Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2α in end-stage liver disease

Abstract

is produced by free radical catalyzed oxidation of arachidonic acid. ADMA and 15(S)-8-iso-PGFza are excreted by the kidneys. Quantification of 1 5(S)-8-iso-PGF2, in the circulation and in urine is a proven method to assess oxidative stress in humans. ADMA has been shown to be present in orthotopic human liver transplantation (OLT) and F2-isoprostanes to be overproduced in the hepatorenal syndrome.2 In the present study we quantified in patients (3 women, 9 men, age 47 ? 13 years) suffering from end-stage liver disease immediately prior to OLT circulating and excretory levels of ADMA by high performance liquid chromatography3 and GC-tandem MS,* respectively, and of 15($-8-i~o-PGF~, by GC-randem MS.5 Five of the patients were in Child-Pugh stage B. Healthy volunteers served as controls. Approval for the study protocol was obtained from the local Institutional Review Board for Studies in Humans. Informed consent was obtained from each patient. We measured elevated ADMA concentrations in the patients' plasma(5.3 t 3.4vs.0.54 2 0.1 pmol/L, P< .O5;Fig. l).Theplasma levels of L-arginine (41.5 ? 7.8 pmol/L) and the biologically inactive symmetric dimethylarginine (SDMA; 0.53 ? 0.20 pmol/L) were normal. Urinary excretion of ADMA in the patients was statistically significantly (P < .05) enhanced compared with that of the control group (5.6 2 1.5 vs. 3.4 t 1.1 pmol/mmol creatinine; Fig. 1). Circulating levels of free plus esterified 1 5(S)-8-iso-PGFzu were 3.2-fold elevated in the patients in comparison with those of healthy volunteers (244 -t 263 vs. 77 2 23 pg/mL; P = .00639). In the patients, 1.5-fold increased levels of urinary 15(S)-8-iso-PGFza were found in comparison with those of the control group (135 ? 83 vs. 88 t 40 nmollmol creatinine; P = .0398). Our results suggest that hepatic dysfunction is a prominent determinant of ADMA concentration in patients suffering from liver diseases. This is supported by the finding that, in the rat, the liver plays an important role in the metabolism of ADMA by taking up large amounts from the systemic circulation.6 Dimethylarginine dimethylaminohydrolase (DDAH) is highly expressed in the liver and removes ADMA by metabolization to L-citrulline. The highly elevated ADMA plasma levels measured in the patients suffering from hepatic disease presumably reflect deteriorated hepatic DDAH activity, to which increased oxidative stress and excessive local production of tumor necrosis factor a could contribute. Elevated ADMA plasma concentration has been recognized as an important risk factor for cardiovascular disease. Accumulation of ADMA in chronic renal failure' and end-stage hepatic failure could be a causative factor in the development of multiple organ failure. High plasma ADMA concentration in critically ill patients has been shown to be an independent risk factor regarding intensive care unit mortality.* Imbalanced ADMA pathway and elevated oxidative stress may contribute to liver pathology and multiple organ failure. The authors thank Bibiana Schubert, MariaTheresia Suchy, and Frank-Mathias Gutzki for excellent technical assistance. Acknowledgment: