Methylarginines and mortality in patients with end stage renal disease: A prospective cohort study

Objectives and methods: Methylarginines like asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are formed by post-translation methylation of arginine residues in proteins. ADMA inhibits nitric-oxide synthase and predicts clinical outcomes in various diseases including end stage renal disease (ESRD). SDMA competes with l-arginine for cell entry and is associated with organ failure in patients with severe illness. We investigated the inter-relationships between methylargines, l-arginine and other risk factors and tested the prediction power of methylargines for mortality in a prospective cohort study including 288 ESRD patients. Results: ADMA and SDMA exceeded the upper limit of the corresponding normal range in almost all cases (98% and 100%, respectively) and were inter-related (r = 0.30, P < 0.001) but only ADMA was associated with l-arginine. SDMA, was inversely related with haemoglobin (r = -0.23, P < 0.001) and this association was independent of other risk factors. During the follow-up, 140 patients died. In unadjusted analysis, ADMA was strongly related to death [hazard ratio (HR) (1 mu mol/L): 2.07, 95% CI: 1.31-3.26] while plasma SDMA and l-arginine were largely unrelated to survival. In a multiple Cox regression model adjusting for potential confounders, ADMA maintained an independent relationship with death [HR: 1.92, 95% CI: 1.16-3.16]. Conclusions: Methylarginines ADMA and SDMA are inter-related. ADMA is associated with l-arginine while SDMA correlates inversely with haemoglobin. ADMA but not SDMA is a death predictor in ESRD. Given the exceedingly high risk for death of this population, establishing whether or not ADMA is causally implicated in the high death risk of ESRD is a research priority. (C) 2009 Elsevier Ireland Ltd. All rights reserved.