Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Abstract

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r(2)=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 μM [54.8-133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1-6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 μM [29.2-189.7 μM] pretransplant versus 11.4 μM [8.9-20.2 μM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 μM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.

Keywords: CKD; ESRD; atherosclerosis; cardiovascular disease; coronary artery disease; mortality.

Figure 1.

Cross-sectional analysis of serum TMAO concentrations by CKD stage. Serum TMAO concentrations were measured in a cohort of patients (n=104) with varying severity of kidney disease, ranging from normal kidney function (controls) to dialysis-dependent ESRD. Patients were grouped according to CKD staging: controls (eGFR≥60 ml/min per 1.73 m²), stage IIIA (eGFR 45–59 ml/min per 1.73 m²), stage IIIB (eGFR 30–44 ml/min per 1.73 m²), stage IV/V (eGFR<30 and not dialysis-dependent), and ESRD (receiving chronic hemodialysis therapy) *P<0.05; ^#P<0.001 compared with control group.

Figure 2.

Relationship between serum and urine TMAO concentrations in CKD. (A) Linear regression analysis depicting the relationship between serum TMAO and eGFR in CKD patients from a cross-sectional cohort (excluding patients with ESRD). (B) Comparison of the spot urine TMAO to creatinine ratio (TMAO:Cr) in controls and CKD patients with residual kidney function. (C) Comparison of the spot fractional excretion of TMAO (FE_TMAO) in controls and patients with CKD with residual kidney function (box plots depict median + interquartile range and whiskers illustrate minimum-maximum values).

Figure 3.

Characterization of serum TMAO changes following renal transplantation. Serum TMAO concentrations in six patients with ESRD prior to and three months following successful renal transplantation.

Figure 4.

Survival curve for TMAO tertiles in a longitudinal cohort. Kaplan–Meier survival analysis based on TMAO tertiles for 220 patients with CKD enrolled in the Diabetes Genome Project study.