{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:32:35Z","timestamp":1765996355902,"version":"3.48.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"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:p>\n                    Chronic kidney disease (CKD) significantly impacts global health. Renal function is evaluated using urinary albumin\u2013creatinine ratio (U-Alb\/Cr ratio) and estimated glomerular filtration rate (eGFR). However, these parameters reflect the damage that has already occurred, limiting their utility for early detection. Therefore, novel biomarkers that can detect CKD before functional decline are urgently needed. Kidney fibrosis is an important pathologic feature of CKD and precedes functional impairment, highlighting its potential as an early indicator of CKD. Indoxyl sulfate (IS), a gut-derived uremic toxin, promotes kidney fibrosis and accelerates CKD progression, highlighting its strong potential as a biomarker for early CKD detection. As most studies on IS focused on the state of impaired renal function, the trend of IS in early-stage or preclinical CKD is unclear. Furthermore, quantifying IS in clinical practice is problematic because it\u2019s primarily measured through high-performance liquid chromatography. A recently developed enzyme method has simplified large-scale IS measurement. Identifying the associated factor with IS, we measured serum IS using enzyme method. We analyzed 674 participants who received specific health checkups and had an eGFR of \u226560\u2009mL\/min\/1.73 m\n                    <jats:sup>2<\/jats:sup>\n                    (non-CKD) after obtaining their consent. In addition to standard examinations, we measured serum IS and administered a questionnaire about the frequency of defecating conditions. In this study, we investigated the level of the serum IS in association with the background characteristics of non-CKD participants. For the first time in this study, the median serum IS level was 3.7 (interquartile range, 2.7\u20135.0) \u00b5mol\/L in individuals with non-CKD participants, and the linear regression analysis revealed that serum IS was significantly correlated with age, eGFR, and constipation. These findings suggest that IS accumulation begins before overt renal dysfunction, supporting its potential as an early biomarker for CKD. Although further longitudinal studies are warranted, our results highlight the clinical relevance of IS in the early detection and intervention of CKD.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0332655","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:28:59Z","timestamp":1765996139000},"page":"e0332655","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["The evaluation of indoxyl sulfate in the general population in Kanegasaki Iwate: A cross-sectional study (KANEGASAKI study)"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4958-302X","authenticated-orcid":true,"given":"Mizuki","family":"Hisano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaya","family":"Abe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kie","family":"Sekiguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eri","family":"Hakozaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiaki","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1264-0684","authenticated-orcid":true,"given":"Kozo","family":"Tanno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshikazu","family":"Abe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Takata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wataru","family":"Obara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"issue":"10225","key":"pone.0332655.ref001","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, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"395","author":"GBD Chronic Kidney Disease Collaboration","year":"2020","journal-title":"Lancet"},{"issue":"3","key":"pone.0332655.ref002","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1053\/j.ajkd.2014.09.023","article-title":"The future burden of CKD in the United States: a simulation model for the CDC CKD Initiative","volume":"65","author":"TJ Hoerger","year":"2015","journal-title":"Am J Kidney Dis"},{"issue":"8","key":"pone.0332655.ref003","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.3390\/ijms18081702","article-title":"Novel Biomarkers in the Diagnosis of Chronic Kidney Disease and the Prediction of Its Outcome","volume":"18","author":"J Rysz","year":"2017","journal-title":"Int J Mol Sci"},{"key":"pone.0332655.ref004","doi-asserted-by":"crossref","first-page":"785375","DOI":"10.3389\/fphar.2021.785375","article-title":"Advances in the progression and prognosis biomarkers of chronic kidney disease","volume":"12","author":"Z Yan","year":"2021","journal-title":"Front Pharmacol"},{"key":"pone.0332655.ref005","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cca.2022.08.025","article-title":"Targeted biomarkers of progression in chronic kidney disease","volume":"536","author":"EP Owens","year":"2022","journal-title":"Clin Chim Acta"},{"issue":"3","key":"pone.0332655.ref006","doi-asserted-by":"crossref","DOI":"10.15252\/emmm.201911729","article-title":"PDGFR-\u03b2 and kidney fibrosis","volume":"12","author":"A Ortiz","year":"2020","journal-title":"EMBO Mol Med"},{"issue":"22","key":"pone.0332655.ref007","doi-asserted-by":"crossref","first-page":"14139","DOI":"10.3390\/ijms232214139","article-title":"Serum biomarkers of renal fibrosis: a systematic review","volume":"23","author":"A Barinotti","year":"2022","journal-title":"Int J Mol Sci"},{"key":"pone.0332655.ref008","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1471-2369-14-56","article-title":"Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-\u03baB","volume":"14","author":"D Bolati","year":"2013","journal-title":"BMC Nephrol"},{"issue":"12","key":"pone.0332655.ref009","doi-asserted-by":"crossref","first-page":"909","DOI":"10.3390\/toxins13120909","article-title":"Indoxyl sulfate contributes to mTORC1-induced renal fibrosis via The OAT\/NADPH Oxidase\/ROS pathway","volume":"13","author":"T Nakano","year":"2021","journal-title":"Toxins (Basel)"},{"issue":"1","key":"pone.0332655.ref010","first-page":"96","article-title":"Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis","volume":"124","author":"T Niwa","year":"1994","journal-title":"J Lab Clin Med"},{"key":"pone.0332655.ref011","doi-asserted-by":"crossref","DOI":"10.1053\/j.jrn.2010.05.002","article-title":"Indoxyl sulfate is a nephro-vascular toxin","volume":"20","author":"T Niwa","year":"2010","journal-title":"J Ren Nutr"},{"key":"pone.0332655.ref012","doi-asserted-by":"crossref","first-page":"154546","DOI":"10.1016\/j.phymed.2022.154546","article-title":"Yishen-Qingli-Huoxue formula attenuates renal fibrosis by inhibiting indoxyl sulfate via AhR\/snai1 signaling","volume":"108","author":"C Chen","year":"2023","journal-title":"Phytomedicine"},{"issue":"14","key":"pone.0332655.ref013","doi-asserted-by":"crossref","first-page":"11329","DOI":"10.3390\/ijms241411329","article-title":"Suppression of indoxyl sulfate accumulation reduces renal fibrosis in sulfotransferase 1a1-deficient mice","volume":"24","author":"H Hou","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0332655.ref014","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1093\/ndt\/gfq580","article-title":"p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease","volume":"26","author":"I-W Wu","year":"2011","journal-title":"Nephrol Dial Transplant"},{"issue":"2","key":"pone.0332655.ref015","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/S0378-4347(00)83112-6","article-title":"Rapid assay for indoxyl sulphate in uremic serum by internal-surface reversed-phase high-performance liquid chromatography","volume":"431","author":"N Takeda","year":"1988","journal-title":"J Chromatogr"},{"issue":"10","key":"pone.0332655.ref016","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.2215\/CJN.03980609","article-title":"Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients","volume":"4","author":"FC Barreto","year":"2009","journal-title":"Clin J Am Soc Nephrol"},{"issue":"1","key":"pone.0332655.ref017","doi-asserted-by":"crossref","first-page":"16528","DOI":"10.1038\/s41598-020-73633-9","article-title":"Plasma indoxyl sulfate levels predict cardiovascular events in patients with mild chronic heart failure","volume":"10","author":"M Imazu","year":"2020","journal-title":"Sci Rep"},{"issue":"5","key":"pone.0332655.ref018","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0079682","article-title":"Heritability and clinical determinants of serum indoxyl sulfate and p-cresyl sulfate, candidate biomarkers of the human microbiome enterotype","volume":"9","author":"L Viaene","year":"2014","journal-title":"PLoS One"},{"issue":"6","key":"pone.0332655.ref019","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1111\/ggi.12811","article-title":"Age-dependent increase in serum levels of indoxyl sulphate and p-cresol sulphate is not related to their precursors: tryptophan and tyrosine","volume":"17","author":"A Wyczalkowska-Tomasik","year":"2017","journal-title":"Geriatr Gerontol Int"},{"issue":"11","key":"pone.0332655.ref020","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1515\/cclm-2019-0218","article-title":"Performance evaluation of an indoxyl sulfate assay kit \u201cNIPRO\u201d","volume":"57","author":"Y Fushimi","year":"2019","journal-title":"Clin Chem Lab Med"},{"issue":"1","key":"pone.0332655.ref021","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/1744-9987.13500","article-title":"Evaluation of a new measurement method of indoxyl sulfate in hemodialysis patients","volume":"25","author":"T Abe","year":"2021","journal-title":"Ther Apher Dial"},{"key":"pone.0332655.ref022","article-title":"KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease","volume":"105","author":"Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group","year":"2024","journal-title":"Kidney Int"},{"issue":"2","key":"pone.0332655.ref023","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/sj.jhh.1001307","article-title":"A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen","volume":"16","author":"T Tanaka","year":"2002","journal-title":"J Hum Hypertens"},{"issue":"1","key":"pone.0332655.ref024","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12986-022-00658-4","article-title":"Monitoring population salt intake using casual urinary sodium: tehran lipid and glucose study","volume":"19","author":"Z Bahadoran","year":"2022","journal-title":"Nutr Metab (Lond)"},{"issue":"1","key":"pone.0332655.ref025","doi-asserted-by":"crossref","first-page":"2170868","DOI":"10.1080\/08037051.2023.2170868","article-title":"Validation of spot urine in estimating 24-h urinary sodium, potassium and sodium-to-potassium ratio during three different sodium diets in healthy adults","volume":"32","author":"EH Groenland","year":"2023","journal-title":"Blood Press"},{"issue":"8","key":"pone.0332655.ref026","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.numecd.2015.04.010","article-title":"Validation of diet and urinary excretion derived estimates of sodium excretion against 24-h urine excretion in a worksite sample","volume":"25","author":"C Kelly","year":"2015","journal-title":"Nutr Metab Cardiovasc Dis"},{"issue":"6","key":"pone.0332655.ref027","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":"3","key":"pone.0332655.ref028","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10157-024-02571-x","article-title":"Effect of monoclonal gammopathy in the progression of acute kidney injury and chronic kidney disease: a retrospective observational study","volume":"29","author":"K Mitani","year":"2025","journal-title":"Clin Exp Nephrol"},{"key":"pone.0332655.ref029","doi-asserted-by":"crossref","first-page":"1495054","DOI":"10.3389\/fpubh.2024.1495054","article-title":"Development of a machine learning tool to predict the risk of incident chronic kidney disease using health examination data","volume":"12","author":"Y Yoshizaki","year":"2024","journal-title":"Front Public Health"},{"issue":"3","key":"pone.0332655.ref030","article-title":"Different renoprotective effects of luseogliflozin depend on the renal function at the baseline in patients with type 2 diabetes: a retrospective study during 12 months before and after initiation","volume":"16","author":"H Ito","year":"2021","journal-title":"PLoS One"},{"key":"pone.0332655.ref031","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.atherosclerosis.2016.01.007","article-title":"Defecation frequency and cardiovascular disease mortality in Japan: the Ohsaki cohort study","volume":"246","author":"K Honkura","year":"2016","journal-title":"Atherosclerosis"},{"issue":"4","key":"pone.0332655.ref032","doi-asserted-by":"crossref","first-page":"875","DOI":"10.3945\/ajcn.113.068122","article-title":"BMI and all-cause mortality in older adults: a meta-analysis","volume":"99","author":"JE Winter","year":"2014","journal-title":"Am J Clin Nutr"},{"issue":"3","key":"pone.0332655.ref033","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u201cEZR\u201d for medical statistics","volume":"48","author":"Y Kanda","year":"2013","journal-title":"Bone Marrow Transplant"},{"key":"pone.0332655.ref034","unstructured":"Trend in the percentage of anti-hypertensive drug users, 2006 to 2019. 2020. https:\/\/view.officeapps.live.com\/op\/view.aspx?src=https%3A%2F%2Fwww.nibiohn.go.jp%2Feiken%2Fkenkounippon21%2Fdownload_files%2Fkeinen_henka%2Fshintai%2F19.xlsx&wdOrigin=BROWSELINK"},{"issue":"9","key":"pone.0332655.ref035","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0074699","article-title":"Incidence of type 2 diabetes in Japan: a systematic review and meta-analysis","volume":"8","author":"A Goto","year":"2013","journal-title":"PLoS One"},{"key":"pone.0332655.ref036","first-page":"52","article-title":"Preventing tobacco use among young adults has significant implications for public health in the future","volume":"72","author":"R Tano","year":"2023","journal-title":"J Natl Inst Public Health"},{"issue":"1","key":"pone.0332655.ref037","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1186\/s12889-023-15322-6","article-title":"Modelling of salt intake reduction by incorporation of umami substances into Japanese foods: a cross-sectional study","volume":"23","author":"S Tanaka","year":"2023","journal-title":"BMC Public Health"},{"issue":"4","key":"pone.0332655.ref038","doi-asserted-by":"crossref","first-page":"548","DOI":"10.3390\/jpm12040548","article-title":"Emerging biomarkers for early detection of chronic kidney disease","volume":"12","author":"M Mizdrak","year":"2022","journal-title":"J Pers Med"},{"issue":"9","key":"pone.0332655.ref039","doi-asserted-by":"crossref","first-page":"3682","DOI":"10.1002\/jps.22592","article-title":"Update on the pharmacokinetics and redox properties of protein-bound uremic toxins","volume":"100","author":"H Watanabe","year":"2011","journal-title":"J Pharm Sci"},{"issue":"3","key":"pone.0332655.ref040","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1053\/j.jrn.2006.04.020","article-title":"Accumulation of indoxyl sulfate in OAT1\/3-positive tubular cells in kidneys of patients with chronic renal failure","volume":"16","author":"K Taki","year":"2006","journal-title":"J Ren Nutr"},{"issue":"3","key":"pone.0332655.ref041","article-title":"Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition","volume":"7","author":"C-Y Sun","year":"2012","journal-title":"PLoS One"},{"issue":"3","key":"pone.0332655.ref042","doi-asserted-by":"crossref","first-page":"420","DOI":"10.7150\/ijbs.37421","article-title":"Gut microbiota as diagnostic tools for mirroring disease progression and circulating nephrotoxin levels in chronic kidney disease: discovery and validation study","volume":"16","author":"I-W Wu","year":"2020","journal-title":"Int J Biol Sci"},{"issue":"2","key":"pone.0332655.ref043","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.arr.2009.10.004","article-title":"Human intestinal microbiota and healthy ageing","volume":"9","author":"K Tiihonen","year":"2010","journal-title":"Ageing Res Rev"},{"issue":"5","key":"pone.0332655.ref044","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1111\/j.1365-2672.2007.03400.x","article-title":"Intestinal bacteria and ageing","volume":"102","author":"EJ Woodmansey","year":"2007","journal-title":"J Appl Microbiol"},{"issue":"1","key":"pone.0332655.ref045","doi-asserted-by":"crossref","first-page":"273","DOI":"10.3390\/ijms25010273","article-title":"Tryptophan metabolism in postmenopausal women with functional constipation","volume":"25","author":"A Blonska","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0332655.ref046","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1681\/ASN.2016060656","article-title":"Constipation and incident CKD","volume":"28","author":"K Sumida","year":"2017","journal-title":"J Am Soc Nephrol"},{"issue":"2","key":"pone.0332655.ref047","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1093\/ndt\/gfz126","article-title":"The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease","volume":"35","author":"F Nanto-Hara","year":"2020","journal-title":"Nephrol Dial Transplant"},{"issue":"11","key":"pone.0332655.ref048","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1161\/HYPERTENSIONAHA.122.18556","article-title":"Gut-immune-kidney axis: influence of dietary protein in salt-sensitive hypertension","volume":"79","author":"DL Mattson","year":"2022","journal-title":"Hypertension"},{"issue":"7","key":"pone.0332655.ref049","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41581-018-0018-2","article-title":"The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease","volume":"14","author":"T Yang","year":"2018","journal-title":"Nat Rev Nephrol"},{"issue":"9","key":"pone.0332655.ref050","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1093\/ndt\/gfaa122","article-title":"Metagenomic profiling of gut microbiome in early chronic kidney disease","volume":"36","author":"N Sato","year":"2021","journal-title":"Nephrol Dial Transplant"},{"issue":"1","key":"pone.0332655.ref051","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40168-022-01443-4","article-title":"Perturbed gut microbiome and fecal and serum metabolomes are associated with chronic kidney disease severity","volume":"11","author":"H Wang","year":"2023","journal-title":"Microbiome"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0332655","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T18:29:11Z","timestamp":1765996151000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0332655"}},"subtitle":[],"editor":[{"given":"Tatsuo","family":"Shimosawa","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0332655","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]}}}