Inhibition of the renin-angiotensin system in advanced chronic kidney disease

Abstract

Background

Inhibitors of the renin-angiotensin system (RAS) — including angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) — slow the progression of mild to moderate chronic kidney disease. However, the results of some studies suggest that discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline.

Methods

In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute at 1.73 m² body surfaces) or discontinue or continue RAS inhibitor therapy. The primary outcome was eGFR at 3 years; The eGFR values ​​obtained after the start of renal replacement therapy were excluded. Secondary outcomes included the development of end-stage renal disease (ESRD); combination of eGFR reduction by more than 50% or initiation of renal replacement therapy, including ESKD; hospitalization; blood pressure; ability to exercise; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.

the results

After 3 years, among the 411 patients enrolled, the least squares mean (±SE) eGFR was 12.6±0.7 ml per minute at 1.73 m² in the interruption group and 13.3±0.6 ml per minute at 1.73 m² in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P=0.42), with a negative value favoring the outcome in the extension group. No heterogeneity in outcome was observed according to prespecified subgroups. ESKD or initiation of renal replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and the continuation group with respect to cardiovascular events (108 vs. 88) and death (20 vs. 22).

Findings

Among patients with advanced and progressive CKD, discontinuation of RAS inhibitors was not associated with a significant difference between groups in the long-term rate of eGFR decline. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISTRCTN number, 62869767.)