Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease

N Engl J Med. 2022 Dec 1;387(22):2021-2032. doi: 10.1056/NEJMoa2210639. Epub 2022 Nov 3.


Background: Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the 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 per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria.

Results: At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 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 continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the 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 continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22).

Conclusions: Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISRCTN number, 62869767.).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin Receptor Antagonists* / adverse effects
  • Angiotensin Receptor Antagonists* / pharmacology
  • Angiotensin Receptor Antagonists* / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors* / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors* / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors* / therapeutic use
  • Angiotensins / pharmacology
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use
  • Glomerular Filtration Rate
  • Humans
  • Kidney Failure, Chronic* / complications
  • Kidney Failure, Chronic* / drug therapy
  • Quality of Life
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / drug therapy
  • Renin-Angiotensin System* / drug effects


  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Angiotensins
  • Antihypertensive Agents

Associated data

  • EudraCT/2013-003798-82
  • ISRCTN/62869767