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Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease
Open accessAbstract
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.
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In the citing paper
“Missailidis et al. measured plasma concentration of TMAO in 80 controls and 179 CKD patients and reported that that elevated TMAO levels are strongly associated with degree of renal function [27].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [27]
In the citing paper
“levels are higher the more the glomerular filtration rate GFR is reduced [49]”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [49]
In the citing paper
“Nonetheless, median values of TMAO concentrations in healthy individuals were reported as ranges of 3 to 6 μmol/L,8, 17, 18, 19 and the study by Shafi et al22 consisted of hemodialysis patients with the substantially high mean vale of TMAO (101.9 μmol/L among total participants).”
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 [18]
In the citing paper
“In 179 CKD stage 3-5 patients, the GFR and impaired renal function were the main variables affecting plasma TMAO concentrations (81).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [81]
In the citing paper
“Serum concentration of TMAO was inversely associated with eGFR and was markedly higher in patients receiving dialysis (59,81); hemodialysis efficiently removed TMAO from blood (8).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [81]
In the citing paper
“Increased TMAO concentrations were associated with systemic inflammatory markers and predicted a reduced fiveyear survival (81).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [81]
In the citing paper
“Renal transplantation corrects the high plasma TMAO concentrations seen in renal failure (81,106).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [81]
In the citing paper
“TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [27]
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“Other studies revealed that TMAO is augmented in renal insufficiency but concentrations normalize after renal transplantation [48] and levels are higher the more the glomerular filtration rate GFR is reduced [49].”
BackgroundSchiattarella, G. G., Sannino, A., Toscano, E., Giugliano, G., Gargiulo, G., Franzone, A., Trimarco, B., Esposito, G., & Perrino, C. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx342 · Cited by 563
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Trimethylamine N-oxide: the good, the bad and the unknown.
Velasquez, M., Ramezani, A., Manal, A., & Raj, D. (2016) · Toxins · doi:10.3390/toxins8110326 · Cited by 504
Metadata
- Authors
- Missailidis, C., Hällqvist, J., Qureshi, A. R., Barany, P., Heimbürger, O., Lindholm, B., Stenvinkel, P., & Bergman, P.
- Affiliations
- Karolinska University Hospital (SE)
- Swedish University of Agricultural Sciences (SE)
- Corresponding author
- Missailidis, Catharina
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-01-11
- Volume
- 11
- Issue
- 1
- Pages
- e0141738
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4709190
- OpenAlex
- W2232990799
- Cited by
- 338
- References
- 34
- Citations by year
- 2026: 22 · 2025: 32 · 2024: 27 · 2023: 36 · 2022: 44 · 2021: 34 · 2020: 42 · 2019: 33 · 2018: 28 · 2017: 27 · 2016: 13
- FWCI
- 34.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Stockholms Läns Landsting (2013-0317)
- Vetenskapsrådet
- 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 › Metabolomics and Mass Spectrometry Studies
- Keywords
- trimethylamine N-oxide, chronic kidney disease, glomerular filtration rate, renal function, kidney transplantation, dialysis, all-cause mortality, systemic inflammation, interleukin-6, fibrinogen, C-reactive protein, choline, betaine, microbial metabolites, prognostic factors
- MeSH terms
- Adult, Aged, Betaine, C-Reactive Protein, Cardiovascular Diseases, Choline, Female, Fibrinogen, Glomerular Filtration Rate, Renal Dialysis, Humans, Inflammation, Longitudinal Studies, Male, Methylamines, Middle Aged, Prognosis, Severity of Illness Index, Biomarkers, Interleukin-6, Multivariate Analysis, Survival Analysis, Kidney Transplantation, Renal Insufficiency, Chronic
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