Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age?

The idea that asymmetric dimethylarginine (ADMA) accumulation may be a cardiovascular risk factor in patients with end-stage renal disease was advanced by Vallance in 1992. During the last decade, the relationship between ADMA and adverse cardiovascular events, including death, in dialysis patients has been investigated thoroughly. Several studies have shown that, independently of other risk factors, ADMA is strongly associated with intima-media thickness of the carotid artery and left ventricular mass, particularly concentric left ventricular hypertrophy. Furthermore, cohort studies in both the general population and the dialysis population showed a strong and independent link between ADMA, all-cause mortality, and cardiovascular events. Circumstantial evidence indicates that norepinephrine and ADMA may be in the same causal pathway leading to cardiovascular complications in patients with end-stage renal disease. Several lines of evidence show that high ADMA levels may exert toxic effects in various cell types. High ADMA levels have been associated with alterations in the regulation of cerebral blood flow and neural function, with insulin resistance, thyroid dysfunction, and alterations in bone homeostasis, fertility, and erectile function. The clinical significance of decreasing plasma ADMA concentrations, if any, is unknown. Well-designed and carefully conducted studies are needed to further clarify the role of ADMA in the pathophysiological states of renal disease and explore possible treatment options to improve the prognosis of patients with elevated ADMA levels. ADMA may enable us to predict risk and follow up the course of renal diseases.