{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:13:21Z","timestamp":1787062401525,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T00:00:00Z","timestamp":1610928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background. Due to the critical shortage of kidneys for transplantation, the identification of modifiable factors related to graft failure is highly desirable. The role of trimethylamine-N-oxide (TMAO) in graft failure remains undetermined. Here, we investigated the clinical utility of TMAO and its dietary determinants for graft failure prediction in renal transplant recipients (RTRs). Methods. We included 448 RTRs who participated in the TransplantLines Cohort Study. Cox proportional-hazards regression analyses were performed to study the association of plasma TMAO with graft failure. Net Benefit, which is a decision analysis method, was performed to evaluate the clinical utility of TMAO and dietary information in the prediction of graft failure. Results. Among RTRs (age 52.7 \u00b1 13.1 years; 53% males), the baseline median TMAO was 5.6 (3.0\u201310.2) \u00b5mol\/L. In multivariable regression analysis, the most important dietary determinants of TMAO were egg intake (Std. \u03b2 = 0.09 [95%CI, 0.01; 0.18]; p = 0.03), fiber intake (Std. \u03b2 = \u22120.14 [95%CI, \u22120.22, \u22120.05]; p = 0.002), and fish and seafood intake (Std. \u03b2 = 0.12 [95%CI, 0.03,0.21]; p = 0.01). After a median follow-up of 5.3 (4.5\u20136.0) years, graft failure was observed in 58 subjects. TMAO was associated with an increased risk of graft failure, independent of age, sex, the body mass index (BMI), blood pressure, lipids, albuminuria, and the Estimated Glomerular Filtration Rate (eGFR) (Hazard Ratio per 1-SD increase of TMAO, 1.62 (95% confidence interval (CI): 1.22; 2.14, p &lt; 0.001)). A TMAO and dietary enhanced prediction model offered approximately double the Net Benefit compared to a previously reported, validated prediction model for future graft failure, allowing the detection of 21 RTRs per 100 RTRs tested, with no false positives versus 10 RTRs, respectively. Conclusions. A predictive model for graft failure, enriched with TMAO and its dietary determinants, yielded a higher Net Benefit compared with an already validated model. This study suggests that TMAO and its dietary determinants are associated with an increased risk of graft failure and that it is clinically meaningful.<\/jats:p>","DOI":"10.3390\/nu13010262","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T03:34:25Z","timestamp":1611113665000},"page":"262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Association of Circulating Trimethylamine N-Oxide and Its Dietary Determinants with the Risk of Kidney Graft Failure: Results of the TransplantLines Cohort Study"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6094-2206","authenticated-orcid":false,"given":"Jose L.","family":"Flores-Guerrero","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9238-1397","authenticated-orcid":false,"given":"Maryse C. J.","family":"Ost\u00e9","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula B.","family":"Baraldi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3917-592X","authenticated-orcid":false,"given":"Margery A.","family":"Connelly","sequence":"additional","affiliation":[{"name":"Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2956-2715","authenticated-orcid":false,"given":"Erwin","family":"Garcia","sequence":"additional","affiliation":[{"name":"Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC 27560, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerjan","family":"Navis","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3356-6791","authenticated-orcid":false,"given":"Stephan J. L.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3844-5254","authenticated-orcid":false,"given":"Robin P. F.","family":"Dullaart","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1111\/ajt.14702","article-title":"An economic assessment of contemporary kidney transplant practice","volume":"18","author":"Axelrod","year":"2018","journal-title":"Am. J. Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1681\/ASN.2018101030","article-title":"The terrible toll of the kidney shortage","volume":"29","author":"McCormick","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/j.1600-6143.2010.03283.x","article-title":"Long-term renal allograft survival in the United States: A critical reappraisal","volume":"11","author":"Lamb","year":"2011","journal-title":"Am. J. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.kint.2018.08.005","article-title":"Long-term renal allograft survival: A quiet revolution","volume":"94","author":"Jardine","year":"2018","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Vickers, A.J., Van Calster, B., and Steyerberg, E.W. (2016). Net benefit approaches to the evaluation of prediction models, molecular markers, and diagnostic tests. BMJ, 352.","DOI":"10.1136\/bmj.i6"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1177\/0272989X06295361","article-title":"Decision curve analysis: A novel method for evaluating prediction models","volume":"26","author":"Vickers","year":"2006","journal-title":"Med. Decis. Mak."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1006\/bbrc.1998.9382","article-title":"Natural methylamine osmolytes, trimethylamine N-oxide and betaine, increase tau-induced polymerization of microtubules","volume":"250","author":"Tseng","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wu, C., Lee, J., Hsu, J., Su, M.M., Wu, Y., Lin, T., Lan, C., Hwang, J., and Lin, L. (2019). Myocardial adipose deposition and the development of heart failure with preserved ejection fraction. Eur. J. Heart Fail., ejhf.1617.","DOI":"10.1002\/ejhf.1617"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.cardfail.2014.11.006","article-title":"Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure","volume":"21","author":"Tang","year":"2015","journal-title":"J. Card. Fail."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pelletier, C.C., Croyal, M., Ene, L., Aguesse, A., Billon-Crossouard, S., Krempf, M., Lemoine, S., Guebre-Egziabher, F., Juillard, L., and Soulage, C.O. (2019). Elevation of trimethylamine-N-oxide in chronic kidney disease: Contribution of decreased glomerular filtration rate. Toxins, 11.","DOI":"10.3390\/toxins11110635"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13781","DOI":"10.1038\/s41598-017-13739-9","article-title":"TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function","volume":"7","author":"Gruppen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature09922","article-title":"Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease","volume":"472","author":"Wang","year":"2011","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nm.3145","article-title":"Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis","volume":"19","author":"Koeth","year":"2013","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Canyelles, M., Tondo, M., Ced\u00f3, L., Farr\u00e0s, M., Escol\u00e0-Gil, J.C., and Blanco-Vaca, F. (2018). Trimethylamine N-oxide: A link among diet, gut microbiota, gene regulation of liver and intestine cholesterol homeostasis and HDL function. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103228"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1681\/ASN.2014111063","article-title":"Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden","volume":"27","author":"Stubbs","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.kint.2017.03.053","article-title":"The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease","volume":"92","author":"Tomlinson","year":"2017","journal-title":"Kidney Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1681\/ASN.2016030374","article-title":"Trimethylamine n-oxide and cardiovascular events in hemodialysis patients","volume":"28","author":"Shafi","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1681\/ASN.2019080852","article-title":"Gut microbial metabolites induce donor-specific tolerance of kidney allografts through induction of T regulatory cells by short-chain fatty acids","volume":"31","author":"Wu","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1161\/CIRCRESAHA.116.305360","article-title":"Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease","volume":"116","author":"Tang","year":"2014","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"(2013). World Medical Association World Medical Association declaration of Helsinki: Ethical principles for medical research involving human subjects. J. Am. Med. Assoc., 310, 2191\u20132194.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.2215\/CJN.04590512","article-title":"Dietary acid load and metabolic acidosis in renal transplant recipients","volume":"7","author":"Engberink","year":"2012","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3109\/09637489509012539","article-title":"Reproducibility of a semiquantitative food frequency questionnaire to assess the intake of fats and cholesterol in the Netherlands","volume":"46","author":"Feunekes","year":"1995","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1017\/S0007114512003455","article-title":"Dietary protein, blood pressure and renal function in renal transplant recipients","volume":"109","author":"Engberink","year":"2013","journal-title":"Br. J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12944-016-0313-5","article-title":"Plasma phospholipid transfer protein activity is inversely associated with betaine in diabetic and non-diabetic subjects","volume":"15","author":"Dullaart","year":"2016","journal-title":"Lipids Health Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1053\/j.ajkd.2010.02.337","article-title":"Estimating GFR Using the CKD Epidemiology Collaboration (CKD-EPI) Creatinine Equation: More Accurate GFR Estimates, Lower CKD Prevalence Estimates, and Better Risk Predictions","volume":"55","author":"Levey","year":"2010","journal-title":"Am. J. Kidney Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.kint.2020.02.010","article-title":"Nomenclature for kidney function and disease: Report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference","volume":"97","author":"Levey","year":"2020","journal-title":"Kidney Int."},{"key":"ref_27","unstructured":"Montgomery, D.C., Peck, E.A., and Vining, G.G. (2012). Introduction to Linear Regression Analysis, John Wiley & Sons, Incorporated. [5th ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Therneau, T.M., and Grambsch, P.M. (2000). Modeling Survival Data: Extending the Cox Model, Springer. Statistics for Biology and Health.","DOI":"10.1007\/978-1-4757-3294-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1053\/j.ajkd.2013.10.059","article-title":"Predicting 5-year risk of kidney transplant failure: A prediction instrument using data available at 1 year posttransplantation","volume":"63","author":"Shabir","year":"2014","journal-title":"Am. J. Kidney Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/sim.2929","article-title":"Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond","volume":"27","author":"Pencina","year":"2008","journal-title":"Stat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/eurheartj\/ehy799","article-title":"Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women","volume":"40","author":"Wang","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1136\/gutjnl-2015-309957","article-title":"High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome","volume":"65","author":"Pellegrini","year":"2016","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.celrep.2018.06.096","article-title":"A Multi-omic Association Study of Trimethylamine N-Oxide","volume":"24","author":"Manor","year":"2018","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Th\u00f8gersen, R., Rasmussen, M.K., Sundekilde, U.K., Goethals, S.A., Van Hecke, T., Vossen, E., De Smet, S., and Bertram, H.C. (2020). Background diet influences TMAO concentrations associated with red meat intake without influencing apparent hepatic TMAO-related activity in a porcine model. Metabolites, 10.","DOI":"10.3390\/metabo10020057"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.jclinepi.2009.11.009","article-title":"Use of Brier score to assess binary predictions","volume":"63","author":"Rufibach","year":"2010","journal-title":"J. Clin. Epidemiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s41512-017-0020-3","article-title":"The Brier score does not evaluate the clinical utility of diagnostic tests or prediction models","volume":"1","author":"Assel","year":"2017","journal-title":"Diagnostic Progn. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1002\/sim.5601","article-title":"A simple decision analytic solution to the comparison of two binary diagnostic tests","volume":"32","author":"Vickers","year":"2013","journal-title":"Stat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hunink, M.G.M., Weinstein, M.C., Wittenberg, E., Drummond, M.F., Pliskin, J.S., Wong, J.B., and Glasziou, P.P. (2014). Decision Making in Health and Medicine, Cambridge University Press.","DOI":"10.1017\/CBO9781139506779"},{"key":"ref_39","unstructured":"R Core Team (2019). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1093\/ndt\/gfk056","article-title":"Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis","volume":"21","author":"Bain","year":"2006","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/jez.10109","article-title":"Elevated levels of trimethylamine oxide in deep-sea fish: Evidence for synthesis and intertissue physiological importance","volume":"293","author":"Treberg","year":"2002","journal-title":"J. Exp. Zool."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"778","DOI":"10.3945\/ajcn.114.087692","article-title":"Effect of egg ingestion on trimethylamine-N-oxide production in humans: A randomized, controlled, dose-response study","volume":"100","author":"Miller","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1681\/ASN.2013080905","article-title":"The gut microbiome, kidney disease, and targeted interventions","volume":"25","author":"Ramezani","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1053\/j.ajkd.2007.11.013","article-title":"Incidence and Risk Factors for Diarrhea Following Kidney Transplantation and Association with Graft Loss and Mortality","volume":"51","author":"Bunnapradist","year":"2008","journal-title":"Am. J. Kidney Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/ajt.14974","article-title":"Gut microbiota dysbiosis and diarrhea in kidney transplant recipients","volume":"19","author":"Lee","year":"2019","journal-title":"Am. J. Transplant."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/ajt.14941","article-title":"Urinary metabolites predict prolonged duration of delayed graft function in DCD kidney transplant recipients","volume":"19","author":"Kostidis","year":"2019","journal-title":"Am. J. Transplant."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1053\/j.ajkd.2010.06.020","article-title":"A simple tool to predict outcomes after kidney transplant","volume":"56","author":"Kasiske","year":"2010","journal-title":"Am. J. Kidney Dis."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/1\/262\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:12:30Z","timestamp":1760159550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/1\/262"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,18]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["nu13010262"],"URL":"https:\/\/doi.org\/10.3390\/nu13010262","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,18]]}}}