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Proteinuria as a Surrogate in Kidney Disease

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. Can we quantitate the “benefits”. Observational studies Prospective gathered information

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Proteinuria as a Surrogate in Kidney Disease

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  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. Predicting likelihood of developing CKD in MGN 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) ex = 2.6 p = 2.6 / 3.6= 72% Cattran…KI 1995

  5. Currently only validation tool that has undergone model fitting and independent data set validation Toronto Finland Italy Chronic renal insufficiency 47/184(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. On Renal Survival 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 100% 90% 50% (PR = 50% in proteinuria and <3.5g/d Troyanov …Cattran KI 2004

  8. Value of proteinuria reduction in MGN

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

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

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

  12. Cytotoxic plus PrednisoneEffect on proteinuria CR and /or PR Treated vs Control Jha Vet al JASN:18:2007

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

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

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

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

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

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

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

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

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

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

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

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

  25. All Obsevational

  26. RCT 6 Mos Rx CNI vs Placebo) Effect on proteinuria Cyclosporine vs Placebo in Steroid Resistant FSGS %REMISSION 12 26 52 78 104

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

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