Fasting Plasma Trimethylamine-N-Oxide as a Risk Marker of Poor Renal Outcomes, Cardiovascular Disease, and Mortality in Patients with Type 1 Diabetes with Diabetic Nephropathy

Background Trimethylamine-N-Oxide (TMAO) is a metabolite of phosphatidylcholine, choline and carnitine produced by the gut microbiota from ingested animal foods. It has been suggested as an independent gut microbiota derived risk factor for renal and cardiovascular disease (CVD). Patients with type 1 diabetes are at increased risk of renal and cardiovascular disease and early mortality. We investigated associations between plasma TMAO and outcomes in a prospective study. Methods TMAO was measured at baseline in 384 patients with type 1 diabetes with diabetic nephropathy (u-AER > 300 mg/g), 61 % were male, mean age was 42 years and eGFR 66 ml/min/1.73m2. Fasting plasma levels of TMAO were measured using stable isotope dilution tandem mass-spectrometry. Endpoints included mean yearly decline in 51Cr EDTA GFR (follow-up (FU) up to 12 years), ESRD (n=65; mean FU: 7.2 years), fatal and non-fatal CVD (n=154; mean FU: 7.5 years) and all-cause mortality (n=134; mean FU: 9.0 years). Associations between TMAO and the endpoints were tested using linear regression or Cox proportional hazard regression in uni- and multivariate analyses adjusting for conventional risk factors at baseline. Results Plasma TMAO was inversely associated with baseline eGFR (R2: 0.42; p<0.001). In univariate analysis higher TMAO was associated with all endpoints (p≤0.002). All endpoints remained significant associated with higher TMAO after adjustment for baseline age, diabetes duration, sex, smoking, systolic blood pressure, cholesterol, HbA1c and u-AER (p ≤ 0.014). After further adjustment for baseline eGFR significance was lost for all endpoints, except for CVD events (HR per doubling: 1.22, [1.05-1.41]; p=0.010). Conclusion In type 1 diabetes patients with diabetic nephropathy, higher fasting plasma TMAO level was predictive of poor renal outcomes, CVD events and mortality independent of conventional risk factors. Only the relation to CVD events remained after further adjustment for baseline eGFR. This elucidated the close relationship between TMAO and renal function.