title: Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease.
abstract: BACKGROUND
  Trimethylamine-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.
  
  
  OBJECTIVE
  To 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Plasma 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.
authors.affiliation: 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.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: 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.).
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Kennedy
authors.affiliation: 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.).
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Buffa
authors.affiliation: 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.).
authors.forename: Brendan
authors.initials: B
authors.lastname: Agatisa-Boyle
authors.affiliation: 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.).
authors.forename: Xinmin S
authors.initials: XS
authors.lastname: Li
authors.affiliation: 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.).
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.affiliation: 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.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007422:Intestines / Q000382:microbiology; D008297:Male; D008744:Methylamines / Q000097:blood / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D008875:Middle Aged; D011379:Prognosis; D051437:Renal Insufficiency / Q000175:diagnosis* / Q000209:etiology; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis* / Q000378:metabolism / Q000382:microbiology; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D008744:Methylamines; C005855:trimethyloxamine
keywords: cardiovascular diseases; chronic kidney disease; fibrosis; gut microbiota; trimethylamine N-oxide