Abstract
Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.
Highlights
Trimethylamine-N-oxide (TMAO) is a small amine plasma compound of 75.1 Da derived from intestinal microbial metabolism
We aimed to determine TMA, TMAO, choline, betaine, and carnitine concentrations in all stages of Chronic Kidney Disease (CKD), using gold standard measured glomerular filtration rate and renal clearance measures in order to assess the role of decreased GFR in TMAO increase
GFR was measured for non-dialysis participants and these were separated into four groups: controls (n = 18), CKD stages 1–2 (n = 49), CKD stages 3a–3b (n = 31), and CKD stages 4–5 (n = 15)
Summary
Trimethylamine-N-oxide (TMAO) is a small amine plasma compound of 75.1 Da derived from intestinal microbial metabolism. TMA is actively absorbed through the intestinal barrier into the bloodstream, N-oxidized by the hepatic enzyme flavin-containing monooxygenase isoform 3 (FMO3) in humans [4], and excreted as TMAO in urine [5,6]. TMAO has no known specific function in human body but a deficit in FMO3 has been shown to lead to a rare pathological status named trimethylaminuria [7]. This disease is characterized by an increased TMA concentration in all body fluids and was initially termed fish malodor syndrome in regard to its main symptom of unpleasant fish smell. Lack of TMAO has not been reported to be associated with any pathological condition
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