{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T14:39:56Z","timestamp":1786372796677,"version":"build-2736575974"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CJASN"],"published-print":{"date-parts":[[2017,11]]},"abstract":"\n Background and objectives<\/jats:title>\n Causes of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression.<\/jats:p>\n <\/jats:sec>\n \n Design, setting, participants & measurements<\/jats:title>\n \n Metabolites were quantified from serum samples of participants in the Modification of Diet in Renal Disease (MDRD) Study, a randomized controlled trial of dietary protein restriction and BP control, using untargeted reverse phase ultraperformance liquid chromatography tandem mass spectrometry quantification. Known, nondrug metabolites (\n n<\/jats:italic>\n =687) were log-transformed and analyzed to discover associations with CKD cause (polycystic kidney disease, glomerular disease, and other cause). Discovery was performed in Study B, a substudy of MDRD with low GFR (\n n<\/jats:italic>\n =166), and replication was performed in Study A, a substudy of MDRD with higher GFR (\n n<\/jats:italic>\n =423).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Overall in MDRD, average participant age was 51 years and 61% were men. In the discovery study (Study B), 29% of participants had polycystic kidney disease, 28% had glomerular disease, and 43% had CKD of another cause; in the replication study (Study A), the percentages were 28%, 24%, and 48%, respectively. In the discovery analysis, adjusted for demographics, randomization group, body mass index, hypertensive medications, measured GFR, log-transformed proteinuria, and estimated protein intake, seven metabolites (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, hippurate, homocitrulline, and 1,5-anhydroglucitol) were associated with CKD cause after correction for multiple comparisons (\n P<\/jats:italic>\n <0.0008). Five of these metabolite associations (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, and hippurate) were replicated in Study A (\n P<\/jats:italic>\n <0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Metabolomic profiling identified several metabolites strongly associated with cause of CKD.<\/jats:p>\n <\/jats:sec>","DOI":"10.2215\/cjn.02560317","type":"journal-article","created":{"date-parts":[[2017,10,2]],"date-time":"2017-10-02T21:00:21Z","timestamp":1506978021000},"page":"1787-1794","source":"Crossref","is-referenced-by-count":61,"title":["Metabolomic Alterations Associated with Cause of CKD"],"prefix":"10.2215","volume":"12","author":[{"given":"Morgan E.","family":"Grams","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, and"},{"name":"Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland;"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne","family":"Tin","sequence":"additional","affiliation":[{"name":"Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland;"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey M.","family":"Rebholz","sequence":"additional","affiliation":[{"name":"Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland;"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tariq","family":"Shafi","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, and"},{"name":"Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland;"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"K\u00f6ttgen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;"},{"name":"Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald D.","family":"Perrone","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Sarnak","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley A.","family":"Inker","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"Levey","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Coresh","sequence":"additional","affiliation":[{"name":"Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland;"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,9,28]]},"reference":[{"key":"B1-20230813","doi-asserted-by":"crossref","first-page":"812","DOI":"10.2215\/CJN.01780408","article-title":"Association of proteinuria with race, cause of chronic kidney disease, and glomerular filtration rate in the chronic kidney disease in children study.","volume":"4","author":"Wong","year":"2009","journal-title":"Clin J Am Soc Nephrol"},{"key":"B3-20230813","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1038\/ki.2014.120","article-title":"Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease.","volume":"86","author":"Spithoven","year":"2014","journal-title":"Kidney Int"},{"key":"B4-20230813","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ebiom.2016.01.027","article-title":"Fatty acid oxidation is impaired in an orthologous mouse model of autosomal dominant polycystic kidney disease.","volume":"5","author":"Menezes","year":"2016","journal-title":"EBioMedicine"},{"key":"B5-20230813","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrneph.2017.30","article-title":"Metabolomics for clinical use and research in chronic kidney disease.","volume":"13","author":"Hocher","year":"2017","journal-title":"Nat Rev Nephrol"},{"key":"B6-20230813","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cca.2013.03.033","article-title":"Metabolomics in chronic kidney disease.","volume":"422","author":"Zhao","year":"2013","journal-title":"Clin Chim Acta"},{"key":"B7-20230813","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.2215\/CJN.11971113","article-title":"Serum metabolomic profiling and incident CKD among African Americans.","volume":"9","author":"Yu","year":"2014","journal-title":"Clin J Am Soc Nephrol"},{"key":"B8-20230813","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1093\/aje\/kwt004","article-title":"Associations between metabolomic compounds and incident heart failure among African Americans: The ARIC Study.","volume":"178","author":"Zheng","year":"2013","journal-title":"Am J Epidemiol"},{"key":"B9-20230813","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1161\/HYPERTENSIONAHA.113.01166","article-title":"Metabolomics and incident hypertension among blacks: The atherosclerosis risk in communities study.","volume":"62","author":"Zheng","year":"2013","journal-title":"Hypertension"},{"key":"B10-20230813","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1159\/000446484","article-title":"Metabolomics of chronic kidney disease progression: A Case-Control Analysis in the Chronic Renal Insufficiency Cohort Study.","volume":"43","author":"Rhee","year":"2016","journal-title":"Am J Nephrol"},{"key":"B11-20230813","doi-asserted-by":"crossref","first-page":"3802","DOI":"10.1021\/acs.jproteome.6b00583","article-title":"Metabolomic Signatures of chronic kidney disease of diverse etiologies in the rats and humans.","volume":"15","author":"Zhang","year":"2016","journal-title":"J Proteome Res"},{"key":"B12-20230813","doi-asserted-by":"crossref","first-page":"26138","DOI":"10.1038\/srep26138","article-title":"Identification of biomarkers for development of end-stage kidney disease in chronic kidney disease by metabolomic profiling.","volume":"6","author":"Kimura","year":"2016","journal-title":"Sci Rep"},{"key":"B13-20230813","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1056\/NEJM199403313301301","article-title":"The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease.","volume":"330","author":"Klahr","year":"1994","journal-title":"N Engl J Med"},{"key":"B14-20230813","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/S0272-6386(96)90099-2","article-title":"Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study.","volume":"27","author":"Levey","year":"1996","journal-title":"Am J Kidney Dis"},{"key":"B15-20230813","doi-asserted-by":"crossref","first-page":"6656","DOI":"10.1021\/ac901536h","article-title":"Integrated, nontargeted ultrahigh performance liquid chromatography\/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems.","volume":"81","author":"Evans","year":"2009","journal-title":"Anal Chem"},{"key":"B16-20230813","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1177\/0192623309336152","article-title":"Untargeted metabolomic profiling as an evaluative tool of fenofibrate-induced toxicology in Fischer 344 male rats.","volume":"37","author":"Ohta","year":"2009","journal-title":"Toxicol Pathol"},{"key":"B17-20230813","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/j.kint.2017.01.007","article-title":"Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.","volume":"91","author":"McMahon","year":"2017","journal-title":"Kidney Int"},{"key":"B18-20230813","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/1097-0142(1950)3:1<32::AID-CNCR2820030106>3.0.CO;2-3","article-title":"Index for rating diagnostic tests.","volume":"3","author":"Youden","year":"1950","journal-title":"Cancer"},{"key":"B19-20230813","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.plipres.2008.03.003","article-title":"Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake.","volume":"47","author":"Hodson","year":"2008","journal-title":"Prog Lipid Res"},{"key":"B20-20230813","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/j.1742-4658.2010.07947.x","article-title":"Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans.","volume":"278","author":"Wanders","year":"2011","journal-title":"FEBS J"},{"key":"B21-20230813","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ebiom.2016.02.035","article-title":"Fat burning problem in cystic kidneys: An emerging common mechanism of chronic kidney disease.","volume":"5","author":"Li","year":"2016","journal-title":"EBioMedicine"},{"key":"B22-20230813","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1194\/jlr.P040501","article-title":"Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy.","volume":"55","author":"Herman-Edelstein","year":"2014","journal-title":"J Lipid Res"},{"key":"B23-20230813","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nm.3762","article-title":"Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.","volume":"21","author":"Kang","year":"2015","journal-title":"Nat Med"},{"key":"B24-20230813","first-page":"E650","article-title":"Human kidney free fatty acid and glucose uptake: Evidence for a renal glucose-fatty acid cycle.","volume":"273","author":"Meyer","year":"1997","journal-title":"Am J Physiol"},{"key":"B25-20230813","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1681\/ASN.2007121377","article-title":"A bench to bedside view of uremic toxins.","volume":"19","author":"Vanholder","year":"2008","journal-title":"J Am Soc Nephrol"},{"key":"B26-20230813","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1681\/ASN.2009111132","article-title":"Metabolite profiling identifies markers of uremia.","volume":"21","author":"Rhee","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"B27-20230813","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1021\/pr300900b","article-title":"Hippurate: The natural history of a mammalian-microbial cometabolite.","volume":"12","author":"Lees","year":"2013","journal-title":"J Proteome Res"},{"key":"B28-20230813","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1681\/ASN.2014060530","article-title":"Alteration of the intestinal environment by lubiprostone is associated with Amelioration of adenine-induced CKD.","volume":"26","author":"Mishima","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"B29-20230813","doi-asserted-by":"crossref","first-page":"F565","DOI":"10.1152\/ajprenal.2000.279.3.F565","article-title":"Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency.","volume":"279","author":"Saito","year":"2000","journal-title":"Am J Physiol Renal Physiol"},{"key":"B30-20230813","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s12640-009-9129-7","article-title":"The kynurenine pathway and inflammation in amyotrophic lateral sclerosis.","volume":"18","author":"Chen","year":"2010","journal-title":"Neurotox Res"},{"key":"B31-20230813","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1681\/ASN.2014121193","article-title":"Tubular secretion in CKD.","volume":"27","author":"Suchy-Dicey","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"B32-20230813","doi-asserted-by":"crossref","first-page":"C1075","DOI":"10.1152\/ajpcell.00619.2004","article-title":"Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites.","volume":"289","author":"Bahn","year":"2005","journal-title":"Am J Physiol Cell Physiol"},{"key":"B33-20230813","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/j.1523-1755.2004.00354.x","article-title":"Characterization of uremic toxin transport by organic anion transporters in the kidney.","volume":"65","author":"Deguchi","year":"2004","journal-title":"Kidney Int"},{"key":"B34-20230813","doi-asserted-by":"crossref","first-page":"26715","DOI":"10.1038\/srep26715","article-title":"Bioengineered kidney tubules efficiently excrete uremic toxins.","volume":"6","author":"Jansen","year":"2016","journal-title":"Sci Rep"},{"key":"B35-20230813","doi-asserted-by":"crossref","first-page":"112","DOI":"10.2215\/CJN.00910306","article-title":"Magnetic resonance measurements of renal blood flow and disease progression in autosomal dominant polycystic kidney disease.","volume":"2","author":"Torres","year":"2007","journal-title":"Clin J Am Soc Nephrol"},{"key":"B36-20230813","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1046\/j.1523-1755.1998.00944.x","article-title":"RNA metabolism in uremic patients: Accumulation of modified ribonucleosides in uremic serum. Technical note.","volume":"53","author":"Niwa","year":"1998","journal-title":"Kidney Int"},{"key":"B37-20230813","doi-asserted-by":"crossref","first-page":"754","DOI":"10.7326\/0003-4819-123-10-199511150-00003","article-title":"Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study.","volume":"123","author":"Peterson","year":"1995","journal-title":"Ann Intern Med"},{"key":"B38-20230813","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0378-3758(99)00041-5","article-title":"Resampling-based false discovery rate controlling multiple test procedures for correlated test statistics.","volume":"82","author":"Yekutieli","year":"1999","journal-title":"J Stat Plan Inference"}],"container-title":["Clinical Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/01277230-201711000-00012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:37:17Z","timestamp":1786369037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/01277230-201711000-00012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,28]]},"references-count":37,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2017]]}},"URL":"https:\/\/doi.org\/10.2215\/cjn.02560317","relation":{},"ISSN":["1555-9041","1555-905X"],"issn-type":[{"value":"1555-9041","type":"print"},{"value":"1555-905X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,28]]}}}