Evidence map›Paper›PMID 25599331›Full record

ArticleCirculation research2015

Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease.

W H Wilson Tang, Zeneng Wang, David J Kennedy, Yuping Wu, Jennifer A Buffa, Brendan Agatisa-Boyle, Xinmin S Li, Bruce S Levison, Stanley L Hazen

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03596749 (The Effect of Sevelamer Carbonate on Serum Trimethylamine-n-Oxide), which is not on this map. Cited by 737 papers, 6 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
737citing papers in PubMed, 6 pooled it
33.8field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03596749 phase3unknown statusnot on this mapstarted 2018, after this paper: background citation

The Effect of Sevelamer Carbonate on Serum Trimethylamine-n-Oxide (TMAO) Level in Patients With Chronic Kidney Disease (CKD) Stage 3b-4: a Protocol of a Randomized, Parallel, Controlled Trial

TypeinterventionalSponsorFan Fan HouRan2018 to 2019Enrolled80ConditionsCKD Stage 3b, CKD Stage 4ArmsSevelamer Carbonate
3 · Its place in the literature

Who cites it

737 citing papers in PubMed, 6 syntheses or guidelines pooled it, 1,163 citations in OpenAlex.

  1. Pooled it
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  14. Supplementation withThe veterinary quarterly · 2026
    Article
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  18. Trimethylamine-N-oxide: the microbial cue in immune-mediated disorders.Trends in endocrinology and metabolism: TEM · 2026
    Review
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  20. Article

677 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 1 country.

W H Wilson TangFrom 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.
Zeneng WangFrom 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.).
David J KennedyFrom 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.).
Yuping WuFrom 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.).
Jennifer A BuffaFrom 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.).
Brendan Agatisa-BoyleFrom 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.).
Xinmin S LiFrom 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.).
Bruce S LevisonFrom 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.).
Stanley L HazenFrom 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.
Cleveland State University · USCleveland Clinic · US

Funding

Clinical and Translational Science Collaborative of ClevelandUL1TR000439 · NCATS · CASE WESTERN RESERVE UNIVERSITY · PI KONSTAN, MICHAEL W. · 2012 to 2016
$50.0M
Structural Determinants Of Ceruloplasmin Inflammatory ActivityP01HL076491 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI PLOW, EDWARD FRANKLIN · 2004 to 2019
$27.3M
Regression of Atherosclerosis CoreP01HL098055 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI FISHER, EDWARD A · 2010 to 2014
$12.1M
Gut Flora Metabolism of Dietary Phosphatidylcholine and CVDR01HL103866 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI HAZEN, STANLEY L · 2010 to 2023
$10.8M
Functional Cardio-MetabolomicsP20HL113452 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI HAZEN, STANLEY L, TANG, WAI HONG WILSON · 2012 to 2016
$4.8M
Nitrative stress in heart failureR01HL103931 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI TANG, WAI HONG WILSON · 2010 to 2014
$3.8M
Dietary Choline, Gut Microbiota, and Susceptibility for Chronic Kidney DiseaseR01DK106000 · NIDDK · CLEVELAND CLINIC LERNER COM-CWRU · PI HAZEN, STANLEY L, TANG, WAI HONG WILSON · 2015 to 2018
$2.8M
NCATS NIH HHS UL1 TR000439NHLBI NIH HHS P01 HL076491NHLBI NIH HHS P01HL076491NHLBI NIH HHS P01 HL098055NHLBI NIH HHS P01HL098055NHLBI NIH HHS P20 HL113452NHLBI NIH HHS P20HL113452NHLBI NIH HHS R01 HL103866NHLBI NIH HHS R01HL103866NHLBI NIH HHS R01 HL103931NHLBI NIH HHS R01HL103931NIDDK NIH HHS R01 DK106000
6 · The paper itself

Abstract

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.

Indexed as

MicrobiotaAgedAged, 80 and overAnimalsBiomarkersCase-Control StudiesFemaleHumansIntestinesMaleMethylaminesMiceMice, Inbred C57BLMiddle AgedPrognosisRenal InsufficiencyBiomarkersMethylaminestrimethyloxaminecardiovascular diseaseschronic kidney diseasefibrosisgut microbiotatrimethylamine N-oxide

Identifiers

PMID25599331
PMCPMC4312512
OpenAlexW2150350691

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.