Asymmetric Dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide syntase predicts mortality in end-stage renal disease (ESRD).

BACKGROUND: The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric-oxide synthase, which has been linked to endothelial dysfunction and atherosclerosis in the general population, is raised in patients with end-stage renal disease and could contribute to the high cardiovascular risk in patients with chronic renal failure. We investigated the relation between cardiovascular risk factors and plasma ADMA concentration in a cohort of haemodialysis patients (n=225), and tested the predictive power of ADMA for mortality and cardiovascular outcomes. METHODS: Patients had standard dialysis three times a week. We accurately recorded cardiovascular events over a mean follow-up of 33.4 months (SD 14.6); these events were reviewed by a panel of physicians. We identified correlates of plasma ADMA by univariate and multivariate analyses. FINDINGS: On univariate analysis, ADMA concentration in plasma was directly related to concentrations of fibrinogen and L-arginine in plasma, duration of dialysis treatment, and serum cholesterol concentration, and was inversely related to serum albumin concentration. On multivariate analysis, only plasma fibrinogen (p=0.0001) and serum albumin (p=0.04) concentrations were independently related to plasma ADMA concentration (multiple r=0.44, p=0.0001). 83 patients died, 53 (64%) by cardiovascular causes. In a Cox's proportional-hazards model, plasma ADMA ranked as the second factor predicting overall mortality (hazard ratio 1.26, 95% Cl 1.11-1.41, p=0.0001) and cardiovascular events (1.17, 1.04-1.33, p=0.008). INTERPRETATION: In haemodialysis patients, plasma ADMA is a strong and independent predictor of overall mortality and cardiovascular outcome. These findings lend support to the hypothesis that accumulation of ADMA is an important risk factor for cardiovascular disease in chronic renal failure.