1. Tazeen H. Jafar, M.D., M.P.H. Professor of Medicine Head, Section of Nephrology Department of Medicine and Community Health Sciences Aga Khan University, Karachi, Pakistan & Adjunct Faculty, Division of Nephrology Tufts Medical Center Boston, MA, US

2. ACE Inhibition in Progressive Renal Disease (AIPRD) Study Group Members of the AIPRD Study Group: Pietro Zucchelli, (Via P Palagi, Italy), Gavin Becker (Melbourne, Australia), Kym Bannister (Adelaide, Australia), Paul Landais (Paris, France), Giuseppe Remuzzi (Bergamo, Italy), Piero Ruggenenti (Bergamo, Italy), Annelisa Perna (Bergamo, Italy), Annelise Kamper (Copenhagen, Denmark), Svend Strandgaard (Copenhagen, Denmark), Benno U. Ihle (Melbourne, Australia), Andres Himmelmann (Goteborg, Sweden), Lennart Hannson (Goteborg, Sweden), Jean-Pierre Grunfeld (Paris, France), Paul E de Jong (Groningen, Netherlands), Dick de Zeeuw (Groningen, Netherlands), Gabe G. Van Essen (Groningen, Netherlands), Alfred J. Apperloo (Groningen, Netherlands), Lamberto Oldrizzi (Verona, Italy), Carmelita. Marcantoni (Verona, Italy), Giuseppe Maschio (Verona, Italy), Ioannis Giatras, (Greece), Shahnaz Shahinfar (Westpoint, USA), Robert Toto (Dallas, USA), Barry M. Brenner (Boston, USA), Joseph Lau (Boston, USA), Nicolaos E. Madias (Boston, USA), Barbara Delano, (Brooklyn, USA), Tauqir Karim (Boston, USA), Ronald Perrone (Boston, USA), Christopher H. Schmid (Boston, USA), Tazeen H Jafar (Karachi, Pakistan and Boston, USA) and Andrew S. Levey (Boston, USA). Funding: Dialysis Clinic, Inc. Paul Teschan Research Fund 1097-5 (Dr. Jafar), NEMC St. Elizabeth’s Hospital Clinical Research Fellowship, Boston, MA (Dr. Jafar), and an unrestricted grant from Merck Research Laboratories, West Point, NJ (Dr. Levey), Supported by grants from NIDDK RO1 DK53869A (Dr. Levey), AHCPR RO1 HS 10064 (Dr. Schmid),

3. Overview AIPRD individual patient data meta-analysis (IPDMA) Main Objectives Methodology Results Proteinuria as Surrogate During Treatment with ACE inhibitors

4. Benefit of ACE inhibitors independent of BP lowering effect could not be established in meta-analysis of group data Giatras, I. et. al. Ann Intern Med 1997;127:337-345 Background-why AIPRD IPDMA? Which antihypertensive agent to use?

5. AIRPD Individual Patient Data Meta- analysis 11 RCTS with 1860 patients with non-diabetic kidney disease Anti-hypertensive regimens with ACE inhibitors vs. those without ACE inhibitors on progression of kidney disease. Minimum follow-up of one year Database closed in 1999 Objectives: 1) To determine whether antihypertensive regimens with ACE inhibitors are superior to those without ACE inhibitors after accounting for patients’ baseline characteristics and change in BP during treatment. 2) To assess the relationship of BP with progression of kidney disease across a wide range of urine protein excretion. (Jafar, TH et. al. Ann Intern Med 2001; Jafar, TH et. al. Ann Intern Med 2003)

6. Characteristics Of Studies Included In Individual Patient Data Meta-analysis StudyZucchelli et al Kamper et al Brenner et al* Toto et al * Van Essen et al Hanned - ouche et al Banni- ster et al Himme- mann et al Ihle et al Maschio et al Rugg- enenti et al Study Characteristics Year of publication1992 1993 1994 19951996 1997/9 Number of patients12155106122103994725567562323 Planned Duration of follow-up (years) 32334312233 Type of ACEICaptoprilEnalapril CilazaprilEnalaprilBenazeprilRamipril ControlNifedipineNSPlacebo Atenolol or acebutalol Atenolol or acebutal ol NifedipineAtenolol or acebutalol Placebo Primary outcomeGFR, CCr, Scr GFRGFR, CCr, Scr GFR, CCr Scr GFR, SCrGFR, Scr GFR GFR, CCr Scr SCrGFR, SCr Method for urine protein 24 h dipstick24 h Authors’ primary conclusion NSACEI better NS ACEI better NSACEI better ACEI better ACEI better ACEI better (Jafar, T. et. al. Ann Intern Med 2001)

7. Methods Mean follow-up 2.2 years Visits=22,610 Primary Outcome (True Endpoints) Composite outcome of doubling of baseline serum creatinine or onset of ESRD (true endpoint) Onset of ESRD (true endpoint) Multivariable models adjusted for study centers Cox proportional hazards regression analysis Treatment effect (ACEI vs other antihypertensive agents) With and without adjustment for proteinuria (surrogate) 1) Change from baseline; 2) current level on treatment Jafar TH et al. Annals Intern Med 2003

8. Definitions Measures of Proteinuria Collection: 24 hours urine specimens in 10 studies and dipstick in one Analyte: Total Urinary Protein (in g/d) Analytical methods: Total protein –automated precipitation assays in 10, dipstick in one Threshold: continuous. All values of urine protein <0.1 g/d converted to 0.1 g/d) Outcomes Doubling of baseline serum creatinine or onset of kidney failure Onset of kidney failure

9. Measures for validating proteinuria as surrogate endpoint in IPD-MA 1) Assessed individual-level association 1) treatment affects the surrogate endpoint (UP) 2) treatment affects the true endpoint (Doubling of serum Creatinine/ onset of kidney failure) 3) “adjusted association”: association treatment and true endpoint after accounting for treatment effect on surrogate and for center effect

10. Cause of Kidney Disease Glomerular diseases 32.9% Hypertensive nephrosclerosis 33.0% Tubulointerstitial diseases 11.8% PKD 7.6% Others 14.7%

11. Comparison Of Randomized Groups All PatientsACE inhibitor groupControl groupP value Number of Patients1860941919 Baseline Characteristics Men n (%)1215 (65)615 (65)600 (65)>0.2 Age in years mean (SD)52 (13) >0.2 Serum Creatinine (mg/dl) mean (SD)2.3 (1.2) >0.2 Systolic BP (mm Hg) mean (SD)148 (22)148 (21)149 (22)>0.2 Diastolic BP (mm Hg) mean (SD)90 (11) 91 (11)>0.2 Urine protein (g/d) mean (SD) (median)1.8 (2.3) (0.98)1.8 (2.5) (0.94)1.8 (2.1) (1.0)>0.2 Follow-up characteristics Systolic BP (mm Hg) mean (SD)142 (17)139 (16)144 (16)<0.001 Diastolic BP (mm Hg) mean (SD)86 (8)85 (7)85 (8)<0.001 Urine protein excretion g/d mean (SD)1.6 (1.8)1.4 (1.8)1.7 (2.0)<0.001 Outcomes Decline in UP g/d (SD)0.20 (1.46)0.43 (1.67)-0.03 (1.16)<0.001 Kidney Failure n (%)176 (9.5)70 (7.4)106 (11.6)0.002 Doubling of serum creatinine or kidney failure n (%)311 (16.8)124 (13.2)187 (20.5)0.001 Death n (%)31 (1.6)20 (2.1)11 (1.2)0.13 Withdrawals n (%)387 (20.8)207 (22.0)180 (19.6)0.2

12. Treatment Effect on Surrogate (Proteinuria)

13. (Jafar, T. et. al. Ann Intern Med 2001) Risk Of Kidney Disease Progression In Patients Taking ACE Inhibitors (Squares) And Controls (Circles), According To Baseline Urinary Protein Excretion Interaction p <0.001

14. Treatment Interaction with Baseline UP After Accounting for Change in UP

15. Treatment Effect of ACE inhibitors on True Endpoints TREATMENT EFFECT (RR) ACE inhibitor VS. CONTROL Kidney failure RR (CI) Doubling of baseline serum creatinine or Kidney Failure RR (CI) Unadjusted0.65 (0.48-0.88)0.63 ( 0.51-0.80) Adjusted for baseline variables0.65 (0.47-0.88)0.60 (0.48-0.76) Adjusted for baseline variables and  SBP 0.68 (0.50-0.93)0.65 (0.51-0.81) Adjusted for baseline variables and  UP 0.69 (0.50-0.95)0.66 (0.52-0.84) Adjusted for baseline variables, and  SBP and  UP 0.71 (0.51-0.97)0.70 (0.55-0.88) (Jafar, T. et. al. Ann Intern Med 2001) Cox proportional hazards regression analysis

16. Doubling of Serum Creatinine or onset of Kidney Failure-AIPRD) Regression of Outcome vs. TreatmentHR (CI) Treatment 0.64 (0.50-0.79) Regression of Outcome vs. Treatment Adjusted for Baseline HR (CI) Treatment 0.58 (0.46- 0.73) Baseline proteinuria (each 1 g/d increase) 1.18 (1.14-1.21) Regression of Outcome vs. Treatment Adjusted for Baseline and Change HR (CI) Treatment 0.65 (0.52-0.82) Baseline proteinuria (each 1 g/d increase) 1.30 (1.26-1.35) Decline in proteinuria (each 1 g/d decrease) 0.84 (0.80-0.87) Note: If treatment is effective, HR for treatment will be <1.0. If proteinuria is a surrogate marker for treatment effect, HR for treatment effect will increase from <1.0 to closer to 1.0 in adjusted models.

17. Treatment Effect According to Current UP

18. Doubling of Serum Creatinine or onset of Kidney Failure-AIPRD) Regression of Outcome vs. Treatment Adjusted for Baseline and current (during treatment) HR (CI) Treatment 0.65 (0.52-0.81) Baseline proteinuria (each 1 g/d increase) 1.09 (1.04-1.14) current proteinuria (each 1 g/d increase) 1.19 (1.15-1.24)

19. Which antihypertensive agent? summary ACEI are superior to other agents in slowing progression of non-diabetic kidney disease in patients with UP of 0.5 g/d or greater This benefit of ACEI is in addition to their BP and UP lowering effects Benefit of ACEI is greater in patients with high levels of proteinuria at initiation of therapy

20. Proteinuria and treatment with ACE inhibitors In patients with non-diabetic kidney disease, High baseline level of proteinuria predicts a higher risk Benefit of ACE inhibitors greater in those with higher levels of proteinuria at baseline This greater benefit can be explained by antiproteinuric effect of ACE inhibitors A lower level of urine protein excretion during treatment predicts a lower risk. At all levels of urine protein during follow-up, the risk is lower in patients treated with ACE inhibitors. Aim to lower urine protein excretion However, urine protein during follow up may not capture full treatment effect of ACE inhibitors

21. Proteinuria -Summary In patients with non-diabetic CKD: Initial proteinuria Robust for risk stratification Treatment indication with ACE inhibitors Change in proteinuria Accounts only partially for treatment effect of ACE inhibitors Validity as surrogate suboptimal, perhaps valuable in those with high levels of proteinuria at baseline Proteinuria on treatment Therapeutic target Continue following Suboptimal surrogate for treatment with ACE inhibitor Continue search for better

22. Limitations Method of assessment of proteinuria varied across studies Insensitive at lower levels of proteinuria Patients not randomized to different levels of proteinuria ?reverse causation Type of ACE inhibitor used varied across studies Dose of ACE inhibitors

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