Meta-analysis: Effect of Monotherapy and Combination Therapy with Inhibitors of the Renin–Angiotensin System on Proteinuria in Renal Disease

1 January 2008 | Volume 148 Issue 1

Background: Reduction of proteinuria is associated with a delayed progression of chronic kidney disease. Reports suggest that angiotensin-receptor blockers (ARBs) reduce proteinuria, but results are variable. The relative effect of ARBs and angiotensin-converting enzyme (ACE) inhibitors, and their combined administration, remains uncertain.

Purpose: To establish the effect of ARB versus placebo and alternative treatments, and the effect of combined treatment with ARBs and ACE inhibitors, on proteinuria.

Data Sources: English-language studies in MEDLINE and the Cochrane Library's Central Register of Controlled Trials (from January 1990 to September 2006), reference lists, and expert contacts.

Study Selection: Randomized trials of ARBs versus placebo, ACE inhibitors, calcium-channel blockers, or the combination of ARBs and ACE inhibitors in patients with or without diabetes and with microalbuminuria or proteinuria for whom data were available on urinary protein excretion at baseline and after 1 to 12 months.

Data Extraction: Two investigators independently searched and abstracted studies.

Data Synthesis: Forty-nine studies involving 6181 participants reported results of 72 comparisons with 1 to 4 months of follow-up and 38 comparisons with 5 to 12 months of follow-up. ARBs reduced proteinuria compared with placebo or calcium-channel blocker over 1 to 4 months (ratio of means, 0.57 [95% CI, 0.47 to 0.68] and 0.69 [CI, 0.62 to 0.77], respectively) and 5 to 12 months (ratio of means, 0.66 [CI, 0.63 to 0.69] and 0.62 [CI, 0.55 to 0.70], respectively). ARBs and ACE inhibitors reduced proteinuria to a similar degree. The combination of ARBs and ACE inhibitors further reduced proteinuria more than either agent alone: The ratio of means for combination therapy versus ARBs was 0.76 (CI, 0.68 to 0.85) over 1 to 4 months and 0.75 (CI, 0.61 to 0.92) over 5 to 12 months; for combination therapy versus ACE inhibitors, the ratio of means was 0.78 (CI, 0.72 to 0.84) over 1 to 4 months and 0.82 (CI, 0.67 to 1.01) over 5 to 12 months. The antiproteinuric effect was consistent across subgroups.

Limitations: Most studies were small, were of variable quality, and did not provide reliable data on adverse drug reactions. Proteinuria reduction is only a surrogate for important progression of renal failure.

Conclusions: The ARBs reduce proteinuria, independent of the degree of proteinuria or underlying disease. The magnitude of effect is similar whether the comparator is placebo or calcium-channel blocker.

Author and Article Information

From Basel Institute for Clinical Epidemiology and Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland, and Munich General Hospitals, Ludwig Maximilians University, Munich, Germany.

See related article: Systematic Review: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers for Treating Essential Hypertension by D.B. Matchar, D.C. McCrory, L.A. Orlando, M.R. Patel, U.D. Patel, M.B. Patwardhan, B. Powers, G.P. Samsa, and R.N. Gray.

See editorial: Inhibitors of the Renin–Angiotensin System: Proven Benefits, Unproven Safety by P.S. Parfrey.

Acknowledgments: The authors thank Gordon Guyatt for constructive discussions and Jan Friedrich for sharing details regarding the methods of generating ratios of means.

Potential Financial Conflicts of Interest: Honoraria: J.F.E. Mann (Boehringer-Ingelheim, Novartis, Aventis). Grants received: J.F.E. Mann (Aventis, Novartis).

Reproducible Research Statement: For information on the protocol, statistical code, and data, contact Dr. Regina Kunz at rkunz{at}uhbs.ch.

Requests for Single Reprints: Regina Kunz, MD, MSc, Basel Institute for Clinical Epidemiology, University Hospital Basel, Hebelstrasse 10, 4031 Basel, Switzerland; e-mail, rkunz{at}uhbs.ch.

Author Contributions: Conception and design: R. Kunz, C. Friedrich, J.F.E. Mann.

Analysis and interpretation of the data: R. Kunz, C. Friedrich, J.F.E. Mann, M. Wolbers.

Drafting of the article: R. Kunz, M. Wolbers.

Critical revision of the article for important intellectual content: R. Kunz, C. Friedrich, J.F.E. Mann, M. Wolbers.

Final approval of the article: R. Kunz, C. Friedrich, J.F.E. Mann, M. Wolbers.

Provision of study materials or patients: R. Kunz, C. Friedrich.

Statistical expertise: R. Kunz, M. Wolbers.

Obtaining of funding: J.F.E. Mann.

Administrative, technical, or logistic support: R. Kunz, C. Friedrich.

Collection and assembly of data: R. Kunz, C. Friedrich.