Removal of asymmetric dimethylarginine during artificial liver support using fractionated plasma separation and adsorption

Objective. Asymmetric dimethylarginine (ADMA) is the most potent endogenous nitric oxide synthase inhibitor. Elevated ADMA levels have been linked to increased mortality in different patient populations. Key regulation of ADMA levels mainly takes place in the liver. Hence, ADMA is elevated in liver disease. There is no specific pharmacological treatment to lower the elevated ADMA levels. Hemodialysis is of limited efficiency in removing ADMA as it is highly protein bound. Prometheus (R) is an extracorporeal liver support system which allows the removal of protein-bound toxins. We assessed the efficiency of the Prometheus (R) system in reducing high ADMA levels in patients with liver failure. Material and methods. We studied nine patients with acute-on-chronic liver failure and concomitant renal failure already necessitating hemodialysis. Seven patients needed intensive care treatment. Two consecutive sessions of Prometheus (R) therapy of each 4 h were performed in all patients. ADMA and its structural isomer symmetrical dimethylarginine (SDMA) were determined using liquid chromatography mass spectrometry. Results. ADMA levels correlated to model for end stage liver disease (MELD) score (r(s) = 0.62; p < 0.0001). Before Prometheus (R) was started, levels of ADMA and SDMA were elevated (1.36 +/- 0.5 mu mol/l and 1.90 +/- 0.4 mu mol/l, respectively). During Prometheus (R) treatments, plasma levels of ADMA dropped by a mean 25% (p < 0.0001) and SDMA levels by 22% (p < 0.0001). However, there was a significant rebound of ADMA levels between the two therapy sessions (p < 0.01). Conclusions. This study shows for the first time that plasma levels of ADMA can be effectively lowered by an artificial liver support system (Prometheus (R)). Effective elimination of ADMA might explain some of the beneficial clinical effects of these systems in patients with liver failure.