Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients

Shafi, Tariq; Powe, Neil R.; Meyer, Timothy W.; Hwang, Seungyoung; Hai, Xin; Melamed, Michal L.; Banerjee, Tanushree; Coresh, Josef; Hostetter, Thomas H.

doi:10.1681/asn.2016030374

Cited by 140 publications

(136 citation statements)

References 36 publications

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“…For instance, TMAO exhibited no significant predictive value on CVEs and mortality in a 4‐year observational cohort including 235 patients with CKD . Similar result was obtained from a more recent U.K. study in patients with HF . Two studies from Norway enrolling patients with CAD and HF also failed to show any evident correlation between TMAO and risk of death .…”

Section: Discussionsupporting

confidence: 66%

Circulating trimethylamine N‐oxide and the risk of cardiovascular diseases: a systematic review and meta‐analysis of 11 prospective cohort studies

You

et al. 2017

J Cellular Molecular Medi

209

129

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Circulating trimethylamine N‐oxide (TMAO), a canonical metabolite from gut flora, has been related to the risk of cardiovascular disorders. However, the association between circulating TMAO and the risk of cardiovascular events has not been quantitatively evaluated. We performed a systematic review and meta‐analysis of all available cohort studies regarding the association between baseline circulating TMAO and subsequent cardiovascular events. Embase and PubMed databases were searched for relevant cohort studies. The overall hazard ratios for the developing of cardiovascular events (CVEs) and mortality were extracted. Heterogeneity among the included studies was evaluated with Cochran's Q Test and I 2 statistics. A random‐effect model or a fixed‐effect model was applied depending on the heterogeneity. Subgroup analysis and meta‐regression were used to evaluate the source of heterogeneity. Among the 11 eligible studies, three reported both CVE and mortality outcome, one reported only CVEs and the other seven provided mortality data only. Higher circulating TMAO was associated with a 23% higher risk of CVEs (HR = 1.23, 95% CI: 1.07–1.42, I 2 = 31.4%) and a 55% higher risk of all‐cause mortality (HR = 1.55, 95% CI: 1.19–2.02, I 2 = 80.8%). Notably, the latter association may be blunted by potential publication bias, although sensitivity analysis by omitting one study at a time did not significantly change the results. Further subgroup analysis and meta‐regression did not support that the location of the study, follow‐up duration, publication year, population characteristics or the samples of TMAO affect the results significantly. Higher circulating TMAO may independently predict the risk of subsequent cardiovascular events and mortality.

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Section: Discussionsupporting

confidence: 66%

Circulating trimethylamine N‐oxide and the risk of cardiovascular diseases: a systematic review and meta‐analysis of 11 prospective cohort studies

You

et al. 2017

J Cellular Molecular Medi

209

129

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“…Details of trimethylamine-N-oxide (TMAO), asymmetric and symmetric dimethylarginines (ADMA and SDMA) measurements have been previously described. 19, 22 …”

Section: Methodsmentioning

confidence: 99%

Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

Shafi

Sirich

Meyer

et al. 2017

Kidney International

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Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dL), a two-fold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98–1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06–1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.

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“…Fortunately, the small volume of distribution enables adequate clearance by dialysis. In HEMO study participants, higher TMAO concentrations were associated with a higher risk of sudden cardiac death, first cardiovascular event, and any-cause death, particularly in whites [46]. A cross-sectional study by Aki Mafune et al observed elevated TMAO levels in CKD patients who underwent cardiovascular surgery ( n = 227) [47].…”

Section: Tmao In Chronic Kidney Diseasementioning

confidence: 99%

Trimethylamine N-Oxide: The Good, the Bad and the Unknown

Velasquez

Ramezani

Manal

et al. 2016

Toxins

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Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.

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Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients

Cited by 140 publications

References 36 publications

Circulating trimethylamine N‐oxide and the risk of cardiovascular diseases: a systematic review and meta‐analysis of 11 prospective cohort studies

Circulating trimethylamine N‐oxide and the risk of cardiovascular diseases: a systematic review and meta‐analysis of 11 prospective cohort studies

Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

Trimethylamine N-Oxide: The Good, the Bad and the Unknown

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