Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

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.

Association of Trimethylamine, Trimethylamine N-oxide, and Dimethylamine with Cardiovascular Risk in Children with Chronic Kidney Disease

“…In the present study, our results are consistent with previous reported data in CKD adults [31,32], showing that TMAO is increased in CKD with a weak inverse correlation (r = −0.283) between plasma TMAO level and eGFR. Our results are also in agreement with a previous report in CKD adults showing urinary excretion is a dominant route for TMAO elimination with a steady fractional excretion of TMAO, regardless of the CKD stages [32]. However, we observed lower urinary TMAO levels in children with CKD stage G2−G4 than those with stage G1.…”

“…Gut microbiota-derived metabolites TMAO, TMA, and DMA from dietary methylamines have recently gained much attention due to their high association with CV risk [8][9][10]29,30]. In the present study, our results are consistent with previous reported data in CKD adults [31,32], showing that TMAO is increased in CKD with a weak inverse correlation (r = −0.283) between plasma TMAO level and eGFR. Our results are also in agreement with a previous report in CKD adults showing urinary excretion is a dominant route for TMAO elimination with a steady fractional excretion of TMAO, regardless of the CKD stages [32].…”

“…However, we observed lower urinary TMAO levels in children with CKD stage G2−G4 than those with stage G1. Either increased or decreased urinary TMAO levels have been reported in adult CKD patients [32,33]. Conflicting results are likewise seen in this study showing that decreased urinary but increased plasma TMAO levels in children with advanced-stage CKD may represent reduced renal excretion of circulating TMAO or increased local renal TMAO metabolism.…”

A simple liquid chromatography/differential ion mobility spectrometry tandem mass spectrometry method for the determination of trimethylamine‐N‐oxide in human serum: An application in dialysis patients

“…2 Accumulating evidence has suggested that TMAO upregulation is implicated in cardiovascular disease 3 and chronic kidney disorders, 4 and is correlated with a high risk of the occurrence of ischemic events. 5 Previous studies showed that TMAO accumulates in chronic kidney disease patients, 6,7 and its elevation is associated with an increased risk of mortality. 7 In particular, a high level of TMAO has been found in hemodialysis patients at the peak midweek predialysis.…”

“…5 Previous studies showed that TMAO accumulates in chronic kidney disease patients, 6,7 and its elevation is associated with an increased risk of mortality. 7 In particular, a high level of TMAO has been found in hemodialysis patients at the peak midweek predialysis. 8 A wide range of mass spectrometry (MS)-based analytical methods coupled with liquid chromatography (LC) or gas chromatography have been developed for the measurement of TMAO in biological samples.…”