kg/day Cyclophosphamide 2mg/kg/day MAINTENANCE: Prednisolone in reducing dosage Azathioprine 2mg/kg/day [plasma exchange unproven] An RCT is badly needed …. and will be difficult to achieve TREATMENT DECISIONS IN IgA NEPHROPATHY Microscopic haematuria Macroscopic haematuria Acute renal failure Crescentic IgA nephropathy Proteinuria > 1g/day Nephrotic syndrome Hypertension Progressive renal insufficiency NEPHROTIC-RANGE PROTEINURIA IN IgA NEPHROPATHY IgAN and nephrotic range proteinuria N = 233 More likely to have normoalbuminaemia than minimal change, FSGS, or membranous Nephrotic-range proteinuria and serum albumin > 35 g/l 95.8% specificity for IgAN Chen M et al. NDT 2011; 26: 1247 NEPHROTIC SYNDROME IN IgA NEPHROPATHY n = 100 – mean follow up 45 months Complete remission 48% Partial remission 32% No remission 20% Spontaneous remission 24% PRIMARY END POINT - DOUBLE SERUM CREATININE 24% More likely if partial or no remission Kim J-K et al. CJASN 2012; 7: 247 NEPHROTIC SYNDROME IN IgA NEPHROPATHY n = 100 Mean follow up 45 months p<0.001 Kim J-K et al. CJASN 2012; 7: 247 NEPHROTIC SYNDROME IN IgA NEPHROPATHY 100 885 P<0.001 Kim J-K et al. CJASN 2012; 7: 247 NEPHROTIC SYNDROME + MICROSCOPIC HAEMATURIA NEPHROTIC SYNDROME + MICROSCOPIC HAEMATURIA Corticosteroids: complete remission of nephrotic syndrome Microscopic haematuria persists Two common glomerular diseases coincide…… Minimal change nephrotic syndrome IgA nephropathy NEPHROTIC SYNDROME IN IgA NEPHROPATHY Minimal change Mesangial hypercellularity Glomerulosclerosis NEPHROTIC SYNDROME IN IgA NEPHROPATHY Randomised controlled trial n = 34 Prednisolone for 4 months: 40-60 mg daily halved after 8 weeks Follow up 38 months Response of proteinuria only in those with minor histological changes Lai - Clin Neph 1986; 26:174 NEPHROTIC SYNDROME IN IgA NEPHROPATHY Minimal change Mesangial hypercellularity Glomerulosclerosis The response to corticosteroids in minimal change does not justify their use in all IgAN with nephrotic syndrome TREATMENT DECISIONS IN IgA NEPHROPATHY Microscopic haematuria Macroscopic haematuria Acute kidney injury Crescentic IgA nephropathy Proteinuria > 1g/day Nephrotic syndrome Hypertension Progressive fall in GFR TREATMENT DECISIONS IN IgA NEPHROPATHY Non-visible haematuria Visible haematuria Acute kidney injury Crescentic IgA nephropathy Proteinuria > 1g/day Nephrotic syndrome Hypertension Progressive fall in GFR PUBLISHED TREATMENT TRIALS IN IgA NEPHROPATHY Often underpowered Often insufficient follow up for ‘hard’ endpoints Most use clinical entry criteria Some have patients beyond ‘the point of no return’ TREATMENT OPTIONS FOR PROGRESSIVE IgA NEPHROPATHY Blood pressure control Renin-angiotensin blockade Corticosteroids Other immunosuppressives TREATMENT OPTIONS FOR PROGRESSIVE IgA NEPHROPATHY Blood pressure control Renin-angiotensin blockade Corticosteroids Other immunosuppression TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY Target Blood Pressure Proteinuria < 1g/24hr 130/80 Proteinuria > 1g/24hr 125/75 RAS Blockade Proteinuria > 1g/24hr 125/75 Combination therapy ? EFFECT OF ACE INHIBITOR PLUS ARB ON PROTEINURIA IN IgA NEPHROPATHY: META-ANALYSIS 6 studies – 109 patients Cheng J et al. Int J Clin Pract 2012; 66: 917 EFFECT OF ACE INHIBITOR PLUS ARB ON PROTEINURIA IN IgA NEPHROPATHY: META-ANALYSIS 6 studies – 109 patients No effect on GFR but Study duration: 2-12 months Cheng J et al. Int J Clin Pract 2012; 66: 917 TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY Target Blood Pressure Proteinuria < 1g/24hr 130/80 SALT Proteinuria > 1g/24hr 125/75 RESTRICTION RAS Blockade Proteinuria > 1g/24hr 125/75 Combination therapy ? DIETARY SODIUM RESTRICTION AMPLIFIES EFFECTS OF RAS BLOCKADE ON PROTEINURIA Lisinopril 40mg/day Valsartan 320mg/day Sodium intake 50 or 200 mmol/day Slagman M et al. BMJ 2011 DIETARY SODIUM RESTRICTION AMPLIFIES EFFECTS OF RAS BLOCKADE ON PROTEINURIA Lisinopril 40mg/day Systolic BP Valsartan 320mg/day Sodium intake 50 or 200 mmol/day Diastolic BP Slagman M et al. BMJ 2011 TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY Proteinuria > 1g/day + hypertension Only if BP target achieved… and proteinuria still >1g/24 hr consider corticosteroids, immunosuppressive regimens … What is the evidence these regimens are effective in these circumstances ? TREATMENT OPTIONS FOR PROGRESSIVE IgA NEPHROPATHY Blood pressure control Renin-angiotensin blockade Corticosteroids Other immunosuppression CORTICOSTEROID TREATMENT FOR IgA NEPHROPATHY Randomised controlled trial – serum creatinine < 130 µmol/L Survival without end point - doubling of serum creatinine Pozzi C et al Lancet 1999; 353; 883 - JASN 2004; 15: 157 CORTICOSTEROID TREATMENT IN IgA NEPHROPATHY Randomised controlled trial – serum creatinine < 133 µmol/L n = 86 creatinine < 133 µmol/l - proteinuria 1-3.5g/24hr 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 CORTICOSTEROID TREATMENT IN IgA NEPHROPATHY Randomised controlled trial – serum creatinine < 133 µmol/L n= 103 2 year treatment regimen Prednisolone 20mg od reducing to 5mg by 6 months Antiproteinuric effect but no effect on renal function Katafuchi AJKD 2003; 41:972 BLOOD PRESSURE CONTROL IN IgA NEPHROPATHY TRIALS Corticosteroids BP (mm Hg) Pozzi 160 150 140 130 120 110 100 90 80 70 60 NKF Recommendation 125/75 Katafuchi CORTICOSTEROIDS PLUS ACE INHIBITOR IN PROTEINURIC IgA NEPHROPATHY TWO SIMILAR STUDIES Proteinuria > 1g/24h - GFR > 50 ml/min Continuous ACE inhibitor + oral CORTICOSTEROIDS for 6-8 months Follow up: 2 years (China), 5 years (Italy) Well maintained BP Lv J et al. 2009 AJKD; 53: 26 Manno C et al. NDT 2009; 24: 3694 BLOOD PRESSURE CONTROL IN IgA NEPHROPATHY TRIALS Corticosteroids Pozzi BP (mm Hg) 160 Katafuchi Manno Lv 150 140 130 120 110 100 90 80 70 60 JNC Recommendation 125/75 CORTICOSTEROIDS PLUS ACE INHIBITOR IN PROTEINURIC IgA NEPHROPATHY ESRD STEROIDS ITALY CONTROL 1/48 8/49 Statistically significant CHINA 1/30 7/33 Lv J et al. 2009 AJKD; 53: 26 Manno C et al. NDT 2009; 24: 3694 CORTICOSTEROIDS PLUS ACE INHIBITOR IN PROTEINURIC IgA NEPHROPATHY STEROIDS ITALY CONTROL 1/48 8/49 Statistically significant CHINA 1/30 7/33 But.. achieved ACE inhibitor dose rather low Lv J et al. 2009 AJKD; 53: 26 Manno C et al. NDT 2009; 24: 3694 CORTICOSTEROIDS PLUS ACE INHIBITOR IN PROTEINURIC IgA NEPHROPATHY STEROIDS ITALY CONTROL 1/48 8/49 Statistically significant CHINA 1/30 7/33 But.. neither study had a ‘run-in‘ period Lv J et al. 2009 AJKD; 53: 26 Manno C et al. NDT 2009; 24: 3694 TREATMENT OPTIONS FOR PROGRESSIVE IgA NEPHROPATHY Blood pressure control Renin-angiotensin blockade Corticosteroids Other immunosuppression IMMUNOSUPPRESSIVE TREATMENT FOR PROGRESSIVE IgA NEPHROPATHY NO ROLE FOR Cyclophosphamide BLOOD PRESSURE CONTROL IN IgA NEPHROPATHY TRIALS Corticosteroids Pozzi BP (mm Hg) 160 Katafuchi Manno Lv 150 140 130 120 110 100 90 80 70 Ballardie 60 JNC Recommendation 125/75 Corticosteroids + Cyclophosphamide IMMUNOSUPPRESSIVE TREATMENT FOR PROGRESSIVE IgA NEPHROPATHY NO ROLE FOR Cyclophosphamide What about Mycophenolate BLOOD PRESSURE CONTROL IN IgA NEPHROPATHY TRIALS Corticosteroids Mycophenolate Pozzi Maes BP (mm Hg) 160 Katafuchi Manno Tang Lv 150 140 130 120 110 100 90 80 70 Ballardie 60 JNC Recommendation 125/75 Corticosteroids + Cyclophosphamide MYCOPHENOLATE IN IgA NEPHROPATHY Benefit BP achieved ACE inhibitors None 125/73 100% salt restricted ESRD reduced 122/71 100% [number of patients] BELGIUM Maes 2004 [34] HONG KONG Tang 2005 [40] TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY Uncertainty • The role of corticosteroids and immunosuppressives after tight BP control and maximal RAS blockade ? • The effect of ancestry on treatment responses Run-in Phase (6 Months) Study Design Optimal supportive therapy for 6 months (ACEi, ARB, target BP < 125/75 mm Hg, Statin, etc.) Responder Drop-Out Study-Phase (3 Years) Non-Responder Proteinuria >0.75 g/d RANDOMISATION Optimal supportive Optimal supportive + Immunosuppression Recruitment-Update STOP IgAN - Status 28.2.2011 - Study patients n=356 400 IgAN patients 350 300 250 200 Randomised n=127 150 100 50 0 8 9 0 08 r 08 08 0 t 08 08 09 r 09 09 0 t 09 09 10 r 10 10 1 t 10 10 11 g g g b p b p b n u n n c b p c c c c c O De Fe A Ju Au O De Fe A Ju Au O De Fe Fe A Ju A Follow-up TREATMENT RECOMMENDATIONS FOR IgA NEPHROPATHY We are still short of evidence ….. So there is room for your own opinion …..