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Progression Risk, Urinary Protein Excretion, and Treatment Effects of Angiotensin-Converting Enzyme Inhibitors in Nondiabetic Kidney Disease

David M. Kent^*, Tazeen H. Jafar, Rodney A. Hayward, Hocine Tighiouart^*, Marcia Landa^*, Paul de Jong, Dick de Zeeuw, Giuseppe Remuzzi^||, Anne-Lise Kamper^¶, Andrew S. Levey^* for the AIRPD Study Group

^* Institute for Clinical Research and Health Policy Studies, Tufts University-New England Medical Center, Boston, Massachusetts; Department of Medicine, Aga Khan University, Karachi, Pakistan; Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; Department of Internal Medicine, University of Groningen, Groningen, Netherlands; ^|| Institute di Recherche Farmacologiche "Mario Negri", Bergamo, Italy; and ^¶ Department of Nephrology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark

Address correspondence to: Dr. David M. Kent, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, 750 Washington Street, #63, Boston, MA 02111. Phone: 617-636-3234; Fax: 617-636-8023; dkent1{at}tufts-nemc.org

Received for publication October 2, 2006. Accepted for publication March 29, 2007.

It is unclear whether patients with nondiabetic kidney disease benefit from angiotensin-converting enzyme inhibitor (ACEI) therapy when they are at low risk for disease progression or when they have low urinary protein excretion. With the use of a combined database from 11 randomized, clinical trials (n = 1860), a Cox proportional hazards model, based on known predictors of risk and the composite outcome kidney failure or creatinine doubling, was developed and used to stratify patients into equal-sized quartiles of risk. Outcome risk and treatment effect were examined across various risk strata. Use of this risk model for targeting ACEI therapy was also compared with a strategy based on urinary protein excretion alone. Control patients in the highest quartile of predicted risk had an annualized outcome rate of 28.7%, whereas control patients in the lowest quartile of predicted risk had an annualized outcome rate of 0.4%. Despite the extreme variation in risk, there was no variation in the degree of benefit of ACEI therapy (P = 0.93 for the treatment x risk interaction). Significant interaction was detected between baseline urine protein and ACEI therapy (P = 0.003). When patients were stratified according to their baseline urinary protein excretion, among the subgroup of patients with proteinuria 500 mg/d, significant treatment effect was seen across all patients with a measurable outcome risk, including those at relatively low risk (1.7% annualized risk for progression). However, there was no benefit of ACEI therapy among patients with proteinuria <500 mg/d, even among higher risk patients (control outcome rate 19.7%). Patients with nondiabetic kidney disease vary considerably in their risk for disease progression, but the treatment effect of ACEI does not vary across risk strata. Patients with proteinuria <500 mg/d do not seem to benefit, even when at relatively high risk for progression.

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