Meta-analysis: Effect of monotherapy and combination therapy with inhibitors of the renin-angiotensin system on proteinuria in renal disease

Background: Reduction of proteinuria is associated with 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 ARBs 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 Central Register of Controlled Trials (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 at 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. The ARBs reduced proteinuria compared with placebo or calcium-channel blockers over 1 to 4 months (ratio of means, 0.57 [95% Cl, 0.47 to 0.68] and 0.69 [Cl, 0.62 to 0.77], respectively) and 5 to 12 months (ratio of means, 0.66 [Cl, 0.63 to 0.69] and 0.62 [Cl, 0.55 to 0.70], respectively). The 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 (Cl, 0.68 to 0.85) over 1 to 4 months and 0.75 (Cl, 0.61 to 0.92) over 5 to 12 months; for combination therapy versus ACE inhibitors, the ratio of means was 0.78 (Cl, 0.72 to 0.84) over 1 to 4 months and 0.82 (Cl, 0.67 to 1.01) over 5 to 12 months. The antiproteinuric effect was consistent across subgroups. Limitations: Most studies were small, varied in quality, and did not provide reliable data on adverse drug reactions. Proteinuria reduction is only a surrogate for important progression of renal failure. Conclusion: The ARBs reduce proteinuria, independent of the degree of proteinuria and of underlying disease. The magnitude of effect is similar regardless of whether the comparator is placebo or calcium-channel blocker. Reduction in proteinuria from ARBs and ACE inhibitors is similar, but their combination is more effective than either drug alone. Uncertainty concerning adverse effects and outcomes that are important to patients limits applicability of findings to clinical practice.