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IgA Nephropathy: Treatment Update

(and a tiny bit on pathogenesis)

Patrick H. Nachman, MD
Professor of Medicine
UNC Kidney Center
University of North Carolina
Chapel Hill, NC USA

Outline
• Pathogenesis:
» Association with GI disease

• Risk factors of progression
• Treatment:
» Major therapeutic options
» Crescentic IgAN
» Point of No Return

Association of IgAN with
Gastrointestinal Disease
• Inflammatory Bowel Disease
• Celiac Disease
• Liver Disease.

5/6/2015

3

Ambruzs JM et al Clin J Am Soc Nephrol 2014;9: 265–270

Ambruzs JM et al Clin J Am Soc Nephrol 2014;9: 265–270

Genome Wide Association Study in IgAN Kiryluk K et al Nature Genetics 2014.46:1187-1196 .

and associated HORMAD2. CARD9 Association with risk of UC and Crohn’s dis. ITGAX Regulation of intestinal IgA-producing plasma cells in Peyer’s patches. TAP1. Deficiency associated with Crohn’s dis. Encodes B cell stimulating cytokine that promotes IgA class switching.MTMR3 with increased IgA levels PSMB8. TAP2 PSMB8 upregulated in tissue with active IBD lesions HLA. HLA-DQB1. OSM. HLA-DRB1 Associated with risk of celiac disease. -6 Anti-microbial peptides.46:1187-1196 . IgAN risk allele is protective of Crohn’s dis.DQA1. and IgA deficiency Risk allele protective for UC Adapted from Kiryluk K et al Nature Genetics 2014. PSMB9.Genome Wide Association Study in IgAN Locus / Gene Role in intestinal mucosal immunity ITGAM. Induced by intestinal bacteria TNFSF13 LIF. -5. -3. VAV3 Required for colonic enterocyte differentiation and prevention of spontaneous ulceration DEFA1. -4.

and no previous renal disease.47(8):678-83. 2013 Sep. J Clin Gastroenterol. • 133.949 age.160 individuals with biopsy proven Celiac disease. .Is IgAN Associated with Celiac Disease? Population-based prospective study: • 27. Individuals with IgAN identified by the 4 Swedish renal pathology centers.and sex-matched reference individuals Welander A et al.

9 . 2015 Mar 6.10(3):372-81. but was not correlated with the decline of eGFR. Clin J Am Soc Nephrol. and non-IgAN glomerular diseases (n=17) • A protein microarray used for detection of IgAN-specific IgA autoantibodies across ~ 9000 human antigens: » 54 proteins mounted highly significant IgA antibody responses in patients with IgAN • Anti-tissue transglutaminase IgA was significantly elevated in IgAN (P<0.001). healthy controls (n=10).Mapping Immunogenic Epitopes in IgAN • Sera from 22 patients with biopsy-proven IgAN. 5/6/2015 Woo SH et al .

S et al. 9(4): e94677 . sex matched controls n=96 Biopsy-proved Celiac dis: n= 30 Tests: IgG and IgA Ab to gliadin. PLoS ONE 2014.IgAN : n= 99 Age-. deamidated gliadin IgA Ab to Transglutaminase 2 -> Ab to Endomysial -> HLA-DQ2 and DQ8 Moeller.

28:27-37 11 . Not correlated with severity of cirrhosis • No specific therapy • Prognosis likely depends on severity of liver disease 5/6/2015 Pouria S et al. Semin Nephrol 2008.IgAN in Liver Disease • Likely related to decreased clearance of IgA by hepatocytes (Asialoglycoprotein Receptor) • High prevalence of mesangial IgA deposits in patients with alcoholic cirrhosis (30-90%) • Hepatic IgAN is often asymptomatic microscopic hematuria • Risk of progression to CKD and ESKD is unknown.

Patterns of Clinical Presentation • Episodic macroscopic hematuria » Acute renal failure with gross hematuria • • • • Asymptomatic hematuria and proteinuria Rapidly progressive glomerulonephritis Chronic renal failure Nephrotic syndrome .

IgA Nephropathy is a Chronic Disease • 1/3 clinical remission: resolution of proteinuria and hematuria • 1/3 progressive decline in GFR to ESRD over 20 yr • 1/3 benign chronic course of persistent hematuria and proteinuria (< 1 g/d) .

4 g proteinuria/day • Normal renal function • Hong Kong population • Mean age 27. 78% female Szeto CC et al.Natural History of “Mild” IgA • 72 consecutive patients with hematuria and < 0. 434 . Am J Med 2001.

Natural History of “Mild” IgA • Median follow up 7 years • 44% adverse events » 33% proteinuric » 26% hypertensive » 7% impaired renal function • 42% persistently abnormal urinalysis • Only 10 patients (14%) went into complete remission Szeto CC et al. 434 . Am J Med 2001.

IgA Nephropathy “Traditional” Risk Factors for Progression • Hypertension (SBP>DBP) • Initial impairment of renal function • Familial disease • Magnitude. 24:179-196 . duration and qualitative aspects of proteinuria D’Amico G. Semin Nephrol 2004.

1197-1203 .Risk Factors for Progression: Creatinine 5/6/2015 Donadio J et al. Nephrol Dial Transplant 2002.

1197-1203 . Nephrol Dial Transplant 2002.Risk Factors for Progression: Proteinuria Donadio J et al.

23:2247-53 . Nephrol Dial Transplant 2008.IgA N MN -15 -12 -9 -6 FSGS -18 ml/min/1.73m2/year Slope -3 0 Interaction between time average proteinuria and rate of renal function decline Adapted from Cattran DC et al.

Reich HN et al J Am Soc Nephrol 2007.2 g/d Group 2. Peak proteinuria: Group 1. 2.Remission of Proteinuria and Prognosis partial remission (1 g/d) associated with similar outcome regardless of peak. Group 3.3 g/d. >3 g/d.18:3177-3183 . 1.

9:617-625 21 .Serum C3 Serum IgA/C3 Renal C3 deposition 5/6/2015 Canetta PA et al. Clin J Am Soc Nephrol 2014.

steroid.IgA Nephropathy: Therapy • ACE inhibitors and/or ARB* • Fish-oils* (omega-3 fatty acids. cyclical IV pulse/oral) • Azathioprine (plus steroids) • Cyclophosphamide* (plus steroids) • Warfarin + dipyridamole* • Azathioprine. warfarin • Mycophenolate mofetil* (plus steroids) • Leflunomide • Cyclosporine (* RCT performed) . alternate-day. dipyridamole*. Omacor) • Glucocorticoids* (daily.

The real question is: what to add to RAS inhibition… .

steroid. Omacor) • Glucocorticoids* (daily. warfarin • Mycophenolate mofetil* (plus steroids) • Leflunomide • Cyclosporine • Tonsillectomy* (* RCT performed) . cyclical IV pulse/oral) • Azathioprine* (plus steroids) • Cyclophosphamide* (plus steroids) • Warfarin + dipyridamole* • Azathioprine.IgA Nephropathy: Therapy • ACE inhibitors and/or ARB* • Fish-oils* (omega-3 fatty acids. dipyridamole*. alternate-day.

0 10 20 Combo 40 50 Time (month) Time (month) # at risk ACE-I 30 30 29 28 10 3 0 29 28 10 3 0 33 32 30 14 3 0 32 30 16 3 0 Lv J et al.50% creatinine increase 1.006 0.2 0.0 Log Rank P<0.4 0.6 0.0 0. 25% eGFR decrease 1. 53(1): 26-32 .8 Log Rank P=0.6 0.8 0.2 Combination ACE inhibitor 0.0 10 Combination ACE inhibitor 20 30 40 50 Patient Not Reaching an End Point Patient Not Reaching an End Point Kidney survival estimated based on an increase up to 50% greater than baseline serum creatinine level and a decrease of 25% in estimated glomerular filtration rate (eGFR). Am J Kidney Dis 2009.4 0.001 0.

Combination therapy represented by solid line Manno C et al. Nephrol Dial Transplant 24(12):3694-701.Kaplan-Meier Analysis of Kidney Survival in the Two Treatment Groups Monotherapy represented by interrupted line. 2009 .

Corticosteroids in IgA Nephropathy • 86 patients • 6-month course of steroid treatment • Either supportive therapy or steroid treatment (IV methylprednisolone) • 9/43 patients in steroid group and 14/43 in control group reached endpoint (50%  in plasma creatinine) by year 5 Pozzi C et al. Lancet 1999. 353(9156):883-887 .

Corticosteroids in IgA Nephropathy Trial Profile 370 patients screened Pozzi C et al. 353:883-887 284 not eligible 86 eligible patients randomized 43 assigned standard treatment 43 assigned steroid treatment 43 completed 6-month trial 43 completed 6-month trial 5 withdrawn 3 dropped out 1 lost to follow up 1 protocol violation 7 withdrawn 1 dropped out 2 lost to follow up 4 protocol violation 43 assigned standard treatment 43 assigned standard treatment . Lancet 1999.

Pozzi C et al. 15(1):157-163 . J Am Soc Nephrol 2004.

J Am Soc Nephrol 2015.VALIGA study 5/6/2015 Tesar V et al.26:**** 30 .

26:**** 31 .VALIGA study 5/6/2015 Tesar V et al. J Am Soc Nephrol 2015.

004 -0. J Am Soc Nephrol 2015.001 ESRD 20 7 0.73m2 per year) -3.001 Reduction in proteinuria to <1g/d 54 84 <0.26:**** 32 .8(-1.3 0.3 (-1.003 Change in proteinuria (g/d) 5/6/2015 Tesar V et al.6 to -0.0 ± 7.2) <0.VALIGA study Outcome RAS B RASB + CS P value Rate of GFR decline (ml/min/1.3) -0.1 to 0.2±8.3 -1.

26:**** 33 . J Am Soc Nephrol 2015.VALIGA study UP < 1 g/d UP 1 to <3 g/d UP > 3 g/d UP < 1 g/d Response to treatment based on time-average proteinuria before treatment UP > 1 g/d Renal survival based on achieving proteinuria < 1 g/d in response to treatment 5/6/2015 Tesar V et al.

5/6/2015 34 .

35 .10: 1783–1790. 2010 .Survival without 50% increase Cr Azathioprine + Steroids vs Steroids alone 5/6/2015 Pozzi C et al J Am Soc Nephrol.

035. Ballardie FW. p = 0. 13(1)142-8 . Tarone-Ware) Mean rate of decline of renal function was reduced > 4-fold in the treatment group. Roberts IS.Prednisone and Cytotoxics in IgA Nephropathy Kaplan-Meier survival functions in treatment and control groups.006. log rank. J Am Soc Nephrol 2002. Preservation of function significant after 2 yr (p = 0.

MMF in the Treatment of IgA Nephropathy • Chen et al.. chronic IgAN vs. NMJC 2002 » Benefit from MMF in GFR and UPEX in 31 patients vs.. KI 2004 » No benefit from MMF in 21 patients vs. 15 controls .. 13 controls • Tang et al.. NDT 2005 » No benefit from MMF in 17 patients with severe. 20 controls • Frisch et al. KI 2005 » Improvement in UPEX in 20 patients on MMF vs. 31 controls (prednisone) • Maes et al.

5 g/d.proteinuria 72 patients Proteinuria 1-3. Nephrol Dial Transplant (2014) 29: 1546–1553 38 . Cr ≤ 1.5 mg/dl Gp A: Tonsillectomy + pulse steroid (Pozzi) Gp B: pulse steroids Complete remission Tonsillectomy + Steroids vs Steroids alone 5/6/2015 Kawamura T et al.

• By MVA tonsillectomy has significant effect on outcome. SIgA. gender. BP. histology. • Tonsillectomy has favorable effect on long-term outcome IF performed early in the course. 2003 .PN3 Efficacy of Tonsillectomy on Long-Term Survival in IgAN • 118 IgAN biopsies 1973-1980 PN4 • 48 post-tonsillectomy. 70 without tonsillectomy • No difference in age. 64% without at 240 months. treatment • Renal survival 90% with tonsillectomy vs. SCr. Kidney Int 63:1861-1867. Xie Y et al. UProt.

4/2/2015 PN4 change to RCT of tonsillectomy Patrick Nachman.Slide 39 PN3 Patrick Nachman. 4/2/2015 .

25:37-41 . Clin Nephrol 1986.3% 82.9 years [ 1 to 22 years] . Group 1 2 3 4 5/6/2015 % Crescents 0 <25 25-50 >50 10-Yr Survival 100% 94.Crescentic IgA Nephropathy • 205 patients. mean F/U 7.5% Abe T et al.8% 25.

• Repeat kidney biopsy: elimination of endocapillary proliferation. then monthly IV cyclophosphamide x 6 months • mean SCr decreased from 2. cellular crescents and karyorrhexis in all 12 patients after 6 months of therapy JA Tumlin et al.Crescentic IgA Nephropathy • 12 patients with crescentic (>10%) proliferative IgA N • Pulse methylpred x 3 days. Nephrol Dial Transplant 2003.35 g/24 h (P=0.03).39 to 1.51±0.18:1321-9 .10 mg/dl (P=0.04 to 1.01).65±0. • proteinuria decreased from 4.

Crescentic IgA N • 25 patients with diffuse crescentic IgA N (median 65% crescentic glomeruli.5g/d) .264 micromol/l.8 [range 8-92]) » 10 did NOT reach ESRD. and UP<1. creatinine 418 +/. (4 with normal SCr. 6 (x2) and 12 (x2) months 5/6/2015 Tang Z et al Am J Nephrol. 15 followed for more than 6 months (median 29. range 50-95%) • 88% with RPGN. • 21 were treated with pulse methylpred + Cyclophos.22:480-6. 2002. » 5 reached ESRD at 0. .

“Point of No Return (PNR)” in Patients with IgAN? • Important controversial issue if potentially toxic therapy is to be avoided in patients who will receive no benefit from treatment • D’Amico et al (1993) raised concept and proposed SCr of 3.0 mg/dL to be PNR in Japanese patients .0 mg/dL as PNR • Scholl et al (1999) concurred with D’Amico • Komatsu et al (2005) found SCr of 2.

0 mg/dL at renal biopsy. • None of the patients who exceeded sCr 2.2 <or= sCr <2.37 (per 0. J Nephrol. 95% CI 1. • Multivariate analysis: Risk factors of ESRD until sCr reached 2. 2005 Nov-Dec.0 mg/dL ( F/U103.36-14.54. PN2 .08-6. • 47 patients with moderate to severe histological lesions and whose 36-month follow-up did not require renal replacement therapy. Komatsu H et al.18(6):690-5.0 mg/dL could return to <2.1).3 +/."Point of no return (PNR)" in progressive IgA nephropathy: • Retrospective analysis the sequential data of patients with 1.56 (per 10 mmHg.5 point.05) » UP: HR 4.3 (36-237) months).0 mg/dl: » MBP: HR 2. (95% CI) 1.

4/2/2015 . acute vs chronic? treatment? what was adjusted for? endpoint is return to Cr <2 vs ESRD? did treatment delay ESRD? Patrick Nachman.Slide 44 PN2 need to review.

5 point.37 (per 0. .05) UP: HR 4. Komatsu H et al.104:6-13 5/6/2015 Risk factors of ESRD until sCr reached 2. 95% CI 1."Point of no return (PNR)" D’Amico G et al.08-6.18:690-5. 2005.56 (per 10 mmHg.36-14.1).0 mg/dl: MBP: HR 2. (95% CI) 1. J Nephrol. Contrib Nephrol 1993.

5/6/2015 Schöll U et al Clin Nephrol. » early acute course followed by a rapid return to the normal range.Point of No Return • 115 patients • 3 courses could be distinguished: » a stable chronic course (91 patients).52(5):285-92. • 16 patients showed a rapid. 46 .5 to 21 months). (only 2 patients) » a progressive course with increasing SCr (22 patients). • After SCr exceeding 3 mg/dl no remissions were observed in the progressive cases. 1999 Nov. SCr doubled from 3 to 6 mg/dl within an average of 10 months (range 2. continuously progressive course until ESKD.

but < 125/75 mm Hg if initial proteinuria is > 1 g/day (not graded) » Rapidly Declining eGFR • Glucocorticoids + cyclophosphamide for crescentic IgA (>50% glomeruli with crescents) with rapid deterioration of eGFR (2D) Wyatt JR.  dose if adverse events are acceptable to achieve urinary protein excretion of < 1 g/day (2D) • 6-mo glucocorticoid therapy if proteinuria > 1 g/day continues after 36 mos of ACEi or ARB.0 g/day. 368:2402-14 . and GFR > 50 ml/min (2C) • Fish oil of proteinuria > 1 g/day continues after 3 to 6 mos (2D) » Blood Pressure • < 130/80 mm Hg if proteinuria is < 1 g/day.  dose depending on BP (1B) • Suggestions » Proteinuria • ACE-I or ARB if urinary proteinuria 0.5-1. Julian BA. N Engl J Med 2013.Treatment According to KDIGO Guidelines • Recommendation » ACE-I or ARB for urinary protein excretion of > 1 g/day.

9:617-625 48 .5-1 g/d with other features suggesting risk of progression Histologic signs suggesting risk of progression (mesangial hypercellularity. endocapillary proliferation.. akin to treatment of minimal change disease 5/6/2015 Canetta PA et al.Approach to Treatment of IgA Nephropathy Patient Clinical Features Interventions All patients BP control < 130/80 mm Hg Strongly consider ACEI or ARB Consider statin Consider tonsillectomy if recurrent tonsillitis +/.e. cyclophosphamide) Enrollment into clinical trials “Point of no return” Low GFR. typically < 30 ml/min/1. Clin J Am Soc Nephrol 2014. segmental sclerosis) Glucocorticoids x 6 mos (trials showing benefits from steroid-treated patients with relatively preserved GFR and proteinuria > 1 g/d) Consider cytotoxics (i.73 m2 Biopsy with severe global glomerulosclerosis and tubular atrophy/interstitial fibrosis No immunosuppression Prepare for transplant or renal replacement therapy Crescentic IgAN Rapidly progressive GN > 30%-50% cellular or fibrocellular crescents on biopsy Pulse + high-dose oral glucocorticoids Consider cyclophosphamide IgAN with minimal change disease Sudden-onset nephrotic syndrome Mesangial IgA deposits on biopsy without sufficient sclerosis to explain proteinuria Glucocorticoids.fish oils per patient preference Mild disease Normal GFR Proteinuria < 500 mg/d Benign histology Normal BP Watchful waiting Enrollment into prospective observational studies Moderate/severe disease Proteinuria > 1 g/d or proteinuria 0.

Current Clinical Trials in IgA Nephropathy • Supportive Versus Immunosuppressive Therapy for the Treatment Of Progressive IgA Nephropathy (STOP-IgAN) . Phase 3 » 148 patients » Group A: Supportive therapy with ACE-inhibitor/ ARB/ Statin » Group B: immunosuppressive treatment: • GFR > or =60 ml/min: steroids • GFR <60 ml/min: steroids plus cyclophosphamide/azathioprine . 49 . the development of ESKD or death from kidney disease.8mg/kg/day (≤ 48mg/day)×2 months. taper by 8mg/day every month to stop within 6-8 months. » Primary outcome measures: patients reaching full clinical remission of their disease at the end of 3-yr study period » GFR loss of 15 ml/min or higher from baseline GFR at end of 3-yr study period • Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING Study) NCT01560052 » 1300 patients » Oral methylprednisolone 0. + ACE inhibitors or ARBs vs ACE inhibitors or ARBs » Primary Outcome Measures: composite of a 50% decrease in eGFR.NCT00554502.

5/6/2015 50 . Proteinuria > 1 g/d . Stable eGFR > 45 ml/min/1.Current Clinical Trials in IgA Nephropathy • Pilot Open Label Study of C5aR inhibitor (CCX168) » 20 patients. 12 week treatment. 8 week follow up.73 » Max tolerated RAAS blockade » 8 week run-in period.