Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients

Abstract

Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3-6 months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Mean age of the patients was 58 years; 35% of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio [95% confidence interval]) of cardiac death (1.45 [1.24 to 1.69]), sudden cardiac death [1.70 (1.34 to 2.15)], first cardiovascular event (1.15 [1.01 to 1.32]), and any-cause death (1.22 [1.09 to 1.36]). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 [1.03 to 2.44]). Compared with blacks in the same quintile, whites in the highest quintile for TMAO (≥135 μM) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.

Keywords: cardiovascular events; epidemiology and outcomes; hemodialysis.

Figure 1.

Distribution of TMAO concentrations are similar in white and black patients of the HEMO Study but the risk of cardiac death is linear in whites and non-linear in blacks. (A) Distribution of TMAO in the HEMO Study. Histogram depicts the overall distribution (vertical gray bars). Lines depict the distribution in whites (broken line) and blacks (solid line). Extreme observations, defined as TMAO >99^th percentile (335 µM), are excluded (n=12). (B) Adjusted hazard of cardiac death. Relative hazard predicted using Cox proportional hazards regression adjusted for age, sex, ICED severity score, cause of ESRD, body mass index (categorized as <18, 18–25 and >25 kg/m²), systolic BP (categorized as <130, 130–160 and >160 mmHg), albumin, relative volume removed on dialysis, and residual kidney function (urinary stdKt/V_UREA calculated from urinary urea clearance). TMAO is modeled as a restricted cubic spline with 5 knots (5^th, 27.5^th, 50^th, 72.5^th, and 95^th percentiles); 10^th percentile is used as the reference (HR=1). The lines represent the adjusted HR in whites (broken line) and blacks (solid line). The shaded area is the 95% CI of the HR (whites, light gray; blacks, dark gray). Vertical bars are the frequency histogram, showing the distribution of TMAO. Extreme observations, defined as TMAO >99^th percentile (335 µM), are excluded (n=12).

Figure 2.

TMAO was poorly correlated with dialysis urea clearance and had a low correlation with nutritional protein intake. (A) Association of TMAO with dialysis urea clearance. Scatterplot of TMAO (y-axis) and dialysis urea clearance (Kt/V_UREA; x-axis). Solid circles represent concentrations in patients randomized to high dialysis dose and open circles represent concentrations in patients randomized to standard dialysis dose. Lines are linear fit from regression of TMAO on Kt/V_UREA, separately in the high dose group (solid line) and standard dose group (broken line). Pearson and Spearman correlation coefficients are presented for the overall cohort. Extreme observations (n=43), defined as TMAO or Kt/V_UREA >99^th percentile are excluded. (B) Association of TMAO with nutritional protein intake. Scatterplot of TMAO (y-axis) and equilibrated nitrogen protein catabolic rate (x-axis). Open circles represent concentrations in whites and solid circles represent concentration in blacks. Lines are linear fit from regression of TMAO on protein catabolic rate, separately in whites (broken line) and blacks (solid line). Pearson and Spearman correlation coefficients are presented for the overall cohort. Extreme observations (n=44), defined as TMAO or protein catabolic rate >99^th percentile are excluded.