title: Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events.
abstract: Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82-32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada. Electronic address: Richard.Kim@Lhsc.on.ca.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada.
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Morse
authors.affiliation: Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ognjenka
authors.initials: O
authors.lastname: Djurdjev
authors.affiliation: Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mila
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada.
authors.forename: Norman
authors.initials: N
authors.lastname: Muirhead
authors.affiliation: Memorial University Newfoundland, St. John's, Newfoundland, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Barrett
authors.affiliation: Department of Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Holmes
authors.affiliation: University of Montreal, Montreal, Quebec, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Madore
authors.affiliation: McMaster University, Hamilton, Ontario, Canada.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Clase
authors.affiliation: University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rigatto
authors.affiliation: Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: alevin@providencehealth.bc.ca.
authors.forename: Adeera
authors.initials: A
authors.lastname: Levin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002170:Canada; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000209:etiology*; D018572:Disease-Free Survival; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008744:Methylamines / Q000097:blood*; D008875:Middle Aged; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000503:physiopathology; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D008744:Methylamines; C005855:trimethyloxamine
keywords: cardiovascular risk; chronic kidney disease; trimethylamine N-oxide