Associations of Trimethylamine N-Oxide With Nutritional and Inflammatory Biomarkers and Cardiovascular Outcomes in Patients New to Dialysis
Open accessAbstract
Objectives Trimethylamine N-oxide (TMAO) is a product of metabolism of phosphatidylcholine (lecithin) and carnitine by the intestinal microbiome. Elevated serum concentrations of TMAO have been linked to adverse cardiovascular outcomes in the general population. We examined correlates of serum TMAO and the relations among serum TMAO concentrations, all-cause mortality, and cardiovascular mortality and hospitalizations in a nationally derived cohort of patients new to hemodialysis (HD).Methods We quantified serum TMAO by liquid chromatography and online tandem mass spectrometry and assessed nutritional and cardiovascular risk factors in 235 patients receiving HD and measured TMAO in pooled serum from healthy controls. We analyzed time to death and time to cardiovascular death or hospitalization using Cox proportional hazards regression.Results Serum TMAO concentrations of patients undergoing HD (median, 43 μM/L; 25th-75th percentile, 28-67 μM/L) were elevated compared with those with normal or near-normal kidney function (1.41 ± 0.49 μM/L). TMAO was directly correlated with serum albumin (Spearman rank correlation, 0.24; 95% CI, 0.12-0.35; P <.001), prealbumin (Spearman rank correlation, 0.19; 95% CI, 0.07-0.31; P = .003), and creatinine (Spearman rank correlation, 0.21; 95% CI, 0.08-0.33; P = .002) and inversely correlated with log C-reactive protein (Spearman rank correlation, -0.18; 95% CI, -0.30 to -0.06; P = .005). Higher serum concentrations of TMAO were not significantly associated with time to death (Spearman rank correlation, 0.84; CI, 0.65-1.09; P = .19) or time to cardiovascular hospitalization or cardiovascular death (Spearman rank correlation, 0.88; CI, 0.57-1.35; P = .55).Conclusions Serum TMAO concentrations were markedly elevated and correlated directly with biochemical markers of nutritional status and inversely with markers of inflammation in patients receiving HD. There was no significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations. In patients receiving dialysis-in contrast with the general population-adverse vascular effects of TMAO may be counterbalanced by associations with nutritional or inflammatory status.
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Inconsistent associations between TMAO-related metabolites and MACE outcomes and death have been observed.
“inconsistent associations have also been observed.10, 22”
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 [10]
In sensitivity analysis replacing RRs for all-cause mortality in these publications, the pooled RR was 1.69 (95% CI, 1.52, 1.89; P<0.001; P heterogeneity=0.6; I2=0%).
“we also performed a sensitivity analysis for the 18 data when we replaced RRs for all‐cause mortality in these publications7, 10, 22, 26; the pooled RR was 1.69 (95% CI, 1.52, 1.89; P<0.001; P heterogeneity=0.6; I2=0%).”
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 [10]
Among the prospective studies, 5 studies did not find a significantly elevated RR in the highest category of TMAO levels as compared with the lowest category, in either unadjusted or multivariate-adjusted models among total participants.
“Among the prospective studies, 5 studies10, 13, 19, 20, 23 did not find a significantly elevated RR in the highest category of TMAO levels as compared with the lowest category, in either unadjusted or multivariate‐adjusted models 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 [10]
Another 3 studies did not show a significantly elevated RR when TMAO was analyzed as a continuous variable in model.
“Also, another 3 studies did not show a significantly elevated RR when TMAO was analyzed as a continuous variable in model.10, 14, 17”
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 [10]
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 [10]
For all-cause mortality, 15 data from 12 articles were available, including 2498 deaths among 11,676 participants.
“For calculating the risk for only all‐cause mortality, 15 data from 12 articles7, 8, 10, 11, 18, 19, 21, 22, 23, 24, 25, 26 were available, including 2498 deaths among 11 676 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 [10]
Serum TMAO was inversely associated with eGFR and markedly higher in dialysis patients.
“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 <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [59]
In the Comprehensive Dialysis Study (235 ESRD patients on hemodialysis or peritoneal dialysis), no relationship was observed between serum TMAO and all-cause mortality or cardiovascular outcomes.
“For example, no relationship was observed between serum TMAO concentrations and all-cause mortality or cardiovascular outcomes in the Comprehensive Dialysis Study, a prospective cohort of 235 patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis (59).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [59]
TMAO is formed from trimethylamine (TMA), which is generated by gut microbiota from dietary choline and phosphatidylcholine (lecithin).
“TMAO is formed from trimethylamine (TMA), which is generated by the action of gut microbiota from dietary choline and phosphatidylcholine (lecithin) [8,9].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [8]
TMAO is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism.
“Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [8]
In 235 hemodialysis patients, serum TMAO concentrations (median 43, 25th-75th percentile 28-67 μM/L) were elevated compared to persons with normal or near normal kidney function (1.41 ± 0.49 μM/L).
“Kaysen et al. measured serum levels of TMAO in 235 hemodialysis patients and reported that serum TMAO concentrations (median 43, (25th–75th percentile 28–67 μM/L)) were elevated in these patients compared to persons with normal or near normal kidney function (1.41 ± 0.49 μM/L) [8].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [8]
In 235 hemodialysis patients, there was no significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations.
“On the other hand, Kaysen et al., did not find any significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations in 235 hemodialysis patients [8].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [8]
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- Authors
- Kaysen, G. A., Johansen, K. L., Chertow, G. M., Dalrymple, L. S., Kornak, J., Grimes, B., Dwyer, T., Chassy, A. W., & Fiehn, O.
- Affiliations
- University of California, Davis (US)
- San Francisco VA Medical Center (US)
- Stanford Medicine (US)
- University of California, San Francisco (US)
- Corresponding author
- Kaysen, George A.
- Venue
- Journal of Renal Nutrition
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 25
- Issue
- 4
- Pages
- 351-356
- ISSN
- 1051-2276 (ISSN-L)
- PMC
- PMC4469547
- OpenAlex
- W2132206770
- Cited by
- 164
- References
- 3
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 19 · 2021: 21 · 2020: 22 · 2019: 17 · 2018: 16 · 2017: 17 · 2016: 14 · 2015: 7
- FWCI
- 15.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Renal Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (N01DK12450, N01-DK-0005, HHSN267200700005C, K23DK093584, N01 DK022498)
- Topics
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Keywords
- trimethylamine N-oxide, hemodialysis, nutritional status, serum albumin, prealbumin, C-reactive protein, inflammation, cardiovascular mortality, all-cause mortality, cardiovascular hospitalization, gut microbiota, phosphatidylcholine, L-carnitine, end-stage renal disease, cardiovascular risk factors, serum creatinine, protein intake, dietary fat intake, dietary fiber
- MeSH terms
- C-Reactive Protein, Cardiovascular Diseases, Chromatography, Liquid, Female, Renal Dialysis, Hospitalization, Humans, Inflammation, Kidney Failure, Chronic, Male, Methylamines, Middle Aged, Nutritional Status, Risk Factors, Cohort Studies, Biomarkers, Comorbidity, Kaplan-Meier Estimate, Tandem Mass Spectrometry
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