1. Proteinuria as a Surrogate Outcome in IgA Nephropathy Ron Hogg MD Scott & White Medical Center Temple, Texas

2. Goals of Presentation Overview of condition Observational studies Relationship between proteinuria and renal impairment in patients with IgA nephropathy Impact of various treatments (eg: ACEi, steroids, omega-3 fatty acids) on changes in proteinuria and progressive renal impairment Relationship between early changes in proteinuria and subsequent fall in varying measures of GFR associated with these treatments

3. IgA Nephropathy: Background Original description by Jean Berger in 1968 Initially referred to as “Berger’s Disease” Thought to have a benign outcome in ‘70s Condition now known to be most common glomerular disease leading to ESRD worldwide

5. Definitions Measures of Proteinuria Collection: 24 hour urine excretion rates Analyte: Total protein Analytical methods: Variable Early change: One year in most cases Outcome measures Measures of kidney disease progression  Kidney failure/ESRD  Decline in mGFR/eGFR  50% increase in serum creatinine (Scr) Mean slopes  mGFR/eGFR

6. Clinical trials Obser- vational studies Baseline UPEX vs. CKD progressionXX Early change in UPEX (6-12 months) vs. CKD progression XX Effect of treatment on CKD progression (comparison of randomized groups) XNA Analyses

7. IgA Nephropathy: Observational studies 1. Predicting Progression in IgA nephropathy. Bartosik et al. Am J Kidney Dis. 2001 2. Early prediction of IgAN progression: Proteinuria and AOPP are strong prognostic markers. Descamps-Latcha etal. Kidney Int. 2004

8. Predicting progression in IgAN Bartosik et al. AJKD: 2001 Retrospective evaluation of the association between rate of decline of renal function (CG-GFR) and multiple variables in 298 adult patients with IgAN Age at presentation: 36+/-13 years (16-73 years) Follow-up from presentation: 70+/-46 months (range 12-231 months) Age at biopsy: 37+/- 13 years (range 16-74 years) Follow-up from renal biopsy: 57+/-44 months (range 12-227 months)

9. Bartosik et al. 2004 Baseline clinical and laboratory data CG-GFR: 76+/-35 ml/min (range 13-225 ml/min) Serum creatinine: 1.54+/-1.0 mg/dl (0.5-8.4 mg/dl) MAP-B: 102+/-15 mmHg (70-162mmHg) UPEX-B: 2.3+/-2.3 g/day (0.1-21.6 g/day)

10. Bartosik et al. 2004 Variables monitored during follow-up Slope of CG - GFR was derived from 10 +/- 7 values of serum creatinine in 90% of patients Rate of decline of CG - GFR was -4.8 +/- 7.5 ml/min/year (0.4ml/min/month) Five year renal survival rate from time of presentation was 80% Ten year renal survival from presentation was 65%

11. Bartosik et al. 2004 Univariate analysis of factors associated with GFR decline VariableP value Age, Race, Sex, MAP-B, Serum creatinine, CG-GFR at baseline ns MAP during follow-up0.001 UPEX at baseline0.001 UPEX during follow-up0.001 Lee Classification of histology (G5)0.001

12. Bartosik et al. 2004 Multiple Linear Regression Analysis Using only clinical and laboratory data, the only independent predictors of slope were MAP-FU and UPEX-FU. The overall model was highly significant (p<0.001) MAP and mean UPEX over progressively longer periods of follow-up were significantly associated with rate of deterioration of CG-GFR

13. Descamps-Latscha. KI: 2004 Prospective cohort study of 120 adult patients identified between 1994 – 1997 and followed until the end of 2002 or start of dialysis Primary end point defined as 50% reduction of CCr from baseline Risk factors evaluated included CRP, UPEX and advanced oxidation protein products (AOPP) 51 patients reached the end point, including 30 patients who had to start dialysis Baseline UPEX was 0.59 +/- 0.62 g/day in 69 patients who did not reach the end point versus 2.67 +/- 1.28 mg/day in the 51 patients who did reach the end point

14. Descamps-Latscha. KI: 2004 1. Univariate Cox regression analysis showed age, proteinuria, hypertension, ACEi, CCr and AOPP levels to be significantly associated with renal outcome Proteinuria >1g/day HR (95% CI) = 16.41 (3.97-67.84, p=0.00001) 2. Multivariate analysis confirmed UPEX to be independent predictor of renal outcome a. With CCr included: HR = 7.78 (1.81-33.4, p=0.006) b. With CCr excluded: HR = 23.7 (5.35-104.8, p=0.0001) 3. Angiotensin II inhibitors were protective HR = 0.19 (0.09-0.44, p=0.001)

15. ACE inhibitors for IgA nephropathy Treatment of IgA nephropathy with ACE inhibitors: A randomized contolled trial Praga et al. JASN: 2003

16. Praga et al: 2003 RCT in 44 Patients with UPEX > 0.5g/day on 3 consecutive measurements and SCr <1.5mg/dl Enrollment lasted 5 years (9/90-9/95) 23 randomized to enalapril 5-40 mg/day 21 randomized to control group BP goal <140/90 mmHg in both groups Follow-up: 78 months (E) vs 74 months (C) Primary outcome: 50% increase in SCr

17. Praga et al: 2003 Rx group: 3 pts (13%) reached end point Controls: 12 pts (57%) reached end point, p<.05 Renal survival at 4 years: 100% in Rx group, 70% in control group Renal survival at 7 years: 92% in Rx group, 55% in control group, p<0.0 Significant effect of the reduction in UPEX after 1 year of treatment was seen on renal survival Odds ratio=0.98, 95%CI 0.96-0.99, p=0.025

18. Omega-3 fatty acids in IgAN Proteinuria patterns and their association with subsequent end stage renal disease in IgA nephropathy Donadio et al. Nephrol Dial Transplant: 2002

19. Donadio et al. 1992 Examined data from 2 trials in patients with IgA nephropathy that had been conducted by the Mayo Collaborative Group to identify which determinants of proteinuria might provide the best predictors of ESRD after 1 year of treatment with O-3FA or placebo UPEX was measured on 24 hour urines at baseline, 6 weeks, 6 months and 1 year in all patients

20. Donadio et al. 2002 HR (CI) One year UPEX vs ESRD1.5 (1.2, 1.9) There were 91 patients available for study after 1 year and 18 ESRD events after year one in Trial #1 There were 63 patients available for study after 1 year and 14 ESRD events after one year in Trial #2

21. Corticosteroids for IgA nephropathy 1. Steroid therapy during the early stage of progressive IgA nephropathy. A 10 year follow-up study Kobayashi et al. Nephron: 1996 2. Corticosteroids in IgA nephropathy: A randomized controlled trial. Pozzi et al. The Lancet: 1999 3. Steroid treatment for severe childhood IgA nephropathy:A randomized controlled trial. Yoshikawa et al. Clin J Am Soc Nephrol: 2006

22. Kobayashi et al. 1996 Ten year + study of subset of patients (n=46) with UPEX 1-2 g/day, CCr >70ml/minute, severe renal histology Original cohort of patients = 363 ( 90 with UPEX above). Previous report on these patients showed persistent UPEX > 1g/day to be associated with progressive renal impairment Patients “allocated” to course of steroids or non-steroidal therapy, usually in order of renal bx Steroids – 20 patients; “controls” – 26 patients

23. Kobayashi et al. 1996 Outcome (ESRD) Treatment vs control20% vs 64% Baseline UPEX (g/day) Treatment group baseline UPEX1.4 Control group baseline UPEX1.3 Follow-up UPEX (g/day) Treatment group0.8 Control group1.5

24. Pozzi et al. 1999 RCT in 86 patients with IgAN who showed UPEX 1- 3.5g/day, plasma creatinine < 1.5g/day Patients enrolled over 8 years (7/87-9/95) Rx: Pulse IV MP 1g/day x 3 consecutive days on months 1, 3, 5 plus PO pred 0.5mg/kg/QOD x 6m 43 patients randomized to the steroid group 43 patients randomized to the control group who received supportive therapy (BP goal 140/90) Study conducted in 7 renal units in Italy

25. Pozzi et al. 1999 Baseline Participants Number of Rx pts / Controls43 / 43 UPEX (mg/day) (mean)2.0 / 1.8 UPEX 6m, 1y, 2y, 3y, 4y, 5yr Rx group1, 0.8, 0.6(2), 0.5, 0.8 Control group1.6, 1.2, 1.4, 1.3, 1.4, 0.8 Study End (5 years) 50% increase in SCr: Rx/C21% / 33% 100% increase in SCr: Rx/C2% / 21%

26. Pozzi et al. 1999 Risk of reaching the 50% increase in serum creatinine endpoint was 59% lower in steroid treated patients vs controls (relative risk 0.41, 95% CI 0.17-0.98, p=0.04) When the reduction in UPEX from 0-6 months was added to the model, this covariate was selected as significant (RR 0.48, CI 0.34-0.69, p<0.0001), and the beneficial effect of steroid Rx was lost from the final model

27. Yoshikawa et al. 2006 RCT conducted by the Japanese Pediatric IgA Nephropathy Treatment study Group 83 children < 16 yrs of age enrolled in 20 centers - 50/83 pts ( 60%) detected by school screening Rx group: pred, Imuran, warfarin, dipyridamole “Control” group: prednisone. Rx duration 2 yrs ACEi prohibited in both groups Primary end point: disappearance of proteinuria Secondary end point: percentage of sclerosed glomeruli on follow up renal biopsies

28. Yoshikawa et al. 2006 Outcome – Remission of proteinuria Treatment vs control (after 2 years)92.3% vs 74.4% Baseline UPEX (g/day) Treatment group baseline UPEX/day1.29g/m 2 “Control” group baseline UPEX/day1.16g/m 2 Follow-up # glomeruli showing sclerosis Treatment group4.6% Control group p=0.000314.6%

29. Conclusions Severity of proteinuria is closely correlated with risk of progressive renal impairment in patients with IgA nephropathy Reduction in proteinuria via multiple therapeutic interventions is associated with improvement in renal outcome The impact of reducing proteinuria in this condition appears to be best attained when the lowering of proteinuria can be sustained