Angiotensin and Renal Disease: The Jury is Still Out

In their meta-analysis, MacKinnon et al1 concluded that combining an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker provides an additional decrease in proteinuria over monotherapy with an angiotensin-converting enzyme inhibitor. The analysis confirms the safety of combination therapy. However, we have concerns with the finding of a superior decrease in proteinuria with combination therapy because the latter results may be susceptible to bias through heterogeneity.

MacKinnon et al1 appropriately did not perform a meta-analysis on the parallel-group trials because of heterogeneity.2 Although the investigators also found significant heterogeneity among the crossover trials, they nevertheless proceeded to perform a meta-analysis. These trials were clinically heterogeneous, studying patients with chronic kidney disease resulting from diabetes and other nephropathies and with baseline proteinuria ranging from protein of 0.9 to 7.9 g/d. To better assess the level of statistical heterogeneity, we calculated an I-squared statistic of 82% for the analysis of effects of combination therapy on proteinuria; values greater than 50% represent significant heterogeneity.2, 3 The investigators appropriately attempted to elucidate the cause of heterogeneity through a subgroup analysis by cause of renal disease. Unfortunately, their conclusion, that combination therapy may provide additional benefit for patients with nondiabetic kidney disease compared with patients with diabetes, also is burdened by statistical heterogeneity. Because there is significant residual heterogeneity even in subgroup analysis, we should be wary of any inferences on the effect of combination therapy on proteinuria and await results from larger trials.