1. Irbesartan Diabetic Nephropathy Trial (IDNT) Collaborative Study Group N Eng J Med 345:851-860, 2001 Edmund J. Lewis, M.D. Muehrcke Family Professor of Nephrology Section of Nephrology Rush University Medical Center Chicago, IL

2. RC Atkins et al: Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. American Journal of Kidney Diseases 45:281-287, 2005

3. Definitions (IDNT) measure of proteinuria: baseline and quarterly 24 hr urine protein outcomes: primary: composite time to doubling serum creatinine plus end stage renal failure (Cr>6mgdl) plus all cause mortality

4. IDNT – Secondary Outcome Renal outcome: doubling of serum creatinine or end stage renal disease (creatinine ≥6 mg/dl, dialysis or transplantation).

5. Analyses IDNT baseline proteinuria vs CKD progression X early change in proteinuria vs CKD progression X effect of treatment On CKD progression X

6. Irbesartan Diabetic Nephropathy Trial (IDNT) DOUBLE MASKED RANDOMIZED PLACEBO CONTROLLED N IRBESARTAN (300 MG)579 AMLODIPINE (10 MG)567 CONTROL569 TOTAL 1715 TARGET BP 135/85 MMHG MEDIAN FOLLOW-UP 30 MONTHS PRIMARY COMPOSITE END POINT: DOUBLING SERUM CREATININE END STAGE RENAL FAILURE (CR>6) MORTALITY

7. Results of the Irbesartan Diabetic Nephropathy Trial VariableIrbesartanAmlodipinecontrol n (%) Doubling Serum Cr98 (16.9)144(25.4)135 (23.7) ESRD82 (14.2)104 (18.3)101 (17.8) Death87 (15.0)83 (14.6)93 (16.3) Primary composite endpoint 189 (32.6)233 (41.1)222 (39.0)

8. Irbesartan Diabetic Nephropathy Trial Baseline N = 1715 Median proteinuria2.9 G/24 hr (interquartile range 1.6 -5.2) Median albuminruia1.9 G/24 hr (interquartile range 1.0.-3.6) 12 months N = 1550 50% decrease proteinuria 29% irbesartan40 amlodipine20 control25 Study end Doubling serum Cr377 ESRD first event 10 Renal end point387 (22%)

9. Is there an association between baseline proteinuria and outcome.

10. Irbesartan Diabetic Nephropathy Trial (IDNT) Association between baseline proteinuria and renal outcomes 24 hr urine protein at baseline % renal outcome at 36 months <1 G/day7.7% 1-211.4 2-422.9 4-834.3 >864.9

11. Renal Outcome by Level of Baseline Proteinuria

12. Irbesartan Diabetic Nephropathy Trial (IDNT) Association between baseline proteinuria and renal endpoints Hazard ratio 95% CI P Doubling baseline proteinuria 2.041.87-2.22<0.001

14. Was the amount of proteinuria altered during the course of the study?

15. Irbesartan Diabetic Nephropathy Trial (IDNT) Decrease in proteinuria at 12 months 95% CIP Irbesartan (300 mg/day)41% (37-46)<0.001 Amlodipine (10 mg/day)11% (4-17)0.004 Control16% (9-22) Proteinuria at 30 months Decrease Irbesartan50% Amolidipine23% Control21%

17. Irbesartan Diabetic Nephropathy Trial (IDNT) 50% Decrease Proteinuria Levels at 12 Months Compared to Baseline Irbesartan40% Amlodipine20%(P<0.001 vs IRB) Control25%(P<0.001 vs IRB)

18. Did alteration in the amount of proteinuria correlate with renal outcomes?

19. Irbesartan Diabetic Nephropathy Trial (IDNT) Impact of Change in Proteinuria at 36 Months Proteinuria Renal End-points (2x Cr s or ESRD) Greater than 50% reduction 9.6% Zero to 50% reduction 26.2% Zero to 50% increase 34.5% More than 50% increase 38.0%

20. Renal Outcome by Level of Proteinuria Change at 12 Months

21. Irbesartan Diabetic Nephropathy Trial (IDNT) Reduction of Risk of Kidney Failure: Relationship to Halving of Proteinuria at 12 Months P vs those not halving Irbesartan (20 mg)0.39 (0.32-0.47)<0.001 Amlodipine (10 mg)0.49 (0.42-0.58)<0.001 Control0.44 (0.38-0.51)<0.001 Amlodipine vs irbesartan p = 0.48 Control vs irb p = 0.245

22. Decreased proteinuria is therefore a marker for an improved renal outcome. Can the proportion of the renoprotective effect of irbesartan which is associated with decreased proteinuria be estimated?

23. Irbesartan Diabetic Nephropathy Trial (IDNT) Irbesartan Hazard Ratio 95% CIP Progressive Kidney Failure (2x Cr s, ESRD) (12 mos) 0.640.48-0.840.001 Adjust for proteinuria0.770.58-1.020.069 Adjust for proteinuria, systolic, diastolic BP 0.780.59-1.030.082

24. Conclusions 1.Baseline proteinuria identifies patients at greatest risk for a poor renal outcome. 2.Proteinuria reduction is more common and greater when irbesartan is used in this patient population. 3.Halving proteinuria is associated with a marked decrease in the risk of a renal endpoint. 4.Proteinuria reduction in the first 12 months of follow-up accounts for some, but not all of the renoprotective effect of irbesartan.