Commentary

Determining Whether to Continue Renin-Angiotension System Blockade in Patients With Advanced Kidney Disease

Michael J. Bloch, MD
03/05/2024

Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Renown Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC

CITATION: Bloch MJ. Determining whether to continue renin-angiotensin system blockade in patients with advanced kidney disease. Consultant360. Published online January 5, 2023.

 

Blockers of the renin-angiotensin-system (RAS), like angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) act as a double-edged sword in patients with chronic kidney disease (CKD). On the one hand, over the long term, we know that at least in stage 3 CKD (eGFR 30-59 mg/ml/1.73m2) RAS-blocking agents can slow the progression of renal decline, particularly in patients with significant proteinuria or albuminuria. But, since they dilate the glomerular efferent arteriole, RAS-blocking agents can reduce filtration fraction and GFR in the short term. Balancing the risks and benefits of RAS blockers in advanced CKD has been a vexing clinical problem with a shortage of high-quality clinical trial data available to guide decision-making. Previous observational studies have provided conflicting results regarding whether to withhold RAS-blocking agents in patients with eGFR <30 mg/ml/1.73m2).1,2 The STOP ACEi Trial was designed to shed light on this lingering question.3

STOP ACEi was a prospective, multicenter, open-label clinical trial where patients with GFR < 30 mg/ml/1.73m2 were randomized to either discontinue or continue their previously prescribed RAS-blocking agents. The primary outcome was achieved eGFR after 3 years. Key secondary outcomes included the development of end-stage renal disease (ESRD), a composite of a decrease in eGFR of > 50% or development of ESRD, hospitalization, cardiovascular (CV) events, exercise capacity, and quality of life. Participants included those with and without diabetes and with and without significant albuminuria or proteinuria, but results were stratified using these variables in prespecified subgroup analysis.

In total, STOP ACEi included 411 participants from 37 centers in the United Kingdom. After 3 years of therapy, the least squares mean eGFR was 12.6 mg/ml/1.73m2 in the discontinuation group and 13.3 mg/ml/1.73m2 in the continuation group, a difference that was not statistically significant. There was no heterogeneity in the outcome observed based on the presence or absence of diabetes or albuminuria/proteinuria. Further, ESRD occurred in 62% of the discontinuation group and 56% in the continuation group, a difference that was not statistically significant. CV events occurred in 108 participants in the discontinuation group and 88 in the continuation group. There were no apparent differences between the groups in terms of hospitalization, death, quality of life, or exercise capacity.

This study was designed to determine the effect of discontinuing RAS-blocking agents in patients with advanced CKD. As such, strictly speaking, the results of this study confirm that there is no clinically significant benefit in discontinuing RAS-blocking agents in patients with advanced CKD. Whether the converse is true—whether there is a clinically significant benefit to continuing RAS blockers—is a more difficult question to answer based on this study. Certainly, in this relatively small clinical trial there was a trend towards the reduced progression of eGFR decline, less ESRD, and fewer CV events in those who continued RAS blockade; whether a larger trial would have led to a statistically significant benefit for continuation remains unknown.

My primary interpretation of this study is that RAS blockers do not need to be routinely discontinued in patients with GFR < 30 mg/ml/1.73m2. But, since there was relative equipoise in these results, if patients are at high risk of acute renal failure, have electrolyte disturbances, rapid deterioration in renal function, orthostatic hypotension, or need to reduce pill burden, it seems reasonable to discontinue RAS blockers in select patients without much worry that we are withholding therapy that is crucial for avoiding ESRD. What remains striking in these results are both the high rate of progression to ESRD and the high incidence of CV events, even in this contemporary cohort receiving maximal traditional therapy.

The results of STOP ACEi stand in sharp contrast to the recently published EMPA-kidney study, where the use of empagliflozin was shown to decrease the composite of clinically significant progression of CKD or death from CV causes after only 2 years of therapy.4 Notably, about 1/3 of the EMPA-KIDNEY cohort had a baseline eGFR < 30 mg/ml/1.73m2. The non-steroidal mineralocorticoid receptor antagonist, finerenone, has also recently been demonstrated to decrease the progression of CKD and reduce CV events in patients with diabetes and some degree of albuminuria, although most patients in the pivotal clinical trial had eGFR > 25 mg/ml/1.73m2.5

While a comparison of these trials certainly does not “close the book” on the usage of RAS-blocking agents in patients with advanced CKD, it does suggest that new chapters need to be opened if we want to slow the progression to ESRD and reduce CV events in this high-risk population.

References:

  1. Fu EL, Evans M, Clase CM, et al. Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study. J Am Soc Nephrol. 2021;32(2):424-435. doi:10.1681/ASN.2020050682
  2. Nakayama T, Morimoto K, Uchiyama K, et al. Effects of renin-angiotensin system inhibitors on the incidence of unplanned dialysis. Hypertens Res. 2022;45(6):1018-1027. doi:10.1038/s41440-022-00877-5
  3. Bhandari S, Mehta S, Khwaja A, et al. Renin–angiotensin system inhibition in advanced chronic kidney disease. N Engl J Med. 2022;387(22):2021-2032. doi:10.1056/NEJMoa2210639
  4. Herrington WG, Staplin N, Wanner C, et al; EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Eng J Med. 2022. doi:10.1056/NEJMoa2204233
  5. Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. New Eng J Med. 2020;383(23):2219-2229. doi:10.1056/NEJMoa2025845