{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:25:24Z","timestamp":1787027124691,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Renin-angiotensin system inhibitors (RASi), comprising angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) are known for cardio- and renoprotection. However, there is uncertainty regarding the continuation of ACEi or ARB treatment in patients with chronic kidney disease (CKD) stages 3\u20135.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this meta-analysis, we systematically searched all relevant studies published in PubMed, Embase, and the Cochrane Library up to 30 May 2024. Our objective was to assess the impacts of continuation or discontinuation of RASi in patients with CKD stages 3\u20135 on all-cause mortality, end-stage kidney disease, major adverse cardiovascular events (MACE), and hyperkalemia. We rated the certainty of the evidence using the Cochrane methods and the GRADE approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The search identified 520 studies, of which 8 studies, encompassing a total of 243,775 patients, were included in the analysis. The incidence of all-cause mortality was 40.3% (29,993 out of 74,447 patients), while ESKD occurred in 27.9% (8,992 out of 32,191 patients), MACE in 37.3% (11,225 out of 30,059 patients), and hyperkalemia in 39.4% (8,533 out of 21,642 patients). Pooled analysis revealed that patients who discontinued RASi therapy had a higher risk of developing ESKD compared to those who continued treatment [Hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.19\u20131.65, P &amp;lt; 0.001], but a lower risk of hyperkalemia [Odds ratio (OR): 0.68, 95% CI: 0.60\u20130.77, P &amp;lt; 0.001]. There were no significant differences between the groups in all-cause mortality (HR: 1.34, 95% CI: 0.91\u20131.95, P = 0.135) and MACE (OR: 1.27, 95% CI: 0.93\u20131.73, P = 0.138).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Patients who discontinued RASi therapy exhibited a higher risk of developing ESKD but a reduced risk of hyperkalemia compared to those who continued RASi treatment. However, there were no significant differences in all-cause mortality and MACE between the two groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>identifer, PROSPERO (CRD42023494698).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1646969","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T05:34:09Z","timestamp":1758864849000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Discontinuation versus continuation of renin\u2013angiotensin system inhibitors in chronic kidney disease stage 3\u20135 patients: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"16","author":[{"given":"I-Wen","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Hsuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vin-Cent","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jui-Yi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Hsien","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3977","DOI":"10.1093\/ndt\/gfp511","article-title":"The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease","volume":"25","author":"Ahmed","year":"2010","journal-title":"Nephrol. Dial. Transpl."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e005428","DOI":"10.1161\/JAHA.116.005428","article-title":"Hyperkalemia after initiating renin-angiotensin system blockade: the stockholm Creatinine measurements (SCREAM) project","volume":"6","author":"Bandak","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1056\/NEJMoa2210639","article-title":"Renin-angiotensin system inhibition in advanced chronic kidney disease","volume":"387","author":"Bhandari","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1056\/NEJMoa011161","article-title":"Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy","volume":"345","author":"Brenner","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/j.jclinepi.2007.10.007","article-title":"Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses","volume":"61","author":"Brok","year":"2008","journal-title":"J. Clin. Epidemiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.xkme.2020.04.002","article-title":"Renin-angiotensin system blockade in advanced kidney disease: stop or continue?","volume":"2","author":"Burnier","year":"2020","journal-title":"Kidney Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"6962654","DOI":"10.1155\/2022\/6962654","article-title":"ACEI and ARB lower the incidence of end-stage renal disease among patients with diabetic nephropathy: a meta-analysis","volume":"2022","author":"Deng","year":"2022","journal-title":"Comput. Math. Methods Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1053\/j.ajkd.2020.10.006","article-title":"Comparative effectiveness of renin-angiotensin system inhibitors and calcium channel blockers in individuals with advanced CKD: a nationwide observational cohort study","volume":"77","author":"Fu","year":"","journal-title":"Am. J. Kidney Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1681\/ASN.2020050682","article-title":"Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study","volume":"32","author":"Fu","year":"","journal-title":"J. Am. Soc. Nephrol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The cochrane Collaboration's tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"B11","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1056\/NEJMoa053107","article-title":"Efficacy and safety of benazepril for advanced chronic renal insufficiency","volume":"354","author":"Hou","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1001\/jamainternmed.2013.12700","article-title":"Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia","volume":"174","author":"Hsu","year":"2014","journal-title":"JAMA Intern Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1161\/CIRCULATIONAHA.120.050686","article-title":"Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options","volume":"143","author":"Jankowski","year":"2021","journal-title":"Circulation"},{"key":"B14","doi-asserted-by":"publisher","first-page":"138","DOI":"10.17085\/apm.21038","article-title":"Trial sequential analysis: novel approach for meta-analysis","volume":"16","author":"Kang","year":"2021","journal-title":"Anesth. Pain Med. Seoul."},{"key":"B15","doi-asserted-by":"publisher","first-page":"S117","DOI":"10.1016\/j.kint.2023.10.018","article-title":"KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease","volume":"105","year":"2024","journal-title":"Kidney Int."},{"key":"B16","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.kint.2022.06.008","article-title":"KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease","volume":"102","year":"2022","journal-title":"Kidney Int."},{"key":"B17","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.kint.2020.11.003","article-title":"KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease","volume":"99","year":"2021","journal-title":"Kidney Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1093\/eurheartj\/ehz425","article-title":"2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes","volume":"41","author":"Knuuti","year":"2020","journal-title":"Eur. Heart J."},{"key":"B19","article-title":"Impact of ACEi\/ARB discontinuation after an episode of hyperkalemia in patients with chronic kidney disease","author":"Leon","year":"2020","journal-title":"A Population-Based Cohort Study"},{"key":"B20","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1053\/j.ajkd.2022.01.002","article-title":"Hyperkalemia-related discontinuation of renin-angiotensin-aldosterone system inhibitors and clinical outcomes in CKD: a population-based cohort study","volume":"80","author":"Leon","year":"2022","journal-title":"Am. J. Kidney Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s13054-016-1299-0","article-title":"Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: a meta-analysis with trial sequential analysis of randomized controlled trials","volume":"20","author":"Liu","year":"2016","journal-title":"Crit. Care"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1016\/j.ajem.2019.02.045","article-title":"Balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients: a systematic review and meta-analysis with trial sequential analysis","volume":"37","author":"Liu","year":"2019","journal-title":"Am. J. Emerg. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1038\/s41440-022-00902-7","article-title":"Role of renin-angiotensin system blockade in advanced CKD: to use or not to use?","volume":"45","author":"Mukoyama","year":"2022","journal-title":"Hypertens. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1038\/s41440-022-00877-5","article-title":"Effects of renin-angiotensin system inhibitors on the incidence of unplanned dialysis","volume":"45","author":"Nakayama","year":"2022","journal-title":"Hypertens. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1007\/s40265-020-01388-8","article-title":"Correction to: management of hypertension in chronic kidney disease","volume":"80","author":"Pugh","year":"2020","journal-title":"Drugs"},{"key":"B26","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1001\/jamainternmed.2020.0193","article-title":"Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate","volume":"180","author":"Qiao","year":"2020","journal-title":"JAMA Intern Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e156","DOI":"10.1111\/j.1755-5922.2010.00258.x","article-title":"Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers","volume":"30","author":"Raebel","year":"2012","journal-title":"Cardiovasc Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1097\/MNH.0000000000000492","article-title":"Blood pressure targets and kidney and cardiovascular disease: same data but discordant guidelines","volume":"28","author":"Roehm","year":"2019","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study","volume":"76","author":"Roth","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"B30","first-page":"S54","article-title":"Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The \u201cGruppo Italiano di Studi Epidemiologici in Nefrologia\u201d (GISEN)","volume":"63","author":"Ruggenenti","year":"1997","journal-title":"Kidney Int. Suppl."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2832","DOI":"10.1681\/ASN.V12122832","article-title":"ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril efficacy in nephropathy","volume":"12","author":"Ruggenenti","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"378","DOI":"10.3390\/jcm11020378","article-title":"Therapeutic advances in diabetic nephropathy","volume":"11","author":"Sawaf","year":"2022","journal-title":"J. Clin. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/sj.ki.5002273","article-title":"Chronic kidney disease management in the United Kingdom: NEOERICA project results","volume":"72","author":"Stevens","year":"2007","journal-title":"Kidney Int."},{"key":"B34","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/jrsm.1164","article-title":"Methods to estimate the between-study variance and its uncertainty in meta-analysis","volume":"7","author":"Veroniki","year":"2016","journal-title":"Res. Synth. Methods"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1093\/ndt\/gfaa300","article-title":"Renin-angiotensin system blocker discontinuation and adverse outcomes in chronic kidney disease","volume":"36","author":"Walther","year":"2021","journal-title":"Nephrol. Dial. Transpl."},{"key":"B36","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1053\/j.ajkd.2018.06.010","article-title":"Use of renin-angiotensin system blockade in advanced CKD: an NKF-KDOQI controversies report","volume":"72","author":"Weir","year":"2018","journal-title":"Am. J. Kidney Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2421","DOI":"10.1001\/jama.288.19.2421","article-title":"Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial","volume":"288","author":"Wright","year":"2002","journal-title":"JAMA"},{"key":"B38","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1053\/j.ajkd.2015.10.011","article-title":"Renin-angiotensin system inhibitors and kidney and cardiovascular outcomes in patients with CKD: a bayesian network meta-analysis of randomized clinical trials","volume":"67","author":"Xie","year":"2016","journal-title":"Am. J. Kidney Dis."},{"key":"B39","doi-asserted-by":"publisher","first-page":"101751","DOI":"10.1016\/j.eclinm.2022.101751","article-title":"Clinical outcomes following discontinuation of renin-angiotensin-system inhibitors in patients with type 2 diabetes and advanced chronic kidney disease: a prospective cohort study","volume":"55","author":"Yang","year":"2023","journal-title":"EClinicalMedicine"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1093\/eurheartj\/ehx118","article-title":"Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease","volume":"38","author":"Zewinger","year":"2017","journal-title":"Eur. Heart J."},{"key":"B41","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1007\/s40265-020-01290-3","article-title":"ACE inhibitor benefit to kidney and cardiovascular outcomes for patients with non-dialysis chronic kidney disease stages 3-5: a network meta-analysis of randomised clinical trials","volume":"80","author":"Zhang","year":"2020","journal-title":"Drugs"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2694","DOI":"10.1038\/s41598-019-38991-z","article-title":"Angiotensin-converting enzyme inhibitors or angiotensin receptor blocker monotherapy retard deterioration of renal function in Taiwanese chronic kidney disease population","volume":"9","author":"Zheng","year":"2019","journal-title":"Sci. Rep."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1646969\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T05:34:10Z","timestamp":1758864850000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1646969\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,26]]},"references-count":42,"alternative-id":["10.3389\/fphar.2025.1646969"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1646969","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,26]]},"article-number":"1646969"}}