• W H Wilson Tang, Zeneng Wang, David J Kennedy, Yuping Wu, Jennifer A Buffa, Brendan Agatisa-Boyle, Xinmin S Li, Bruce S Levison, and Stanley L Hazen.
• From the Department for Cellular and Molecular Medicine, Lerner Research Institute (W.H.W.T., Z.W., D.J.K., J.A.B., B.A.-B., X.S.L., B.S.L., S.L.H.); Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic Foundation, OH (W.H.W.T., S.L.H.); and Department of Mathematics, Cleveland State University, OH (Y.W.). tangw@ccf.org hazens@ccf.org.
• Circ. Res. 2015 Jan 30;116(3):448-55.

RationaleTrimethylamine-N-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis.ObjectiveTo both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction.Methods And ResultsWe first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, <60 mL/min per 1.73 m(2)). Median TMAO level among CKD subjects was 7.9 μmol/L (interquartile range, 5.2-12.4 μmol/L), which was markedly higher (P<0.001) than in non-CKD subjects (n=3166). Within CKD subjects, higher (fourth versus first quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. After adjustments for traditional risk factors, high-sensitivity C-reactive protein, estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio, 1.93; 95% confidence interval, 1.13-3.29; P<0.05). TMAO provided significant incremental prognostic value (net reclassification index, 17.26%; P<0.001 and differences in area under receiver operator characteristic curve, 63.26% versus 65.95%; P=0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction.ConclusionsPlasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.© 2014 American Heart Association, Inc.

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