1. Proteinuria as a Surrogate in Kidney Disease In primary GN membranous nephropathy and focal and segmental glomerulosclerosis assocciated with the nephrotic syndrome Daniel Cattran M.D.

2. Can we quantitate the “benefits” Observational studies Prospective gathered information Timed urine collection (24 hrs) On review used protein /creatinine ratios to substantiate values and changes Relationship to outcome (RCT)

3. Time to event Proteinuria Complete remission < 0.3 g/d and normal creatinine Partial remission 0.3-3.5g/d and 50% reduction from peak proteinuria and stable creatinine Progression Kidney survival Doubling baseline creatinine Rate of progression(slope of cr cl )

4. i pp=12g/d, delta crcl (mls/mo) = –3, crcl i= 96 X = 1.26 + (0.3 x 12) + (-0.3 x -3) + (-0.05 x 96) e x = 2.6 p = 2.6 / 3.6= 72% Cattran…KI 1995 Predicting likelihood of developing CKD in MGN

5. Currently only validation tool that has undergone model fitting and independent data set validation Toronto Finland Italy Chronic renal insufficiency47/184(26%) 13/78(17%) 25/101(25%) Sensitivity Proteinuria >3,5 g/d 93% 100% 84% Model 89% 77% 60% Specificity Proteinuria >3.5 g/day 38% 30% 17% Model 86% 89% 92% Positive predictive value Proteinuria >3.5 g/day 34% 24% 25% Model 67% 59% 64% Negative predictive value Proteinuria >3.5 g/day 94% 100% 76% Model 94% 95% 82% Accuracy 52% 43% 34% Model 85%87% 79% Cattran…KI 1997

6. MGN Effect of long-term proteinuria reduction on rate of progression Troyanov …Cattran KI 2004

7. No remission vs Partial Remission vs Complete Remission Changes odds re:ESRD from 1in 2 to 1in 10 with PR to none with CR at 10 years 90% 50% 100% Troyanov …Cattran KI 2004 (PR = 50% in proteinuria and <3.5g/d On Renal Survival

8. Value of proteinuria reduction in MGN

9. Data to support relationship between proteinuria reduction and long term outcome

10. IV MP 1gx3 + Pred 0.5mg/kg od alternating monthly with cyclophosamide 2.5 mg/kg over 6/12 Improves with cytotoxic/steroid therapy RCT’S MGN

11. Repeat RCT Cytotoxic plus Prednisone Jha Vet al JASN:18:2007

12. Cytotoxic plus Prednisone Effect on proteinuria CR and /or PR Treated vs Control

13. Jha Vet al JASN:18:2007 Effect on outcome Renal survival of decrease in proteinuria but delayed as expected Treated 90% Control 65%

14. Jha Vet al JASN:18:2007 And eGFR was improved (but >50% control treated later in study so likely blunted treatment effect) 20mls/min And effect on progression rate(eGFR)

15. Cattran et al K. I., 2001 Other therapy similar results RCT CNI’S CSA 3- 4mg/kg Nephrotic syndrome (MGN)improved with 6 mos CSA 3- 4mg/kg + 10 mg prednisone od x 6/12 (Cattran …KI 2001 )

16. More prolonged CNI Treatment of IMN I) Initial TREATMENT GROUPS CsA +Pred(0.6mg/kg w taper) 26pts (11 CR, 15 PR) CsA alone(2-3 mg/kg ) 17 pts (4 CR, 13 PR) II) TREATMENT REGIMEN beyond 12mos Pred tapered to ~0.1 mg/kg BW CsA tapered to ~1.5 mg/kg BW over 2 months F/U 22+/-16 mos Alexopoulos et al, Nephrol Dial Transplant 21(11):3127,2006 Alexopoulos et al, Nephrol Dial Transplant 21(11):3127,2006

17. RCT Tacrolimus monotherapy in Nephrotic MGN Praga et al KI 71:2007 Alternate CNI

18. Praga et al KI 71:2007 Effect of 12 months tacrolimus monotherapy on protinuria in MGN

19. Praga et al KI 71:2007 Effect on slowing progression(50 % change in creatinine) Tac 5%versus control 25% 25% 5%

20. Primary FSGS - NATURAL HISTORY COURSE COURSE n Spontaneous complete remission - 5 - 10% n Rapidly progressive renal failure -10 - 15% n Slowly progressive renal -40 - 60% n Slowly progressive renal failure -40 - 60% n Persistent proteinuria -20 - 30%

21. Baseline characteristics 281 nephrotic FSGS Troyonov…Cattran JASN 2005

22. Effect of proteinuria reduction on rate of progression (slope of Cr Cl)

23. Effect of proteinuria reduction on survival (from ESRD)

24. FSGS Renal survival related to proteinuria remission: complete, partial and no remission 4 CR PR NR 100% 80% 40%

25. Data to support relationship between proteinuria reduction and long term outcome

26. All Obsevational

27. Cyclosporine vs Placebo in Steroid Resistant FSGS 12265278104 % REMISSION RCT 6 Mos Rx CNI vs Placebo) Effect on proteinuria

28. 23 26 22 25 19 18 15 12 7 Placebo (n) Cyclosporine (n) Placebo Cyclosporine p<0.05 CNI vs Placebo in Steroid Resistant FSGS Effect on Cr Cl