Associations of Trimethylamine N-Oxide With Nutritional and Inflammatory Biomarkers and Cardiovascular Outcomes in Patients New to Dialysis

Abstract

Background 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 hemodialysis 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 (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). TMAO was directly correlated with serum albumin (Spearman rank correlation 0.24, 95% CI 0.12, 0.35; P < 0.001), prealbumin (0.19, 95% CI 0.07, 0.31; P =0.003), and creatinine (0.21, 95% CI 0.08, 0.33; P =0.002), and inversely correlated with log CRP (−0.18, 95% CI −0.30, – 0.06; P =0.005). Higher serum concentrations of TMAO were not significantly associated with time to death (0.84, CI 0.65, 1.09 P=0.19) or time to cardiovascular hospitalization or cardiovascular death (0.88, CI 0.57, 1.35 P =0.55). 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 hemodialysis. There was no significant association between serum TMAO concentrations and all-cause mortality or cardiovascular death or hospitalizations. In patients receiving dialysis – in contrast to the general population – adverse vascular effects of TMAO may be counterbalanced by associations with nutritional or inflammatory status.

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

“…While the studies show the ability of TMAO to promote atherosclerosis [10,11,17,18,30,31], there are numerous contrasting results [19,[32][33][34][35][36]. Treatment of male Fischer 344 rats by L-carnitine in drinking water for 1 year induced tenfold higher TMAO plasma concentration when compared to the control (2.5 vs. 25.0 μM) [36].…”

The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease

“…In a cohort of 235 hemodialysis patients, no association was found between blood TMAO concentrations and cardiovascular mortality, but TMAO did correlate with serum albumin, creatinine and inversely with CRP. 42 An attenuated or even reverse association between traditional disease markers such as high blood pressure or blood cholesterol and cardiovascular outcomes has previously been reported in the hemodialysis population, likely due to confounding by comorbidity 3,4 and TMAO may be subject to the same phenomenon. For example, much like albumin, lower TMAO levels in some hemodialysis patients could reflect poor nutritional and overall health status.…”

“…For example, much like albumin, lower TMAO levels in some hemodialysis patients could reflect poor nutritional and overall health status. 42 Because of such confounding, interventional studies are likely to be the only reliable method to test the hypothesis that TMAO contributes to CV disease in the context of CKD.…”

Trimethylamine N-Oxide as a Novel Therapeutic Target in CKD

“…However, a recent report by Kaysen et al did not observe a significant increase in both all-cause and cardiovascular mortality risk in a national cohort of patients new to dialysis, despite markedly elevated TMAO levels. 15 These findings have challenged the extension of TMAO-associated cardiorenal risk to more advanced CKD stages.…”