Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease

PLoS One. 2016 Jan 11;11(1):e0141738. doi: 10.1371/journal.pone.0141738. eCollection 2016.


Background: The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population.

Objective: To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality.

Methods: Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3-5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed.

Results: GFR was the dominant variable affecting TMAO (β = -0.41; p<0.001), choline (β = -0.38; p<0.001), and betaine (β = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3-5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32-14.2; p = 0.016).

Conclusion: Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3-5 patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Betaine / blood
  • Biomarkers / blood
  • C-Reactive Protein / metabolism
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / diagnosis*
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / mortality
  • Choline / blood
  • Female
  • Fibrinogen / metabolism
  • Glomerular Filtration Rate
  • Humans
  • Inflammation
  • Interleukin-6 / blood
  • Kidney Transplantation*
  • Longitudinal Studies
  • Male
  • Methylamines / blood*
  • Middle Aged
  • Multivariate Analysis
  • Prognosis
  • Renal Dialysis
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / diagnosis*
  • Renal Insufficiency, Chronic / mortality
  • Severity of Illness Index
  • Survival Analysis


  • Biomarkers
  • IL6 protein, human
  • Interleukin-6
  • Methylamines
  • Betaine
  • Fibrinogen
  • C-Reactive Protein
  • trimethyloxamine
  • Choline

Grants and funding

This study was funded by Stockholms läns landsting 20130317 and Vetenskapsrådet 2013-2709. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.