Tazeen H. Jafar, M.D., M.P.H.Professor of MedicineHead, Section of NephrologyDepartment of Medicine and Community Health SciencesAga Khan University, Karachi, Pakistan&Adjunct Faculty, Division of NephrologyTufts Medical CenterBoston, MA, US
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),
Overview
AIPRD individual patient data meta-analysis (IPDMA) Main Objectives Methodology Results
Proteinuria as Surrogate During Treatment with ACE inhibitors
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?
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)
Characteristics Of Studies Included In Individual Patient Data Meta-analysis
Study Zucchelli et al
Kamper et al
Brenner et al*
Totoet 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
StudyCharacteristics
Year of publication 1992 1992 1993 1993 1994 1994 1994 1995 1996 1996 1997/9
Number of patients 121 55 106 122 103 99 47 255 67 562 323
Planned Durationof follow-up (years)
3 2 3 3 4 3 1 2 2 3 3
Type of ACEI Captopril Enalapril Enalapril Enalapril Enalapril Enalapril Enalapril Cilazapril Enalapril Benazepril Ramipril
Control Nifedipine NS Placebo Placebo Atenololor
acebutalol
Atenololor
acebutalol
Nifedipine Atenololor
acebutalol
Placebo Placebo Placebo
Primary outcome GFR, CCr, Scr
GFR GFR, CCr, Scr
GFR, CCr Scr
GFR, SCr GFR, Scr
GFR GFR GFR, CCr Scr
SCr GFR, SCr
Method for urine protein
24 h 24 h 24 h 24 h 24 h 24 h 24 h dipstick 24 h 24 h 24 h
Authors’ primaryconclusion
NS ACEIbetter
NS NS NS ACEIbetter
NS ACEIbetter
ACEIbetter
ACEIbetter
ACEIbetter
(Jafar, T. et. al. Ann Intern Med 2001)
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
Definitions
Measures of ProteinuriaCollection: 24 hours urine specimens in 10 studies and dipstick
in oneAnalyte: 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
Measures for validating proteinuria as surrogate endpoint in IPD-MA1) 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
Cause of Kidney Disease Glomerular diseases 32.9% Hypertensive nephrosclerosis 33.0% Tubulointerstitial diseases 11.8% PKD 7.6% Others 14.7%
Comparison Of Randomized Groups
Outcomes
<0.001-0.03 (1.16)0.43 (1.67)0.20 (1.46)Decline in UP g/d (SD)
All Patients ACE inhibitor group Control group P value
Number of Patients 1860 941 919
Baseline Characteristics
Men n (%) 1215 (65) 615 (65) 600 (65) >0.2
Age in years mean (SD) 52 (13) 52 (13) 52 (13) >0.2
Serum Creatinine (mg/dl) mean (SD) 2.3 (1.2) 2.3 (1.2) 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) 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
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
Treatment Effect on Surrogate (Proteinuria)
(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
Treatment Interaction with Baseline UP After Accounting for Change in UP
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)
Unadjusted 0.65 (0.48-0.88) 0.63 ( 0.51-0.80)
Adjusted for baseline variables 0.65 (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
Doubling of Serum Creatinine or onset of Kidney Failure-AIPRD)
Regression of Outcome vs. Treatment HR (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.
Treatment Effect According to Current UP
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)
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
Proteinuria and treatment with ACE inhibitorsIn 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 excretionn However, urine protein during follow up may not
capture full treatment effect of ACE inhibitors
Proteinuria -SummaryIn 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
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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