Implications of MDRD for Validity of Proteinuria as a Surrogate Endpoint

MDRD Follow-up Randomized Trial Phase: –2 to 4 years of planned follow-up, –Mean actual follow-up, with censoring due to ESRD and death was 2.2 years –Primary outcome was iothalamate GFR slope, with iGFR measured every 4 months Long-Term Follow-up:ESRD and Death ascertained through Dec 31, 2000.

Individual Level Association

Impact of Reduction of Proteinuria in MDRD Study -- Results Interpretation: A 1 g/d initial decline in urine protein excretion was associated with a reduction in the mean slope in the period after 4 months of 0.92 ml/min/yr in Study A and of 1.32 ml/min/y in Study B Peterson JC et al, Ann Int Med 1995; 123:754

Association of GFR Slope with Initial GFR in MDRD and AASK Study Mean Initial GFR (ml/min/1.73m 2 ) Mean Initial UP (g/day) % of Variance in GFR Slope Explained MDRD Study A g/d14.0% MDRD Study B g/d13.2% AASK Study g/d17.5%

Baseline GFR <= 24.5 <= 24.5 Baseline GFR Baseline GFR > 55.5 > 55.5 Cumulative Incidence Follow-Up Time (Months ) Baseline UP ≤ 1 g/day Baseline UP > 1 g/day Individual-Level Association of Baseline UP with Incidence of ESRD Stratified by Baseline GFR (N = 1617 MDRD Enrollees)

Diet Interventions

Study A Study B Effect of Diet Interventions on % Change in Proteinuria from Baseline to 12 Months Percent Change Low Protein Usual Protein Keto Acid Low Protein Box-plots extend from 25 th to 75 th percentiles

Study B: No significant different in GFR slope or time to ESRD or Death between Very Low and Low Protein diet groups.

Implications of BP Intervention

Effect of BP Goal on Percent Change in Proteinuria from Baseline to 12 Months Percent Change > 3 UsualLowUsualLowUsual LowUsualLow < 0.3 BP Group Baseline 24 Hr UP (g/day) Box-plots extend from 25 th to 75 th percentiles

> 3 UsualLowUsualLowUsual LowUsualLow < 0.3 BP Group Baseline 24 Hr UP (g/day) Box-plots extend from 25 th to 75 th percentiles Effect of BP Goal on Absolute Change in Proteinuria from Baseline to 12 Months

Effect of Low BP Goal in Study A Change in GFR (ml/min/1.73m 2 ) Low BP Usual BP P=.01 p = 0.01 p = 0.30

MDRD: Impact of Blood Pressure Goal on Rate of Progression as a function of Proteinuria Klahr S, N Engl J Med 1994; 330:877

MDRD Long-Term Cumulative Incidence of ESRD 554/840 (66%) of Randomized Patients Reached ESRD ____ Usual Goal Low Goal Unadjusted P-value: Adjusted HR: % CI: ( ), p < 0.001

> 3g 1-3 g g <0.3 g All N=840 N=410 N=159 N=175 N=96 Hazard Ratio Baseline UP (g/day) Hazard Ratios for Low BP Goal by Level of Baseline UP (g/day) ESRD Alone ESRD/Death

MDRD Trial Effects Assessment Summary Compar- ison Δ UP 3-Yr Slope Chronic Slope Long-term ESRD or Death Low vs. Usual Protein Low Protein (small) NULL Low Protein Equivocal Very Low vs. Low Protein NULL Low vs. Usual BP Low BP (big) NULLLow BP Low vs. Usual BP Effect Modification by Baseline UP: General consistency between effect on absolute Δ UP and effects on slope & clinical endpoints.

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Extra Slides

MDRD: Long Term Outcomes - 2 Sarnak et al, Ann Int Med 2005; 142:342

MDRD: Cumulative Variance of GFR Slopes Explained by Covariates Hunsicker LG et al. Kidney Int 1997; 51:

624/840 (74%) of Randomized Patients Reached ESRD or Death Low BP Usual BP Unadjusted P-value: Adjusted HR: % CI: ( ), p = MDRD Long-Term Cumulative Incidence of ESRD/Death

MDRD: Cumulative Variance of GFR Slopes Explained by Covariates Hunsicker LG et al. Kidney Int 1997; 51:

UP > 3g/day UP 1-3g/day UP g/day UP < 0.3 g/day Percent Change Effect of Low Protein Diet on Change in Proteinuria