High uric acid ameliorates indoxyl sulfate-induced endothelial dysfunction and is associated with lower mortality among hemodialysis patients

Abstract

High uric acid (UA) can act as a pro-oxidant in normal physiological conditions; however, emerging evidence is still debatable with regard to the association between high UA and poor outcomes among chronic hemodialysis (HD) patients. In the present study, 27,229 stable prevalent HD patients were enrolled and divided into four groups according to the quartiles of baseline UA concentration, and 5737 died during a median follow-up of 38 months. Multivariate Cox regression analysis showed that a UA level of <6.1 mg/dL was associated with a higher risk of all-cause mortality compared with a UA level of >8.1 mg/dL [HR, 1.20, 95% CI (1.10-1.31)] adjusting for baseline demographic and biochemical parameters. Moreover, a UA level of <6.1 mg/dL was associated with greater risks of cardiovascular mortality [HR, 1.26, 95% CI (1.13-1.41)] and stroke-related mortality [HR, 1.59, 95% CI (1.12-2.25)], respectively. In vitro experiments further showed an increase in oxidative stress and an inhibition nitric oxide synthesis by indoxyl sulfate (IS) in human aortic endothelial cells, which were significantly attenuated by UA in a dose-dependent manner. We concluded that higher UA in serum was associated with lower risk of all-cause and cardiovascular mortality among HD patients probably through its antioxidant property in ameliorating the IS-related vascular toxicity.