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Analysis of the Relationship between Norepinephrine and Asymmetric Dimethyl Arginine Levels among Patients with End-Stage Renal Disease

Francesca Mallamaci^*, Giovanni Tripepi^*, Renke Maas, Lorenzo Malatino, Rainer Böger and Carmine Zoccali^*

*CNR-IBIM, Institute of Biomedicine, Clinical Epidemiology, and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy; Institute of Clinical Pharmacology, Hamburg Medical School, Hamburg, Germany; and Department of Internal Medicine, Catania University, Catania, Italy.

Correspondence to Dr. Carmine Zoccali, CNR, Istituto di Biomedicina, Epidemiologia Clinica, e Fisiopatologia, delle Malattie Renali e dell’Ipertensione Arteriosa, c/o Divisione di Nefrologia, Ospedali Riuniti, Via Vallone Petrara, 89124 Reggio Calabria, Italy. Phone: 0039-0965-397010; Fax: 0039-0965-397000; E-mail: carmine.zoccali{at}tin.it

ABSTRACT. High sympathetic activity and alterations in nitric oxide synthesis attributable to accumulation of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have recently been identified as potential causal mechanisms for the high cardiovascular mortality rates among patients with ESRD. The link between these risk factors has not been studied. Therefore, the relationship between plasma norepinephrine (NE) and ADMA levels was examined in a large cohort of hemodialysis patients (n = 224), and whether these factors interacted in predicting all-cause mortality and new cardiovascular event rates among those patients was investigated. Plasma ADMA levels were strongly associated with plasma NE levels (P < 0.001) and to a lesser extent with heart rate (P < 0.01). In multivariate analyses, the ADMA-NE correlation was observed to be independent of age, gender, serum albumin levels, arterial pressure and antihypertensive treatment, duration of dialysis treatment, diabetes mellitus, and other risk factors. NE was an independent significant predictor of both death and cardiovascular events in Cox models not including ADMA. However, when ADMA was introduced into those models, NE became a largely nonsignificant predictor of those outcomes, whereas plasma ADMA levels emerged as a highly significant predictor of both death (P < 0.001) and cardiovascular events (P < 0.001). These findings suggest that ADMA is an intervening factor in the causal pathway leading to those outcomes. Plasma NE and ADMA concentrations are strongly related among patients with ESRD. These two factors are likely to be involved in the same causal pathway leading to death and cardiovascular events among those patients.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673