{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:01:52Z","timestamp":1787238112379,"version":"build-2736575974"},"reference-count":51,"publisher":"Georg Thieme Verlag KG","issue":"01","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Metab Res"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hyperhomocysteinemia is common in chronic kidney disease; however, whether\n                    homocysteine-lowering therapy slows chronic kidney disease progression remains\n                    uncertain. Following the Preferred Reporting Items for Systematic reviews and\n                    Meta-Analyses guideline, we systematically searched PubMed and Web of Science\n                    (inception to January 2025) for randomized controlled trials evaluating folic\n                    acid alone or combined with vitamin B versus placebo\/usual care\/low-dose\n                    regimens in populations across the chronic kidney disease spectrum. The primary\n                    end point was composite kidney outcomes (all-cause mortality, cardiovascular\n                    events, and kidney disease progression). Relative risks with 95% confidence\n                    intervals were pooled using fixed- or random-effect models according to\n                    heterogeneity. Nine trials comprising 23,638 participants met inclusion\n                    criteria. Overall heterogeneity for the primary outcome was low (I\u00b2=27%),\n                    and homocysteine-lowering therapy was associated with a marginal reduction in\n                    composite kidney outcomes (relative risk=0.96 and 95% confidence\n                    interval=0.92\u20131.00; p\u2009=\u20090.04). Subgroup analyses suggested a greater\n                    benefit in participants with normal to moderate chronic kidney disease (relative\n                    risk=0.89 and 95% confidence interval=0.81\u20130.97; p=0.008) and in\n                    non-White populations (relative risk=0.89 and 95% confidence interval=0.81\u20130.97;\n                        p=0.008). No significant effects were observed for cardiovascular\n                    events (relative risk=0.94 and 95% confidence interval=0.84\u20131.06) or all-cause\n                    mortality (relative risk=0.99 and 95% confidence interval 0.87\u20131.11). In\n                    conclusion, homocysteine-lowering therapy yields, at most, a small reduction in\n                    composite kidney outcomes with limited clinical significance and provides no\n                    detectable benefits for cardiovascular events or mortality.<\/jats:p>","DOI":"10.1055\/a-2780-5656","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:07:31Z","timestamp":1769818051000},"page":"13-22","source":"Crossref","is-referenced-by-count":1,"title":["A Meta-Analysis of the Effects of Homocysteine-Lowering Therapy on\n                    Chronic Kidney Disease"],"prefix":"10.1055","volume":"58","author":[{"given":"Hua","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Clinical Nutrition, Qilu Hospital of\n                    Shandong University Qingdao, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Clinical Nutrition, Qilu Hospital of\n                    Shandong University Qingdao, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Clinical Psychology, The Affiliated\n                    Hospital of Qingdao University, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanpei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, Qilu Hospital of\n                    Shandong University Qingdao, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, Qilu Hospital of\n                    Shandong University Qingdao, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, Qilu Hospital of\n                    Shandong University Qingdao, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuantao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition, Qilu Hospital of\n                    Shandong University Qingdao, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/S0140-6736(16)32064-5","article-title":"Chronic Kidney Disease","volume":"389","author":"A C Webster","year":"2017","journal-title":"Lancet (London, Engl)"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0140-6736(20)30045-3","article-title":"Global, regional, and national burden of chronic kidney disease, 1990\u20132017: a\n                    systematic analysis for the Global Burden of Disease Study 2017","volume":"395","author":"GBD Chronic Kidney Disease\n                        Collaboration","year":"2020","journal-title":"Lancet (London, Engl)"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"825","DOI":"10.7326\/0003-4819-158-11-201306040-00007","article-title":"Evaluation and management of chronic kidney disease: synopsis of the kidney\n                    disease: improving global outcomes 2012 clinical practice guideline","volume":"158","author":"P E Stevens","year":"2013","journal-title":"Ann Intern Med"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1053\/ajkd.2002.31990","article-title":"Slowing the progression of chronic renal failure: economic benefits and\n                    patients\u2019 perspectives","volume":"39","author":"H S Trivedi","year":"2002","journal-title":"Am J Kidney Dis"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrneph.2017.17","article-title":"Cardiovascular disease in haemodialysis: role of the intravascular innate immune\n                    system","volume":"13","author":"K N Ekdahl","year":"2017","journal-title":"Nat Rev Nephrol"},{"key":"ref6","first-page":"1","article-title":"The natural history of homocystinuria due to cystathionine beta-synthase\n                    deficiency","volume":"37","author":"S H Mudd","year":"1985","journal-title":"Am J Hum Genet"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1159\/000444900","article-title":"Homocysteine in Renal Injury","volume":"2","author":"Y Long","year":"2016","journal-title":"Kidney Dis (Basel, Switz)"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"e27202","DOI":"10.1097\/MD.0000000000027202","article-title":"Synergistic association of hyperuricemia and hyperhomocysteinemia with chronic\n                    kidney disease in middle-aged adults and the elderly population","volume":"100","author":"P T Liu","year":"2021","journal-title":"Medicine"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1159\/000514360","article-title":"Plasma Homocysteine Is a Predictive Factor for Accelerated Renal Function\n                    Decline and Chronic Kidney Disease in a Community-Dwelling Population","volume":"46","author":"W Xiao","year":"2021","journal-title":"Kidney Blood Press Res"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1161\/01.RES.0000108264.67601.2C","article-title":"Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via\n                    oxidative stress","volume":"94","author":"K K Au-Yeung","year":"2004","journal-title":"Circ Res"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s12013-010-9079-y","article-title":"Homocysteine to hydrogen sulfide or hypertension","volume":"57","author":"U Sen","year":"2010","journal-title":"Cell Biochem Biophys"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.3390\/ijms17101733","article-title":"The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human\n                    Health","volume":"17","author":"H \u0160kovierov\u00e1","year":"2016","journal-title":"Int J Mol Sci"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1159\/000142363","article-title":"5-methyltetrahydrofolate administration is associated with prolonged survival\n                    and reduced inflammation in ESRD patients","volume":"28","author":"G Cianciolo","year":"2008","journal-title":"Am J Nephrol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1093\/ndt\/gfw090","article-title":"Association of serum vitamin B12 and folate with mortality in incident\n                    hemodialysis patients","volume":"32","author":"M Soohoo","year":"2017","journal-title":"Nephrol, Dialysis, Transplant"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1001\/jamainternmed.2016.4687","article-title":"Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The\n                    Renal Substudy of the China Stroke Primary Prevention Trial","volume":"176","author":"X Xu","year":"2016","journal-title":"JAMA Intern Med"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"4162","DOI":"10.3390\/nu14194162","article-title":"Supplementation with Folic Acid and Cardiovascular Outcomes in End-Stage Kidney\n                    Disease: A Multi-Institution Cohort Study","volume":"14","author":"Y R Tu","year":"2022","journal-title":"Nutrients"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1161\/CIRCULATIONAHA.109.904672","article-title":"B vitamins and the risk of total mortality and cardiovascular disease in\n                    end-stage renal disease: results of a randomized controlled trial","volume":"121","author":"J Heinz","year":"2010","journal-title":"Circulation"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1186\/s40795-025-01178-z","article-title":"Efficacy of folic acid supplementation in the prevention of cardiovascular\n                    disease \u2013 a systematic review and meta-analysis of randomized controlled\n                    trials","volume":"11","author":"P Ghattas Hasbun","year":"2025","journal-title":"BMC Nutr"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"e70080","DOI":"10.1111\/jebm.70080","article-title":"Intervention at Circulating Homocysteine Levels>10 \u00b5mol\/L for Primary\n                    Prevention of Cardiovascular Diseases: A Systematic Review and Dose-Response\n                    Meta-Analysis","author":"Z Huang","year":"2025","journal-title":"J Evidence-Based Med"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1093\/nutrit\/nuaf155","article-title":"Efficacy of B Vitamin Supplementation on Global Cognitive Function in Older\n                    Adults: A Systematic Review and Meta-analysis","volume":"83","author":"J Berg","year":"2025","journal-title":"Nutr Rev"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jclinepi.2021.02.003","article-title":"Updating guidance for reporting systematic reviews: development of the PRISMA\n                    2020 statement","volume":"134","author":"M J Page","year":"2021","journal-title":"J Clin Epidemiol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/S0197-2456(99)00026-4","article-title":"Assessing the quality of randomized trials: reliability of the Jadad scale","volume":"20","author":"H D Clark","year":"1999","journal-title":"Controlled Clin Trials"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.2307\/2533446","article-title":"Operating characteristics of a rank correlation test for publication bias","volume":"50","author":"C B Begg","year":"1994","journal-title":"Biometrics"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1093\/ajcn\/84.5.989","article-title":"Population reference values for plasma total homocysteine concentrations in US\n                    adults after the fortification of cereals with folic acid","volume":"84","author":"V Ganji","year":"2006","journal-title":"Am J Clin Nutr"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1159\/000093680","article-title":"Homocysteine-lowering vitamin B treatment decreases cardiovascular events in\n                    hemodialysis patients","volume":"24","author":"M Righetti","year":"2006","journal-title":"Blood Purif"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/j.jacc.2005.10.064","article-title":"Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid\n                    Supplementation Trial (ASFAST) in chronic renal failure: a multicenter,\n                    randomized, controlled trial","volume":"47","author":"S Zoungas","year":"2006","journal-title":"J Am Coll Cardiol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1001\/jama.298.10.1163","article-title":"Effect of homocysteine lowering on mortality and vascular disease in advanced\n                    chronic kidney disease and end-stage renal disease: a randomized controlled\n                    trial","volume":"298","author":"R L Jamison","year":"2007","journal-title":"JAMA"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/j.1542-4758.2007.00171.x","article-title":"Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the\n                    prevention of cardiovascular events","volume":"11","author":"A C Vianna","year":"2007","journal-title":"Hemodial Int Int Symp Home Hemodial"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1097\/01.ASN.0000110181.64655.6C","article-title":"Randomized trial of folic acid for prevention of cardiovascular events in\n                    end-stage renal disease","volume":"15","author":"E M Wrone","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1093\/ndt\/gfm485","article-title":"Homocysteine lowering with folic acid and B vitamins in people with chronic\n                    kidney disease \u2013 results of the renal Hope-2 study","volume":"23","author":"J F Mann","year":"2008","journal-title":"Nephrol, Dialysis, Transplant"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1161\/CIRCULATIONAHA.110.000588","article-title":"Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant\n                    recipients: primary results from the Folic Acid for Vascular Outcome Reduction\n                    in Transplantation trial","volume":"123","author":"A G Bostom","year":"2011","journal-title":"Circulation"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1097\/MNH.0000000000000597","article-title":"Screening for chronic kidney disease: moving toward more sustainable health\n                    care","volume":"29","author":"S Curtis","year":"2020","journal-title":"Curr OpNephrology Hypertens"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1053\/j.ajkd.2009.01.266","article-title":"Homocysteine as a risk factor for cardiovascular disease in patients treated by\n                    dialysis: a meta-analysis","volume":"54","author":"J Heinz","year":"2009","journal-title":"Am J Kidney Dis"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"482","DOI":"10.2215\/CJN.05310610","article-title":"Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney\n                    disease: a meta-analysis","volume":"6","author":"X Qin","year":"2011","journal-title":"Clin J Am Soc Nephrol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.clnu.2012.12.009","article-title":"Homocysteine-lowering therapy with folic acid is effective in cardiovascular\n                    disease prevention in patients with kidney disease: a meta-analysis of\n                    randomized controlled trials","volume":"32","author":"X Qin","year":"2013","journal-title":"Clin Nutr (Edinburgh, Scotl)"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"H1971","DOI":"10.1152\/ajpheart.91503.2007","article-title":"Mechanisms and potential therapeutic targets for folic acid in cardiovascular\n                    disease","volume":"294","author":"A L Moens","year":"2008","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1161\/01.RES.86.11.1129","article-title":"Folic acid reverts dysfunction of endothelial nitric oxide synthase","volume":"86","author":"E S Stroes","year":"2000","journal-title":"Circ Res"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1007\/s12035-016-9736-2","article-title":"Oxidative Stress Markers in Vitamin B12 Deficiency","volume":"54","author":"U K Misra","year":"2017","journal-title":"Mol Neurobiol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.kint.2020.10.012","article-title":"The case for early identification and intervention of chronic kidney disease:\n                    conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO)\n                    Controversies Conference","volume":"99","author":"M G Shlipak","year":"2021","journal-title":"Kidney Int"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"10084","DOI":"10.3390\/ijms221810084","article-title":"Chronic Kidney Disease: Strategies to Retard Progression","volume":"22","author":"M T Yan","year":"2021","journal-title":"Int J Mol Sci"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.semnephrol.2022.04.001","article-title":"Sex and gender differences in chronic kidney disease and access to care around\n                    the globe","volume":"42","author":"G G Garc\u00eda","year":"2022","journal-title":"Sem Nephrol"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"6259","DOI":"10.3390\/ijms22126259","article-title":"Homocysteine and Age-Related Central Nervous System Diseases: Role of\n                    Inflammation","volume":"22","author":"A Tawfik","year":"2021","journal-title":"Int J Mol Sci"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1001\/jamainternmed.2021.4813","article-title":"Accounting for Age in the Definition of Chronic Kidney Disease","volume":"181","author":"P Liu","year":"2021","journal-title":"JAMA Intern Med"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.arr.2018.10.010","article-title":"Homocysteine and age-associated disorders","volume":"49","author":"E A Ostrakhovitch","year":"2019","journal-title":"Ageing Res Rev"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"100726","DOI":"10.1016\/j.xcrm.2022.100726","article-title":"Race, ancestry, and genetic risk for kidney failure","volume":"3","author":"S B Nicholas","year":"2022","journal-title":"Cell Rep Med"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"809","DOI":"10.2215\/CJN.12710820","article-title":"Social Determinants of Kidney Health: Focus on Poverty","volume":"16","author":"K C Norris","year":"2021","journal-title":"Clin J Am Soc Nephrol"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1080\/13557858.2017.1395814","article-title":"Chronic kidney disease and socio-economic status: a cross sectional study","volume":"25","author":"R E Ritte","year":"2020","journal-title":"Ethnicity Health"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1001\/jama.2015.2274","article-title":"Efficacy of folic acid therapy in primary prevention of stroke among adults with\n                    hypertension in China: the CSPPT randomized clinical trial","volume":"313","author":"Y Huo","year":"2015","journal-title":"JAMA"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ekir.2024.09.018","article-title":"In Defense of Age-Based Estimated GFR Thresholds to Define CKD","volume":"10","author":"P Delanaye","year":"2025","journal-title":"Kidney Int Rep"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1053\/j.jrn.2025.03.002","article-title":"Plant-Based Diet and Chronic Kidney Disease: A Systematic Review and\n                    Meta-Analysis","volume":"35","author":"Z Dang","year":"2025","journal-title":"J Ren Nutr"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1053\/j.ajkd.2023.09.020","article-title":"Adherence to Plant-Based Diets and Risk of CKD Progression and All-Cause\n                    Mortality: Findings From the Chronic Renal Insufficiency Cohort (CRIC)\n                    Study","volume":"83","author":"S Amir","year":"2024","journal-title":"Am J Kidney 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