Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events
Open accessAbstract
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.
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Most study participants were from Europe and the United States and included mainly approximately 65-90% whites.
“Fifth, most of the study participants were from Europe and the United States and included mainly (approximately of 65–90% of total study participants) whites,10, 19, 20, 23 so that our results might not be applicable to other race/ethnic groups such as Asians and Africans.”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [20]
TMAO is biologically active and has been proposed as a contributor to chronic human diseases such as atherosclerosis.
“Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [61]
Many studies linking TMAO to heart disease also found that people with higher TMAO had decreased renal function.
“Many of the studies that identified an association between TMAO and heart disease also found that people with higher TMAO had decreased renal function (61,109).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [61]
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- Authors
- Kim, R. B., Morse, B. L., Djurdjev, O., Tang, M., Muirhead, N., Barrett, B., Holmes, D. T., Madore, F., Clase, C. M., Rigatto, C., Levin, A., Agharazii, M., Blouin, J., Samson, F., Akbarii, A., Cheesman, J., Courtney, J., Hamer, S., Delic, E., Cronin, V., Barré, P., Golden, J., Barrett, B., Langille, E., Adams, S., Morgan, J., Clase, C., Moreau, C., Cooper, S., Forzley, B., Caron, S., Granger, S., Valley, S., Sather, H., Cournoyer, S., Menard, L., Roy, M., Skidmore, H., Beaudry, D., Dionne, J., Chow, J., Sahraei, V., Donnelly, S., Dacouris, N., Marticorena, R., Hemmelgarn, B., Gulewich, S., Hamilton, T., Keown, P., Zalunardo, N., Rogers, D., Tut, R., Paquette, M., Yung, R., Levin, A., Ferguson, N., Tang, M., Chiu, H., Carlson, K., Sioson, L., Perry, T., Sheriff, Z., Rozen, N., Lok, C., Cross, M., Forrester, C., Cotoi, A., Madore, F., Maltais, M., Moist, L., Gallo, K., Langford, S., Slamen, L., Cram, D., Muirhead, N., Edgar, M. J., Gray, T., Edgar, C., Groeneweg, K., McKinnon, E., McRae, E., Blackie, K., Nathoo, B., Lau, K., Parmar, M., Gelinas, S., Leblanc, M., Lépine, L., Rigatto, C., Friesen, D., Soroka, S., Fleet, S., Squires, J., Thanamayooran, S., Binder, M., Hines, C., McNeil, B., McDougall, P., Howard, J., Gillis, D., Hines, K., Tobe, S., Chessman, M., Perkins, N., Agelopoulos, M., Knox, S., Richards, T., Tonelli, M., Szigety, S., Opgenorth, D., Yeates, K., & Mahoney, K.
- Affiliations
- Western University (CA)
- University of British Columbia (CA)
- Memorial University of Newfoundland (CA)
- McMaster University (CA)
- University of Manitoba (CA)
- Corresponding author
- Kim, Richard B.
- ORCID
- Kim, Richard B.
- Morse, Bridget L.
- Holmes, Daniel T.
- Agharazii, Mohsen
- Golden, Jeffrey
- Dionne, Janis
- Hemmelgarn, Brenda
- Keown, Paul
- Zalunardo, Nadia
- Chiu, Helen
- Rozen, Naama
- Lok, Charmaine
- Moist, Louise
- Gallo, Kerri
- Langford, Sarah
- Parmar, Malvinder
- Hines, Christine
- McNeil, Brenda
- Tobe, Sheldon
- Perkins, Nancy
- Tonelli, Marcello
- Opgenorth, Dawn
- Yeates, Karen
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 89
- Issue
- 5
- Pages
- 1144-1152
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W2300515179
- Cited by
- 179
- References
- 33
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 15 · 2023: 21 · 2022: 19 · 2021: 20 · 2020: 23 · 2019: 15 · 2018: 19 · 2017: 13 · 2016: 6 · 2012: 1
- FWCI
- 17.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-89753)
- Topics
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- trimethylamine N-oxide, chronic kidney disease, cardiovascular events, ischemic cardiovascular events, gut microbiota, L-carnitine, choline, cardiovascular risk factors
- MeSH terms
- Aged, Aged, 80 and over, Canada, Cardiovascular Diseases, Female, Glomerular Filtration Rate, Humans, Kidney, Male, Methylamines, Middle Aged, Prospective Studies, Risk Factors, Severity of Illness Index, Time Factors, Biomarkers, Up-Regulation, Risk Assessment, Disease-Free Survival, Renal Insufficiency, Chronic, Kaplan-Meier Estimate, Tandem Mass Spectrometry
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