{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:55:40Z","timestamp":1782849340785,"version":"3.54.5"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swedish Research Council EpiHealth study"},{"DOI":"10.13039\/501100005423","name":"Uppsala University Hospital","doi-asserted-by":"crossref","award":["PIVUS80 and POEM"],"award-info":[{"award-number":["PIVUS80 and POEM"]}],"id":[{"id":"10.13039\/501100005423","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Uppsala University Hospital ALF grants and establishment funding"},{"name":"Swedish National Strategic Research Initiative EXODIAB"},{"name":"Swedish Kidney Foundation"},{"DOI":"10.13039\/501100006415","name":"Family Ernfors Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006415","id-type":"DOI","asserted-by":"crossref"}]}],"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>A reduction in kidney function cause metabolites that normally are cleared by the kidney to accumulate. These accumulated metabolites could potentially link kidney function to an increased risk of cardiovascular disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To assess the relationships between creatinine-based estimated glomerular filtration rate (eGFR) and the metabolome (791 endogenous metabolites) in the general population, as well as the cortisol to cortisone ratio.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Patients and methods<\/jats:title>\n                    <jats:p>Three population-based cohorts, Epihealth, PIVUS and POEM (total n\u2009=\u20093,444), were used with a discovery\/validation approach. Metabolomics was measured by mass spectroscopy. eGFR was calculated using the 2021 CKD-EPI creatinine-based equation. Multivariable linear regression was used to assess the correlations between each metabolite concentration and eGFR, adjusting for sex, % fat mass, cardiovascular risk factors and medications. The metabolites significant in the linear regression were analyzed using MultiVariable Mendelian Randomization (MVMR), adjusting for diabetes and BMI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nighty-six metabolites were significantly associated to eGFR and had the same direction of association in both linear regression and MVMR. The vast majority of these associations were negative. Apart from creatinine, N-acetylalanine, N,N-dimethyl-pro-pro, N,N,N-trimethyl-alanylproline betaine (TMAP) were the top findings. Pathway enrichment analysis (Metaboloanalyst 6.0) found five significantly enriched pathways, two of which involved amino acid metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec005\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In a general population with only mild to moderately reduced kidney function, several metabolites were associated with kidney function, including the cortisol to cortisone ratio. This finding is of interest since several of these metabolites might link reduced kidney function to an increased risk of cardiovascular disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0347652","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:29:28Z","timestamp":1782847768000},"page":"e0347652","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of kidney function on the metabolome in the general population"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4708-3583","authenticated-orcid":true,"given":"Johan","family":"Ljunggren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Delgado-Velandia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2247-8454","authenticated-orcid":true,"given":"Johan","family":"Sundstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Engstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Gustav","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6933-4637","authenticated-orcid":true,"given":"Johan","family":"\u00c4rnl\u00f6v","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen F.","family":"Dekkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f6lve","family":"Elmst\u00e5hl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Lind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-5585","authenticated-orcid":true,"given":"Maria K.","family":"Svensson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"issue":"1","key":"pone.0347652.ref001","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s12882-023-03147-9","article-title":"A Metabolomics study of metabolites associated with the glomerular filtration rate","volume":"24","author":"H Peng","year":"2023","journal-title":"BMC Nephrol"},{"key":"pone.0347652.ref002","article-title":"Chronic Kidney Disease.","volume-title":"StatPearls [Internet]","author":"SR Vaidya","year":"2022"},{"issue":"13","key":"pone.0347652.ref003","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1056\/NEJMoa041031","article-title":"Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization","volume":"351","author":"AS Go","year":"2004","journal-title":"N Engl J Med"},{"key":"pone.0347652.ref004","doi-asserted-by":"crossref","first-page":"6656033","DOI":"10.1155\/2020\/6656033","article-title":"Oxidative Storm Induced by Tryptophan Metabolites: Missing Link between Atherosclerosis and Chronic Kidney Disease","volume":"2020","author":"I Kwiatkowska","year":"2020","journal-title":"Oxid Med Cell Longev"},{"issue":"3","key":"pone.0347652.ref005","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2215\/CJN.07420619","article-title":"Proteomics and metabolomics in kidney disease, including insights into etiology, treatment, and prevention","volume":"15","author":"RF Dubin","year":"2020","journal-title":"Clin J Am Soc Nephrol"},{"issue":"5","key":"pone.0347652.ref006","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1093\/ndt\/gfy094","article-title":"Metabolomic profiling to improve glomerular filtration rate estimation: a proof-of-concept study","volume":"34","author":"J Coresh","year":"2019","journal-title":"Nephrol Dial Transplant"},{"issue":"1","key":"pone.0347652.ref007","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.kint.2016.08.021","article-title":"An overview of renal metabolomics","volume":"91","author":"S Kalim","year":"2017","journal-title":"Kidney Int"},{"issue":"4","key":"pone.0347652.ref008","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11883-021-00910-x","article-title":"Trimethylamine N-Oxide (TMAO), Diet and Cardiovascular Disease","volume":"23","author":"MS Thomas","year":"2021","journal-title":"Curr Atheroscler Rep"},{"issue":"4","key":"pone.0347652.ref009","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1681\/ASN.2014111099","article-title":"A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population","volume":"27","author":"P Sekula","year":"2016","journal-title":"J Am Soc Nephrol"},{"issue":"3","key":"pone.0347652.ref010","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.kint.2023.11.007","article-title":"Evaluation of novel candidate filtration markers from a global metabolomic discovery for glomerular filtration rate estimation","volume":"105","author":"NF Fino","year":"2024","journal-title":"Kidney Int"},{"key":"pone.0347652.ref011","doi-asserted-by":"crossref","first-page":"6190333","DOI":"10.1155\/2022\/6190333","article-title":"Identification of Metabolite Markers Associated with Kidney Function","volume":"2022","author":"H Peng","year":"2022","journal-title":"J Immunol Res"},{"key":"pone.0347652.ref012","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.cca.2018.08.037","article-title":"Metabolites related to eGFR: Evaluation of candidate molecules for GFR estimation using untargeted metabolomics","volume":"489","author":"SM Titan","year":"2019","journal-title":"Clin Chim Acta"},{"issue":"1","key":"pone.0347652.ref013","doi-asserted-by":"crossref","first-page":"6831","DOI":"10.1038\/s41598-019-42992-3","article-title":"Untargeted metabolomics reveals N, N, N-trimethyl-L-alanyl-L-proline betaine (TMAP) as a novel biomarker of kidney function","volume":"9","author":"TJ Velenosi","year":"2019","journal-title":"Sci Rep"},{"issue":"5","key":"pone.0347652.ref014","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0096955","article-title":"Assessment of metabolomic and proteomic biomarkers in detection and prognosis of progression of renal function in chronic kidney disease","volume":"9","author":"E Nkuipou-Kenfack","year":"2014","journal-title":"PLoS One"},{"key":"pone.0347652.ref015","doi-asserted-by":"crossref","first-page":"1075809","DOI":"10.3389\/fendo.2022.1075809","article-title":"Cortisol excess in chronic kidney disease - A review of changes and impact on mortality","volume":"13","author":"MS Sagmeister","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"2","key":"pone.0347652.ref016","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2337\/db20-1120","article-title":"Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: A Multicohort Nontargeted Metabolomics Observational and Mendelian Randomization Study","volume":"71","author":"S Ahmad","year":"2022","journal-title":"Diabetes"},{"issue":"1","key":"pone.0347652.ref017","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1053\/j.ackd.2017.10.007","article-title":"Kidney Function in Obesity-Challenges in Indexing and Estimation","volume":"25","author":"AR Chang","year":"2018","journal-title":"Adv Chronic Kidney Dis"},{"issue":"1","key":"pone.0347652.ref018","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1080\/03009734.2018.1515282","article-title":"Population-based cardiovascular cohort studies in Uppsala","volume":"124","author":"L Lind","year":"2019","journal-title":"Ups J Med Sci"},{"issue":"2","key":"pone.0347652.ref019","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s10654-013-9787-x","article-title":"EpiHealth: a large population-based cohort study for investigation of gene-lifestyle interactions in the pathogenesis of common diseases","volume":"28","author":"L Lind","year":"2013","journal-title":"Eur J Epidemiol"},{"issue":"3","key":"pone.0347652.ref020","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1148\/radiol.2019191035","article-title":"Voxel-wise Study of Cohort Associations in Whole-Body MRI: Application in Metabolic Syndrome and Its Components","volume":"294","author":"L Lind","year":"2020","journal-title":"Radiology"},{"issue":"11","key":"pone.0347652.ref021","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1161\/01.ATV.0000184769.22061.da","article-title":"A comparison of three different methods to evaluate endothelium-dependent vasodilation in the elderly","volume":"25","author":"L Lind","year":"2005","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"2","key":"pone.0347652.ref022","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1093\/jalm\/jfz026","article-title":"Precision of a clinical metabolomics profiling platform for use in the identification of inborn errors of metabolism","volume":"5","author":"L Ford","year":"2020","journal-title":"J Appl Lab Med"},{"issue":"19","key":"pone.0347652.ref023","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1056\/NEJMoa2102953","article-title":"New creatinine- and cystatin C\u2013based equations to estimate GFR without race","volume":"385","author":"LA Inker","year":"2021","journal-title":"N Engl J Med"},{"issue":"1","key":"pone.0347652.ref024","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s10654-010-9521-x","article-title":"LifeGene--a large prospective population-based study of global relevance","volume":"26","author":"C Almqvist","year":"2011","journal-title":"Eur J Epidemiol"},{"issue":"11","key":"pone.0347652.ref025","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1007\/s00125-019-4960-8","article-title":"In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study","volume":"62","author":"K Beijer","year":"2019","journal-title":"Diabetologia"},{"issue":"7","key":"pone.0347652.ref026","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s41588-021-00870-7","article-title":"Computationally efficient whole-genome regression for quantitative and binary traits","volume":"53","author":"J Mbatchou","year":"2021","journal-title":"Nat Genet"},{"issue":"17","key":"pone.0347652.ref027","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1093\/bioinformatics\/btq340","article-title":"METAL: fast and efficient meta-analysis of genomewide association scans","volume":"26","author":"CJ Willer","year":"2010","journal-title":"Bioinformatics"},{"issue":"2","key":"pone.0347652.ref028","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/s41588-024-02044-7","article-title":"A scalable variational inference approach for increased mixed-model association power","volume":"57","author":"H Loya","year":"2025","journal-title":"Nat Genet"},{"issue":"8003","key":"pone.0347652.ref029","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","article-title":"Genetic drivers of heterogeneity in type 2 diabetes pathophysiology","volume":"627","author":"K Suzuki","year":"2024","journal-title":"Nature"},{"issue":"1","key":"pone.0347652.ref030","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1186\/s12882-018-1126-8","article-title":"Glomerular filtration rate: new age- and gender- specific reference ranges and thresholds for living kidney donation","volume":"19","author":"A Fenton","year":"2018","journal-title":"BMC Nephrol"},{"issue":"5","key":"pone.0347652.ref031","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/sj.ki.5002374","article-title":"Age- and gender-specific reference values of estimated GFR in Caucasians: The Nijmegen Biomedical Study","volume":"72","author":"JFM Wetzels","year":"2007","journal-title":"Kidney Int"},{"issue":"18","key":"pone.0347652.ref032","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1093\/bioinformatics\/btq418","article-title":"MetPA: a web-based metabolomics tool for pathway analysis and visualization","volume":"26","author":"J Xia","year":"2010","journal-title":"Bioinformatics"},{"issue":"20","key":"pone.0347652.ref033","article-title":"Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study","volume":"7","author":"D Wen","year":"2022","journal-title":"JCI Insight"},{"issue":"2","key":"pone.0347652.ref034","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1530\/eje.1.01954","article-title":"Expression of renal 11beta-hydroxysteroid dehydrogenase type 2 is decreased in patients with impaired renal function","volume":"153","author":"M Quinkler","year":"2005","journal-title":"Eur J Endocrinol"},{"issue":"7","key":"pone.0347652.ref035","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1210\/js.2018-00088","article-title":"Lower Renal Function Is Associated With Derangement of 11-\u03b2 Hydroxysteroid Dehydrogenase in Type 2 Diabetes","volume":"2","author":"CM Gant","year":"2018","journal-title":"J Endocr Soc"},{"key":"pone.0347652.ref036","article-title":"Progressive 11\u03b2-hydroxysteroid dehydrogenase type 2 insufficiency as kidney function declines","author":"T Uslar","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"pone.0347652.ref037","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.122.026885","article-title":"Large-Scale Metabolomics and the Incidence of Cardiovascular Disease","volume":"12","author":"L Lind","year":"2023","journal-title":"J Am Heart Assoc"},{"issue":"3","key":"pone.0347652.ref038","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41591-021-01266-0","article-title":"Plasma metabolites to profile pathways in noncommunicable disease multimorbidity","volume":"27","author":"M Pietzner","year":"2021","journal-title":"Nat Med"},{"issue":"3","key":"pone.0347652.ref039","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s11255-023-03779-8","article-title":"Metabolic implications of amino acid metabolites in chronic kidney disease progression: a metabolomics analysis using OPLS-DA and MBRole2.0 database","volume":"56","author":"J Kang","year":"2024","journal-title":"Int Urol Nephrol"},{"issue":"12","key":"pone.0347652.ref040","doi-asserted-by":"crossref","first-page":"3387","DOI":"10.1039\/C5MB00489F","article-title":"Analysis of urinary metabolomic profiling for unstable angina pectoris disease based on nuclear magnetic resonance spectroscopy","volume":"11","author":"Z Li","year":"2015","journal-title":"Mol Biosyst"},{"issue":"8","key":"pone.0347652.ref041","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0237579","article-title":"Untargeted high-resolution plasma metabolomic profiling predicts outcomes in patients with coronary artery disease","volume":"15","author":"A Mehta","year":"2020","journal-title":"PLoS One"},{"key":"pone.0347652.ref042","doi-asserted-by":"crossref","first-page":"637621","DOI":"10.3389\/fcvm.2021.637621","article-title":"Serum Metabonomic Study of Patients With Acute Coronary Syndrome Using Ultra-Performance Liquid Chromatography Orbitrap Mass Spectrometer","volume":"8","author":"L Song","year":"2021","journal-title":"Front Cardiovasc Med"},{"issue":"5","key":"pone.0347652.ref043","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/sdi.12099","article-title":"Water-soluble vitamins in people with low glomerular filtration rate or on dialysis: a review","volume":"26","author":"CM Clase","year":"2013","journal-title":"Semin Dial"},{"issue":"1","key":"pone.0347652.ref044","doi-asserted-by":"crossref","first-page":"5370","DOI":"10.1038\/s41467-022-33050-0","article-title":"An online atlas of human plasma metabolite signatures of gut microbiome composition","volume":"13","author":"KF Dekkers","year":"2022","journal-title":"Nat Commun"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0347652","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:29:38Z","timestamp":1782847778000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0347652"}},"subtitle":[],"editor":[{"given":"Anil","family":"Bhatia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0347652","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}