{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:58:12Z","timestamp":1787662692306,"version":"build-2736575974"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Hyperuricemia is highly prevalent in chronic kidney disease (CKD) patients, but the evidence for a relationship between uric acid (UA) and clinical outcomes in CKD patients is limited and inconsistent. We hypothesized that UA has a different impact on clinical outcomes according to the underlying disease causing CKD.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This study prospectively investigated the associations between UA and renal and non-renal outcomes according to the underlying disease causing CKD in 2,797 Japanese patients under the care of nephrologists. The patients were categorized into four groups: primary renal disease (n = 1306), hypertensive nephropathy (n = 467), diabetic nephropathy (n = 275), and other nephropathy (n = 749). The renal outcome was defined as end-stage renal disease (ESRD), and the non-renal outcome was defined as a composite endpoint of cardiovascular events (CVEs) and all-cause mortality.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>During a median 4.8-year follow-up, 359 (12.8%) patients reached the renal outcome, and 260 (9.3%) reached the non-renal outcome. In the all-patient analysis, hyperuricemia was not associated with the risks for renal and non-renal outcomes, but in primary renal disease (PRD) and hypertensive renal disease (HTN) patients, hyperuricemia was significantly associated with non-renal outcomes. Per 1 mg\/dl higher UA level, multivariable adjusted hazard ratio was 1.248 (95% CI: 1.003 to 1.553) for PRD, and 1.250 (1.035 to 1.510) for HTN. Allopurinol did not reduce the risks for renal and non-renal outcomes, both in all patients and in the subgroup analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The effect of hyperuricemia on clinical outcomes in CKD patients varies according to the underlying disease causing CKD. Hyperuricemia is an independent risk factor for non-renal outcomes in primary renal disease and hypertensive renal disease patients. Allopurinol did not decrease the risks for renal and non-renal outcomes.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0249240","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T20:23:46Z","timestamp":1616703826000},"page":"e0249240","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Different clinical impact of hyperuricemia according to etiologies of chronic kidney disease: Gonryo Study"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8773-0967","authenticated-orcid":true,"given":"Kimio","family":"Watanabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gen","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Miyazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadayoshi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"issue":"4","key":"pone.0249240.ref001","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/S0272-6386(04)00934-5","article-title":"Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort","volume":"44","author":"K Iseki","year":"2004","journal-title":"Am J Kidney Dis"},{"issue":"2","key":"pone.0249240.ref002","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1053\/j.ajkd.2007.05.013","article-title":"Relationship of Uric Acid With Progression of Kidney Disease","volume":"50","author":"M Chonchol","year":"2007","journal-title":"Am J Kidney Dis"},{"issue":"2","key":"pone.0249240.ref003","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1053\/j.ajkd.2010.01.019","article-title":"Association of uric acid with change in kidney function in healthy normotensive individuals","volume":"56","author":"G Bellomo","year":"2010","journal-title":"Am J Kidney Dis"},{"issue":"7","key":"pone.0249240.ref004","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/hr.2013.11","article-title":"Changes in serum uric acid have a reciprocal effect on eGFR change: A 10-year follow-up study of community-based screening in Okinawa, Japan","volume":"36","author":"K Iseki","year":"2013","journal-title":"Hypertens Res"},{"issue":"17","key":"pone.0249240.ref005","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1056\/NEJMra0800885","article-title":"Uric Acid and Cardiovascular Risk Daniel","volume":"359","author":"DI Feig","year":"2008","journal-title":"N Engl J Med"},{"issue":"18","key":"pone.0249240.ref006","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1001\/jama.283.18.2404","article-title":"Serum uric acid and cardiovascular mortality: The NHANES I Epidemiologic Follow-up Study, 1971\u20131992","volume":"283","author":"J Fang","year":"2000","journal-title":"JAMA"},{"issue":"12","key":"pone.0249240.ref007","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1093\/ndt\/gfv225","article-title":"Uric acid is not associated with decline in renal function or time to renal replacement therapy initiation in a referred cohort of patients with Stage III, IV and v chronic kidney disease","volume":"30","author":"H Nacak","year":"2015","journal-title":"Nephrol Dial Transplant"},{"issue":"4","key":"pone.0249240.ref008","doi-asserted-by":"crossref","first-page":"541","DOI":"10.2215\/CJN.09420911","article-title":"Association of Hyperuricemia with renal outcomes, cardiovascular disease, and mortality","volume":"7","author":"WC Liu","year":"2012","journal-title":"Clin J Am Soc Nephrol"},{"issue":"1","key":"pone.0249240.ref009","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1053\/j.ajkd.2012.07.021","article-title":"Uric acid as a target of therapy in CKD","volume":"61","author":"DI Jalal","year":"2013","journal-title":"Am J Kid Dis"},{"issue":"4","key":"pone.0249240.ref010","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1001\/archinternmed.2008.605","article-title":"Risk factors for end-stage renal disease\u201425-year follow-up","volume":"169","author":"CY Hsu","year":"2009","journal-title":"Arch Intern Med"},{"issue":"6","key":"pone.0249240.ref011","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1053\/j.ajkd.2017.12.009","article-title":"Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation","volume":"71","author":"RJ Johnson","year":"2018","journal-title":"Am J Kidney Dis"},{"issue":"1","key":"pone.0249240.ref012","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1093\/ndt\/15.1.34","article-title":"Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy","volume":"15","author":"J Syrj\u00e4nen","year":"2000","journal-title":"Nephrol Dial Transplant"},{"issue":"6","key":"pone.0249240.ref013","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.2337\/dc10-0227","article-title":"High-Normal Serum Uric Acid Increases Risk of Early Progressive Renal Function Loss in Type 1","volume":"33","author":"LH Ficociello","year":"2010","journal-title":"Diabetes. Diabetes Care"},{"issue":"5","key":"pone.0249240.ref014","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1053\/j.ajkd.2008.12.021","article-title":"Uric Acid and Long-term Outcomes in CKD","volume":"53","author":"M Madero","year":"2009","journal-title":"Am J Kidney Dis"},{"issue":"6","key":"pone.0249240.ref015","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.2337\/dc10-0227","article-title":"High-Normal Serum Uric Acid Increases Risk of Early Progressive Renal Function Loss in Type 1","volume":"33","author":"LH Ficociello","year":"2010","journal-title":"Diabetes. Diabetes Care"},{"issue":"10","key":"pone.0249240.ref016","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2215\/CJN.02700409","article-title":"Uric Acid Levels Have No Significant Effect on Renal Function in Adult Renal Transplant Recipients: Evidence from the Symphony Study","volume":"4","author":"HU Meier-Kriesche","year":"2009","journal-title":"Clin J Am Soc Nephrol"},{"issue":"4","key":"pone.0249240.ref017","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1159\/000045939","article-title":"Serum uric acid and renal prognosis in patients with IgA nephropathy","volume":"87","author":"I Ohno","year":"2001","journal-title":"Nephron"},{"issue":"4","key":"pone.0249240.ref018","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1053\/j.ajkd.2014.11.016","article-title":"Allopurinol and Progression of CKD and Cardiovascular Events: Long-term Follow-up of a Randomized Clinical Trial","volume":"65","author":"M Goicoechea","year":"2015","journal-title":"Am J Kidney Dis"},{"issue":"8","key":"pone.0249240.ref019","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.2215\/CJN.01580210","article-title":"Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk","volume":"5","author":"M Goicoechea","year":"2010","journal-title":"Clin J Am Soc Nephrol"},{"issue":"40","key":"pone.0249240.ref020","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta18400","article-title":"Allopurinol for the treatment of chronic kidney disease: a systematic review","volume":"18","author":"N Fleeman","year":"2014","journal-title":"Health Technol Assess"},{"issue":"26","key":"pone.0249240.ref021","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1056\/NEJMoa1916624","article-title":"Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes","volume":"382","author":"A Doria","year":"2020","journal-title":"N Engl J Med"},{"issue":"26","key":"pone.0249240.ref022","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1056\/NEJMoa1915833","article-title":"Effects of Allopurinol on the Progression of Chronic Kidney Disease","volume":"382","author":"SV Badve","year":"2020","journal-title":"N Engl J Med"},{"issue":"2","key":"pone.0249240.ref023","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1093\/ndt\/gft378","article-title":"Effects of uric acid-lowering therapy on renal outcomes: A systematic review and meta-analysis","volume":"29","author":"B Bose","year":"2014","journal-title":"Nephrol Dial Transplant"},{"issue":"6","key":"pone.0249240.ref024","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1053\/j.ajkd.2008.12.034","article-title":"Revised Equations for Estimated GFR From Serum Creatinine in Japan","volume":"53","author":"S Matsuo","year":"2009","journal-title":"Am J Kidney Dis"},{"issue":"4","key":"pone.0249240.ref025","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s10157-012-0742-z","article-title":"Effect of allopurinol on cardiovascular incidence among hypertensive nephropathy patients: The Gonryo study","volume":"17","author":"H Terawaki","year":"2013","journal-title":"Clin Exp Nephrol"},{"issue":"10","key":"pone.0249240.ref026","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2215\/CJN.02700409","article-title":"Uric acid levels have no significant effect on renal function in adult renal transplant recipients: Evidence from the symphony study","volume":"4","author":"HU Meier-Kriesche","year":"2009","journal-title":"Clin J Am Soc Nephrol"},{"issue":"4","key":"pone.0249240.ref027","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1093\/ndt\/gfu352","article-title":"Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: The German Chronic Kidney Disease (GCKD) study","volume":"30","author":"J Jing","year":"2015","journal-title":"Nephrol Dial Transplant"},{"issue":"5","key":"pone.0249240.ref028","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1681\/ASN.2019101015","article-title":"Fructose production and metabolism in the kidney","volume":"31","author":"T Nakagawa","year":"2020","journal-title":"J Am Soc Nephrol"},{"issue":"2","key":"pone.0249240.ref029","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s10157-012-0746-8","article-title":"Japan Renal Biopsy Registry and Japan Kidney Disease Registry: Committee Report for 2009 and 2010","volume":"17","author":"H Sugiyama","year":"2013","journal-title":"Clin Exp Nephrol"},{"issue":"1","key":"pone.0249240.ref030","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1523-1755.2005.00074.x","article-title":"Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats","volume":"67","author":"LG S\u00e1nchez-Lozada","year":"2005","journal-title":"Kidney Int"},{"issue":"5","key":"pone.0249240.ref031","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1161\/hy1101.092839","article-title":"Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism","volume":"38","author":"M Mazzali","year":"2001","journal-title":"Hypertension"},{"issue":"6","key":"pone.0249240.ref032","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1053\/j.ajkd.2018.06.028","article-title":"Febuxostat Therapy for Patients With Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized Trial","volume":"72","author":"K Kimura","year":"2018","journal-title":"Am J Kidney Dis"},{"key":"pone.0249240.ref033","article-title":"KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease","author":"Kidney disease: Improving global outcomes (KDIGO) CKD work group","year":"2013","journal-title":"Kidney Int Suppl ernational Supplements"},{"issue":"6","key":"pone.0249240.ref034","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1161\/01.STR.0000221716.55088.d4","article-title":"Uric acid is a risk factor for myocardial infarction and stroke: The Rotterdam Study","volume":"37","author":"MJ Bos","year":"2006","journal-title":"Stroke"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249240","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T20:24:10Z","timestamp":1616703850000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249240"}},"subtitle":[],"editor":[{"given":"Ping-Hsun","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,25]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0249240","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,25]]}}}