title: Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Missailidis
authors.affiliation: Department of Forest Genetics and Plant Physiology, Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Hällqvist
authors.affiliation: Department of Clinical Science Intervention and Technology. Division of Renal Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Abdel Rashid
authors.initials: AR
authors.lastname: Qureshi
authors.affiliation: Department of Clinical Science Intervention and Technology. Division of Renal Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Barany
authors.affiliation: Department of Clinical Science Intervention and Technology. Division of Renal Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Heimbürger
authors.affiliation: Department of Clinical Science Intervention and Technology. Division of Renal Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Lindholm
authors.affiliation: Department of Clinical Science Intervention and Technology. Division of Renal Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Stenvinkel
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Bergman
mesh_terms: D000328:Adult; D000368:Aged; D001622:Betaine / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis* / Q000209:etiology / Q000401:mortality; D002794:Choline / Q000097:blood; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005919:Glomerular Filtration Rate; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood; D016030:Kidney Transplantation; D008137:Longitudinal Studies; D008297:Male; D008744:Methylamines / Q000097:blood*; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000150:complications / Q000175:diagnosis* / Q000401:mortality; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D008744:Methylamines; D001622:Betaine; D005340:Fibrinogen; D002097:C-Reactive Protein; C005855:trimethyloxamine; D002794:Choline