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 BO ¨ GER, † 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. Abstract. High sympathetic activity and alterations in nitric oxide synthesis attributable to accumulation of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have re- cently 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 rela- tionship 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 inves- tigated. 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 ob- served 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 inde- pendent 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 re- lated among patients with ESRD. These two factors are likely to be involved in the same causal pathway leading to death and cardiovas- cular events among those patients. Cardiovascular risk factors among patients with ESRD do not coincide with those typically observed in the general population (1), and it has been emphasized that traditional risk factors only partly explain such patients’ high risk of death and cardiovascular complications (1,2). Although the relative contributions of tradi- tional and emerging risk factors are still debated, there is a consensus that ESRD is a situation of unique epidemiologic complexity (3), because traditional risk factors, such as arterial pressure (4), cholesterol levels (5), and advanced glycation end product levels (6), demonstrate paradoxical inverse relationships with mortality and adverse cardiovascular outcome rates. Among emerging risk factors in ESRD, the levels of norepi- nephrine (NE) and the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) seem to be of major interest. Levels of both NE (7) and ADMA (8) predict adverse cardiovascular outcomes among hemodialysis patients and are strongly associated with left ventricular concentric hyper- trophy and left ventricular systolic dysfunction (9,10). These parallel links may underlie common mechanisms leading to heart disease and cardiovascular complications. Therefore, an analysis of the relationship between plasma NE and ADMA levels and their interaction in predicting death and cardiovascular outcomes may provide useful clues for an understanding of the mechanisms mediating the adverse effects of these risk factors in ESRD. In this study, we took advantage of the Cardiovascular Risk Extended Evaluation in Dialysis Patients cohort database, which included measurements of both NE and ADMA levels. This analysis had two objectives, i.e., to study the relationship between circulating NE and ADMA levels and determine whether the relationship is independent of other risk factors and to study the interaction between NE and ADMA levels with respect to the high mortality and cardiovascular morbidity rates for patients with ESRD. We undertook a detailed survival analysis of the long-term follow-up data for the Cardiovascular Risk Extended Evaluation in Dialysis Patients cohort, which now extend to 5.5 yr. Materials and Methods Protocol The protocol was in conformity with the ethical guidelines of our institutions, and informed consent was obtained from each participant. All studies were performed on a midweek nondialysis day, between 8 a.m. and 1 p.m. Received September 2, 2003. Accepted October 18, 2003. Correspondence to Dr. Carmine Zoccali, CNR, Istituto di Biomedicina, Epi- demiologia 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@tin.it 1046-6673/1502-0435 Journal of the American Society of Nephrology Copyright © 2004 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000106717.58091.F6 J Am Soc Nephrol 15: 435–441, 2004