Prior studies in rodents have demonstrated trimethylamine-N-oxide (TMAO) to be a direct promoter of atherosclerosis. Patients with chronic kidney disease (CKD) exhibit accelerated development of atherosclerosis that contributes to the high cardiovascular mortality in this group. According to a new study performed by a research team led by Jason R. Stubbs, MD, of the University of Kansas Medical Center in Kansas City, CKD patients have elevated serum concentrations of TMAO that correlate with increased coronary atherosclerosis burden.

“Based on evidence that TMAO production is dependent on dietary precursors and the intestinal microbiome,” Dr. Stubbs’ group concluded in a report published online ahead of print in the Journal of the American Society of Nephrology, “TMAO may represent a novel modifiable risk factor and therapeutic target for reducing cardiovascular mortality in patients with CKD.”

Intestinal bacteria metabolize dietary L-carnitine and choline to trimethylamine, which is then oxidized via hepatic flavin monooxygenase enzymes to form TMAO, the authors explained.

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Previous studies have demonstrated an association between elevated TMAO levels and cardiovascular events in humans with preserved kidney function, “providing solid clinical evidence to support a link between TMAO and cardiovascular pathology.” No studies have examined the relationship between TMAO and atherosclerosis in CKD patients.

Dr. Stubbs and his colleagues measured serum concentrations and urinary excretion of TMAO in a cohort of 104 CKD patients and examined the effect of renal transplantation in 6 of these patients. In addition, the researchers examined the relationship between serum TMAO and coronary atherosclerosis burden, as well as overall mortality, in a separate cohort of 220 CKD patients undergoing coronary angiography.

Study results showed a strong inverse association between serum TMAO and estimated glomerular filtration rate. TMAO concentrations were significantly higher in dialysis-dependent patients compared with healthy controls (median 94.4 vs. 3.3 µM). In the 6 renal transplant recipients, TMAO concentrations declined significantly from 71.2 µM pre-transplant to 11.4 µM post-transplant, Dr. Stubbs’ group reported.  Furthermore, the researchers observed a statistically significant and independent positive correlation between TMAO concentration and coronary atherosclerosis burden as defined by modified Gensini score. In addition, each 10 µM increment in TMAO concentration was associated with a 26% increase in long-term mortality risk independent of traditional cardiac risk factors.

“The current investigation advances our understanding of cardiovascular disease in CKD by providing a novel mechanistic link to explain the presence of accelerated atherosclerosis in patients with reduced kidney function,” the authors concluded. “As such, our study demonstrates a strong inverse relationship between circulating concentrations of TMAO, a novel atherogenic compound, and residual kidney function in patients with CKD, and defines TMAO as an independent predictor of coronary atherosclerosis in this population.”