{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T23:09:00Z","timestamp":1774998540799,"version":"3.50.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"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. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>There have been contradictory findings regarding the relationship between serum uric acid levels and prognosis in acute ischemic stroke. Whether this association is nonlinear due to uric acid\u2019s paradoxical properties (antioxidant and prooxidant) is unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We searched PubMed, Web of Science, and Embase databases until December 2022. Cohort studies reporting serum uric acid levels and functional outcome, mortality, or neurological complications in patients with acute ischemic stroke were included. Summary effect estimates were calculated using a random-effect model. Moreover, dose\u2013response relationships were assessed by the generalized least squares trend estimation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Altogether, 13 cohort studies were identified in this study. Compared to the lowest baseline serum uric acid levels, the highest levels were associated with decreased risk of poor functional outcome (OR\u2009=\u20090.70, 95% CI 0.54\u20130.91, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup> =\u200929%), hemorrhagic transformation (OR\u2009=\u20090.15, 95% CI 0.05\u20130.42, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup> =\u200979%), and post-stroke depression (OR\u2009=\u20090.04, 95% CI 0.00\u20130.95, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup> =\u200989%), but not associated with mortality and symptomatic intracerebral hemorrhage. A nonlinear relationship was observed in poor functional outcome (U-shaped, <jats:italic>P<\/jats:italic> for nonlinearity\u2009=\u20090.042), hemorrhagic transformation (inverse, <jats:italic>P<\/jats:italic> for nonlinearity\u2009=\u20090.001), and post-stroke depression (inverse, <jats:italic>P<\/jats:italic> for nonlinearity\u2009=\u20090.002). In addition, there was a single study reporting a U-shaped association in post-stroke epilepsy (<jats:italic>P<\/jats:italic> for nonlinearity &amp;lt;0.001). Furthermore, another study reported a positive curvilinear association in stroke recurrence (<jats:italic>P<\/jats:italic> for nonlinearity &amp;lt;0.05). The insufficient number of original articles for some prognostic indicators should be considered when interpreting the results of this meta-analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In patients with acute ischemic stroke, serum uric acid levels are nonlinearly associated with the risk of poor functional outcome (U-shaped). More evidence is needed to confirm the association between serum uric acid levels and neurological complications following acute ischemic stroke.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2023.1223015","type":"journal-article","created":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T08:29:12Z","timestamp":1693556952000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Serum uric acid and prognosis in acute ischemic stroke: a dose\u2013response meta-analysis of cohort studies"],"prefix":"10.3389","volume":"15","author":[{"given":"Wenyuan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zicheng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangwang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenxiang","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1177\/0271678X20967459","article-title":"Effect of uric acid in animal models of ischemic stroke: a systematic review and meta-analysis","volume":"41","author":"Aliena-Valero","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/s00415-009-0153-6","article-title":"Course of matrix metalloproteinase-9 isoforms after the administration of uric acid in patients with acute stroke: a proof-of-concept study","volume":"256","author":"Amaro","year":"2009","journal-title":"J. Neurol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1161\/STROKEAHA.106.480699","article-title":"A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke","volume":"38","author":"Amaro","year":"2007","journal-title":"Stroke"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.neuroscience.2011.02.047","article-title":"Caffeine and uric acid mediate glutathione synthesis for neuroprotection","volume":"181","author":"Aoyama","year":"2011","journal-title":"Neuroscience"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.21037\/atm-22-4494","article-title":"Increased serum uric acid level is associated with better outcome after endovascular treatment for acute ischemic stroke-a prospective cohort study","volume":"10","author":"Bai","year":"2022","journal-title":"Ann Transl Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/S1474-4422(10)70313-6","article-title":"Neurological complications of acute ischaemic stroke","volume":"10","author":"Balami","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1515\/CCLM.2010.065","article-title":"Decrease in uric acid in acute ischemic stroke correlates with stroke severity, evolution and outcome","volume":"48","author":"Brouns","year":"2010","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/S1474-4422(14)70054-7","article-title":"Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b\/3 trial","volume":"13","author":"Chamorro","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1007\/s11011-020-00601-7","article-title":"Lower uric acid level may be associated with hemorrhagic transformation but not functional outcomes in patients with anterior circulation acute ischemic stroke undergoing endovascular thrombectomy","volume":"35","author":"Chen","year":"2020","journal-title":"Metab. Brain Dis."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"150","DOI":"10.2174\/1567202619666220707093427","article-title":"U-shaped association between serum uric acid and Hemorrhagic transformation after thrombolysis","volume":"19","author":"Cheng","year":"2022","journal-title":"Curr. Neurovasc. Res."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the global burden of disease study 2019","volume":"20","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"Dersimonian","year":"1986","journal-title":"Control. Clin. Trials"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1016\/S0140-6736(16)00163-X","article-title":"Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials","volume":"387","author":"Goyal","year":"2016","journal-title":"Lancet"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1093\/oxfordjournals.aje.a116237","article-title":"Methods for trend estimation from summarized dose-response data, with applications to meta-analysis","volume":"135","author":"Greenland","year":"1992","journal-title":"Am. J. Epidemiol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e1897","DOI":"10.1097\/MD.0000000000001897","article-title":"Low serum levels of uric acid are associated with development of poststroke depression","volume":"94","author":"Gu","year":"2015","journal-title":"Medicine (Baltimore)"},{"key":"ref16","first-page":"2079","article-title":"Antioxidant and radical scavenging activities of uric acid","volume":"20","author":"Gulcin","year":"2008","journal-title":"Asian J. Chem."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1159\/000355020","article-title":"Effects of uric acid levels on outcome in severe ischemic stroke patients treated with intravenous recombinant tissue plasminogen activator","volume":"71","author":"Lee","year":"2014","journal-title":"Eur. Neurol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1097\/NRL.0000000000000234","article-title":"Serum uric acid level and outcome of patients with ischemic stroke: a systematic review and Meta-analysis","volume":"24","author":"Lei","year":"2019","journal-title":"Neurologist"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"52","DOI":"10.3389\/fpsyt.2020.00052","article-title":"Lower serum uric acid is associated with post-stroke depression at discharge","volume":"11","author":"Li","year":"2020","journal-title":"Front. Psych."},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10092185","article-title":"J-shaped relationship of serum uric acid with Unfavorable short-term outcomes among patients with acute ischemic stroke","volume":"10","author":"Liu","year":"","journal-title":"Biomedicine"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.2147\/NDT.S373493","article-title":"Uric acid and clinical outcomes in young patients with ischemic stroke","volume":"18","author":"Liu","year":"","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.1161\/STROKEAHA.115.009960","article-title":"Uric acid therapy improves clinical outcome in women with acute ischemic stroke","volume":"46","author":"Llull","year":"2015","journal-title":"Stroke"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ijcard.2015.08.109","article-title":"Regulation of uric acid metabolism and excretion","volume":"213","author":"Maiuolo","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1093\/aje\/kwr265","article-title":"Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software","volume":"175","author":"Orsini","year":"2012","journal-title":"Am. J. Epidemiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"674398","DOI":"10.3389\/fneur.2021.674398","article-title":"The relationship between elevated serum uric acid and risk of stroke in adult: an updated and dose-response Meta-analysis","volume":"12","author":"Qiao","year":"2021","journal-title":"Front. Neurol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1080\/15257770802138558","article-title":"Uric acid: the oxidant-antioxidant paradox","volume":"27","author":"Sautin","year":"2008","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.atherosclerosis.2009.08.012","article-title":"Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study","volume":"209","author":"Seet","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1007\/s12031-019-01404-x","article-title":"Serum uric acid and risk of Hemorrhagic transformation in patients with acute ischemic stroke","volume":"70","author":"Song","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1006\/abbi.2000.1721","article-title":"Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid","volume":"376","author":"Squadrito","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur. J. Epidemiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1016\/0895-4356(96)00025-X","article-title":"Inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis","volume":"49","author":"Sun","year":"1996","journal-title":"J. Clin. Epidemiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"3113","DOI":"10.1007\/s10072-021-05760-8","article-title":"Lower uric acid level may be associated with hemorrhagic transformation after intravenous thrombolysis","volume":"43","author":"Tian","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1111\/ene.14643","article-title":"Prognostic significance of uric acid change in acute ischemic stroke patients with reperfusion therapy","volume":"28","author":"Wang","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s12640-018-9930-2","article-title":"Serum uric acid is highly associated with epilepsy secondary to cerebral infarction","volume":"35","author":"Wang","year":"2019","journal-title":"Neurotox. Res."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1177\/0300060517752996","article-title":"High serum uric acid levels are a protective factor against unfavourable neurological functional outcome in patients with ischaemic stroke","volume":"46","author":"Wang","year":"2018","journal-title":"J. Int. Med. Res."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1007\/s12035-015-9134-1","article-title":"Serum uric acid levels and outcomes after acute ischemic stroke","volume":"53","author":"Wang","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1161\/STROKEAHA.121.034580","article-title":"Associations of early systolic blood pressure control and outcome after thrombolysis-eligible acute ischemic stroke: results from the ENCHANTED study","volume":"53","author":"Wang","year":"2022","journal-title":"Stroke"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1159\/000491609","article-title":"U-shaped relationship between functional outcome and serum uric acid in ischemic stroke","volume":"47","author":"Yang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1111\/ene.14202","article-title":"Uric acid level and risk of symptomatic intracranial haemorrhage in ischaemic stroke treated with endovascular treatment","volume":"27","author":"Yuan","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1007\/s12640-015-9561-9","article-title":"Prognostic significance of uric acid levels in ischemic stroke patients","volume":"29","author":"Zhang","year":"2016","journal-title":"Neurotox. Res."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"3016","DOI":"10.1016\/j.numecd.2021.07.031","article-title":"Association between uric acid and the prognosis of acute ischemic stroke: a systematic review and meta-analysis","volume":"31","author":"Zhang","year":"2021","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1080\/01616412.2020.1792688","article-title":"Effect of renal function on association between uric acid and prognosis in acute ischemic stroke patients with elevated systolic blood pressure","volume":"42","author":"Zheng","year":"2020","journal-title":"Neurol. Res."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"822350","DOI":"10.3389\/fnagi.2022.822350","article-title":"Elevated serum uric acid increases the risk of ischemic stroke recurrence and its inflammatory mechanism in older adults","volume":"14","author":"Zhu","year":"2022","journal-title":"Front. Aging Neurosci."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1223015\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T08:29:15Z","timestamp":1693556955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2023.1223015\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,1]]},"references-count":45,"alternative-id":["10.3389\/fnagi.2023.1223015"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2023.1223015","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,1]]},"article-number":"1223015"}}