Plasma trimethylamine N-oxide and its metabolic precursors and risk of mortality, cardiovascular and renal disease in individuals with type 2-diabetes and albuminuria

Abstract

Aims The trimethylamine N-oxide (TMAO) pathway is related to intestinal microbiota and has been associated to risk of cardiovascular disease (CVD). We investigated associations between four plasma metabolites in the TMAO pathway and risk of all-cause mortality, CVD and deterioration in renal function in individuals with type 2-diabetes (T2D) and albuminuria. Materials and methods Plasma concentrations of TMAO, choline, carnitine, and betaine were measured by liquid chromatography-tandem mass spectrometry at baseline in 311 individuals with T2D and albuminuria. Information on all-cause mortality and fatal/non-fatal CVD during follow-up was obtained from registries. The association of each metabolite, and a weighted sum score of all four metabolites, with the endpoints were examined. Serum creatinine was measured at follow-up visits and the renal endpoint was defined as eGFR-decline of ≥30%. Associations were analysed using proportional hazards models adjusted for traditional risk factors. Results Baseline mean(SD) age was 57.2(8.2) years and 75% were males. Follow-up was up to 21.9 years (median (IQR) follow-up 6.8 (6.1–15.5) years for mortality and 6.5 (5.5–8.1) years for CVD events). The individual metabolites and the weighted sum score were not associated with all-cause mortality (n = 106) or CVD (n = 116) (adjusted p≥0.09). Higher choline, carnitine and the weighted sum score of the four metabolites were associated with higher risk of decline in eGFR (n = 106) (adjusted p = 0.001, p = 0.03 and p<0.001, respectively). Conclusions In individuals with T2D and albuminuria, higher choline, carnitine and a weighted sum of four metabolites from the TMAO pathway were risk markers for deterioration in renal function during long-term follow-up. Metabolites from the TMAO pathway were not independently related to risk of all-cause mortality or CVD.

Nephroprotective Plants: A Review on the Use in Pre-Renal and Post-Renal Diseases

“…TMAO increases endogenous inflammation, promotes atherogenesis, and modulates lipid metabolism. It has been shown in vivo studies and clinical trials that the intake of vegetable protein decreases the TMAO levels [ 96 , 97 ], supporting the benefice of a plant-based diet and the use of plant supplements to treat pre-renal diseases.…”

TCA Cycle and Fatty Acids Oxidation Reflect Early Cardiorenal Damage in Normoalbuminuric Subjects with Controlled Hypertension

“…In particular, TMAO modulates lipid metabolism and increases vascular cell activation and endogenous inflammation, promoting atherogenesis. In type 2 diabetic subjects with albuminuria, the combination of a sub-set of TMAO pathway metabolites were shown to be associated with a higher risk of renal function decline [14]. Tricarboxylic acid cycle (TCA) metabolites also showed a prediction capacity for CKD progression in individuals with type 2 diabetes, independent of traditional cardio-renal risk factors, including eGFR and albuminuria [15].…”

Plasma Trimethylamine-N-Oxide Is an Independent Predictor of Long-Term Cardiovascular Mortality in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome

“…Moreover, some previous reports have also shown the association between TMAO and CV events in patients with ACS (39,40). A number of studies and meta-analyses confirmed the association between higher concentration of TMAO and higher risk of MACE, including CV and all-cause death and mortality during follow-up periods of up to 4 years (14,21,(41)(42)(43)(44)(45)(46). Interestingly, higher levels of TMAO were related to increased incidence of all-cause mortality in a dose-dependent manner, namely 7.6% per each 10 µmol/L increment of TMAO in a median followup period of 4.3 yr (47).…”