Renin-Angiotensin System Inhibitors in Advanced CKD: a #NephJC Editorial on STOP-ACEi

#NephJC is a recurring twitter-based journal club. #NephJC editorials highlight the discussed article and summarize key points from the NephJC TweetChat. #NephJC is a recurring twitter-based journal club. #NephJC editorials highlight the discussed article and summarize key points from the NephJC TweetChat. Renin-angiotensin system (RAS) inhibitors have been the preferred antihypertensive agents in the setting of chronic kidney disease (CKD) since the 1990s. Their use has been consistently demonstrated to slow the progression of kidney disease, along with beneficial blood pressure and proteinuria lowering effects.1Lewis E.J. Hunsicker L.G. Bain R.P. Rohde R.D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.N Engl J Med. 1993; 329: 1456-1462Crossref PubMed Scopus (5067) Google Scholar, 2Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (5107) Google Scholar, 3GISENRandomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, nondiabetic nephropathy.Lancet. 1996; 349: 1857-1863Google Scholar, 4Jafar T.H. Schmid C.H. Landa M. et al.Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data.Ann Intern Med. 2001; 135: 73-87Crossref PubMed Scopus (901) Google Scholar, 5Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6237) Google Scholar Although RAS blockade is a pillar of proteinuric CKD management, questions remain around whether they can be safely continued in patients with advanced CKD and whether they remain nephroprotective in later stages of the disease. Ongoing RAS inhibitor use has been historically challenging in patients with advanced CKD, particularly those with diabetes, where hyperkalemia may be difficult to manage.6Palmer B.F. Managing hyperkalemia caused by inhibitors of the renin–angiotensin–aldosterone system.N Engl J Med. 2004; 351: 585-592Crossref PubMed Scopus (488) Google Scholar,7Einhorn L.M. Zhan M. Hsu V.D. et al.The frequency of hyperkalemia and its significance in chronic kidney disease.Arch Intern Med. 2009; 169: 1156-1162Crossref PubMed Scopus (442) Google Scholar This commonly leads to RAS inhibitor discontinuation. The recent advent of novel potassium binding therapies, such as sodium zirconium cyclosilicate and patiromer, has strengthened the armamentarium against hyperkalemia and has helped ease the challenge of RAS inhibitor continuation in this setting.8Palmer B.F. Potassium binders for hyperkalemia in chronic kidney disease-diet, renin-angiotensin-aldosterone system inhibitor therapy, and hemodialysis.Mayo Clin Proc. 2020; 95: 339-354Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar However, data from a 2010 prospective cohort study in the United Kingdom demonstrated a significant increase in estimated glomerular filtration rate (eGFR) after discontinuation of RAS inhibitors in patients with advanced CKD.9Ahmed A.K. Kamath N.S. El Kossi M. El Nahas A.M. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease.Nephrol Dial Transplant. 2010; 25: 3977-3982Crossref PubMed Scopus (134) Google Scholar These authors proposed that the RAS inhibitor discontinuation delayed the onset of kidney replacement therapy (KRT) in that cohort, and they encouraged providers to reconsider RAS inhibitor use in patients with CKD stages 4 and 5.9Ahmed A.K. Kamath N.S. El Kossi M. El Nahas A.M. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease.Nephrol Dial Transplant. 2010; 25: 3977-3982Crossref PubMed Scopus (134) Google Scholar The notion that discontinuation would improve kidney function and allow for time to plan for KRT (eg, access planning or preemptive kidney transplantation) was plausible. Conversely, ongoing RAS inhibitor use in advanced CKD is supported by its beneficial effects, including blood pressure control and proteinuria reduction, along with cardioprotection and benefit in reducing mortality, which are of great importance in this population with a high prevalence of cardiovascular (CV) comorbid conditions.10Fu E.L. Evans M. Clase C.M. 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: 424-435Crossref PubMed Scopus (41) Google Scholar,11Qiao Y. Shin J.I. Chen T.K. et al.Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate.JAMA Intern Med. 2020; 180: 718-726Crossref PubMed Scopus (74) Google Scholar Given this conflicting risk to benefit balance in this area of advanced CKD, there was true equipoise. The STOP-ACEI trial investigators sought to address whether discontinuing RAS inhibitors in patients with stage 4-5 CKD would slow the CKD progression in this high-risk population.12Bhandari S. Mehta S. Khwaja A. et al.Renin-angiotensin system inhibition in advanced chronic kidney disease.N Engl J Med. 2022; 387: 2021-2032Crossref PubMed Scopus (18) Google Scholar The STOP-ACEI study was a multicenter, randomized, open-label trial. Participants were adults with stage 4-5 CKD (eGFR < 30 mL/min/1.73 m2) being treated with an angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, or both for >6 months and with a progressive decline defined as glomerular filtration rate loss >2 mL/min/1.73 m2/year for 2 years. The participants were randomized 1:1 to either continue RAS inhibitor therapy or to discontinue it and were followed for 3 years with follow-up visits at 3-month intervals. In the continuation group, the choice of RAS inhibitor agent and dosage were left to provider discretion. The study blood pressure target was <140/85 mm Hg in both the continuation and discontinuation groups, and providers were allowed to choose any guideline-recommended antihypertensives to achieve this target. The primary outcome was the eGFR at 3 years using the 4-variable MDRD175 (Modification of Diet in Renal Disease) Study equation, censored at time of KRT initiation. Secondary endpoints included time to development of end-stage kidney disease and a composite including decrease in eGFR > 50%, development of end-stage kidney disease, and initiation of KRT.12Bhandari S. Mehta S. Khwaja A. et al.Renin-angiotensin system inhibition in advanced chronic kidney disease.N Engl J Med. 2022; 387: 2021-2032Crossref PubMed Scopus (18) Google Scholar A total of 17,290 patents were screened at 39 centers in the United Kingdom. Of these, 411 patients were randomized, 205 to the RAS inhibitor continuation group and 206 to the discontinuation group. The cohort was predominantly male (68%) and White (85%) with a median age of 63 years, and only 37% of participants had diabetes. Participants were not limited to those with traditionally heavy proteinuric CKD and included those with hereditary and polycystic kidney diseases (19.7%), renovascular disease (16.5%), tubulointerstitial disease (1.5%), as well as unknown etiologies (17.3%). For the primary outcome, there was no significant difference in the eGFR at 3 years, with mean eGFR in mL/min/1.73 m2 of the continuation group at 12.6 ± 0.7 compared to 13.3 ± 0.6 in the discontinuation group (P = 0.42). At 3 years, end-stage kidney disease occurred less often in the continuation group (115 patients, 56%) compared with the discontinuation group (128 patients, 62%). Although not reaching statistical significance, the point estimate of the hazard ratio of 1.28 (95% confidence interval, 0.99-1.65) favors RAS inhibitor continuation in this regard. Of the 490 serious adverse events, 21 were potentially related to the trial group assignment, with no significant between-group differences reported. CV events were included in the adverse events and were notably higher in the discontinuation arm (108 events) compared with the continuation arm (88 events), though no formal statistical comparison was done. There were 6 hyperkalemia events reported overall, of which 2 occurred in the discontinuation arm and 4 occurred in the continuation arm.12Bhandari S. Mehta S. Khwaja A. et al.Renin-angiotensin system inhibition in advanced chronic kidney disease.N Engl J Med. 2022; 387: 2021-2032Crossref PubMed Scopus (18) Google Scholar The 2 NephJC Twitter discussions, held on November 29 and 30, 2022, included a combined 169 participants and 753 tweets. The NephJC tweetchats started with an inquiry about a vexing question for nephrologists regarding RAS inhibitors: should we continue them or not once the eGFR drops lower than 30 mL/min/1.73 m2? A poll at the onset of the chats revealed that only 12.9% of 326 respondents would stop RAS inhibitors at a specific eGFR cutoff, whereas almost 50% would continue RAS inhibitors until the start of dialysis (Fig 1). The respondents, mainly nephrologists, highlighted hyperkalemia rather than eGFR as the main determinant of when they choose to stop RAS inhibitors. The chat participants emphasized the low numbers of recruited patients with heart failure or diabetes, and they lamented the fact that only 17% had a prior history of CV events (a group that may benefit most from RAS inhibitor therapy). The STOP-ACEi authors’ decision to focus on progressive CKD with eGFR decline > 2 mL/min/year likely accounted for many of the 17,000 screened participants to be ineligible. Of the 1,210 eligible participants, only 411 were randomized. Patients with higher risk for hyperkalemia or with compelling indications for RAS inhibitor continuation may have been advised by their physicians not to enroll. This could affect generalizability of the study outcome. Chat participants suggested that the Kidney Failure Risk Equation could have been utilized for CKD progression risk rather than the glomerular filtration rate-only based inclusion criterion. Another important point of discussion was the absence of information regarding RAS inhibitor doses and whether they were titrated up to maximum doses. At baseline, one-third of the study participants in both groups were treated with alpha-blockers, the same proportion being on loop diuretics. In the discontinuation group, RAS inhibitors were replaced with alternative blood pressure agents to achieve specified blood pressure targets; however, no information was provided regarding preferred class or doses. Tweetchat participants were surprised that the primary endpoint of eGFR at 3 years was not significantly different between the 2 study groups. Moreover, in the discontinuation group, there was no increase in eGFR, unlike the previous study.9Ahmed A.K. Kamath N.S. El Kossi M. El Nahas A.M. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease.Nephrol Dial Transplant. 2010; 25: 3977-3982Crossref PubMed Scopus (134) Google Scholar There was, however, a 28% decrease in incidence of KRT in the continuation group (95% confidence interval, 0.99-1.65), as well as fewer CV events (108 in the discontinuation group versus 88 in the continuation group). However, this study was not adequately powered to examine effects on CV outcomes, which frustrated some chart participants (Fig 2B). These results were interestingly somewhat concordant with a target trial emulation study from Fu et al,10Fu E.L. Evans M. Clase C.M. 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: 424-435Crossref PubMed Scopus (41) Google Scholar which reported a higher absolute 5-year risk of death (40.9% versus 54.5%) as well as major adverse CV events (47.6% versus 59.5%) with RAS inhibitor discontinuation. However, the same study also reported a lower risk of KRT (36.1% versus 27.9%) with RAS inhibitor discontinuation. This may reflect the inclusion of different populations because STOP-ACEi only included participants with progressive CKD, unlike the target trial emulation observational study. Hyperkalemia is a nemesis of all nephrologists who want to continue RAS inhibitors, no matter the eGFR (Fig 1). Curiously, hyperkalemia was registered in only 4 patients in the STOP-ACEi continuation arm (versus 2 in the discontinuation arm). This is likely because of the stringent inclusion and exclusion criteria but may also reflect a selection bias. In an effort to explain why the number of hyperkalemia events were so low, chat participants suggested that following a low-potassium diet may have been recommended, and subsequently the role of dietary potassium was argued (Fig 2A). Although there was no data regarding concomitant potassium binder use, 40% of study participants did receive bicarbonate supplementation. Chat voices emphasized the importance of concomitant RAS inhibitor and flozin (sodium/glucose cotransporter 2 inhibitor) treatment in reducing hyperkalemia. To allay concerns about hyperkalemia, the European Heart Failure Long-Term Registry study discovered that after adjustment for RAS inhibitor discontinuation, hyperkalemia was no longer associated with mortality, suggesting hyperkalemia may primarily be a risk factor for RAS inhibitor discontinuation rather than adverse outcomes.13Rossignol P. Lainscak M. Crespo-Leiro M.G. et al.Unravelling the interplay between hyperkalaemia, renin-angiotensin-aldosterone inhibitor use and clinical outcomes. Data from 9222 chronic heart failure patients of the ESC-HFA-EORP Heart Failure Long-Term Registry.Eur J Heart Fail. 2020; 22: 1378-1389Crossref PubMed Scopus (67) Google Scholar Discontinuation of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers in patients with advanced CKD does not significantly improve kidney function, but it may be associated with increased CV events and a trend toward faster onset of kidney failure. The decision to discontinue RAS inhibitors should not be based on an arbitrary eGFR value of 30 mL/min/1.73 m2, but rather it should be individualized after considering proteinuria, blood pressure, and CV comorbid conditions.

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