Relationship of asymmetric dimethylarginine to dialysis treatment and atherosclerotic disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelia l nitric oxide (NO) synthase. its concentration is elevated in patients wit h end-stage renal disease (ESRD), in part because it is excreted via the ki dneys In addition, ADMA is degraded by the enzyme dimethylarginine dimethyl aminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylam ine. Activity of DDAH is decreased by oxidized low density lipoprotein (LDL ) or tumor necrosis factor-alpha (TNF-alpha) in vitro yielding increased le vels of ADMA. Furthermore, plasma levels of ADMA are elevated in hyperhomoc yst(e)inemia and in hypertensive patients on a high salt diet. Data ft om s everal experimental studies suggest that ADMA concentrations in a pathophys iologically high range (3 to 10 mu mol/L) significantly inhibit vascular NO formation by NO synthase in the presence of L-arginine in isolated human b lood vessels, cultured macrophages, and in cultured endothelial cells. It h as been well demonstrated that ADMA accumulates in chronic renal failure. A lthough there is controversy concerning the absolute concentration of ADMA, all authors found a two- to sixfold increase in ADMA levels in patients in chronic renal failure as compared to controls. Different dialysis treatmen t strategies differentially affect ADMA levels. The presence of atheroscler osis is associated with higher ADMA levels in patients with normal renal fu nction as well as in dialysis patients, but this phenomenon may be unrelate d to renal handling of ADMA. Reduced NO elaboration secondary to accumulati on of ADMA may be an important pathogenic factor for atherosclerosis in chr onic renal Failure and ADMA may be a new uremic toxin. Clinical studies on the effect of ADMA are needed to Further elucidate its pathophysiological r ole in atherosclerosis and uremia.