We have evaluated the involvement of hepatic preconditioning mediators (adenosine, adenosine A1 and A2 receptors) during normothermic recirculation (NR) in a model of liver transplantation from non-heart-beating donor (NHBD) pigs.Application of NR after 20 min of warm ischemia (WI) reversed the lethal injury associated with transplantation of NHBD livers (achieving 5-day survival and diminishing glutathione S-transferase (GST), aspartate aminotransferase (AST) and hyaluronic acid (HA)).Adenosine administration prior to WI simulated the effect of NR. Measuring adenosine, we found that during NR, hepatic adenosine levels increased and xanthine levels decreased. Then when we blocked A2 receptors the effect of NR was abolished, whereas the blocking of A1 receptors further protected the liver. Furthermore, A2 blocking improved hepatic perfusion during NR whereas A1 blocking reduced it.The study suggests that NR has a preconditioning effect by maintaining adequate adenosine and xanthine levels. During NR, adenosine protects the liver through A2 activation and damages it through A1 activation although simultaneous stimulation of both receptors exerts a clear beneficial effect. The possible relation of NR mechanism with other preconditioning mediators such as cAMP and nitric oxide synthesis are discussed.

Limited sampling strategies have been developed to predict full AUCs. The goal of this study was to develop a limited sampling strategy to estimate the AUC of tacrolimus in adult renal transplant patients and to evaluate its predictive performance in an independent patient population. A total of 27 tacrolimus pharmacokinetic profiles were studied. Blood samples were collected before the dose (0) and at 0.5, 1, 2, 4, 6, 8, and 12 hours postdose. The study was divided into 2 phases. In phase 1, the goal was to obtain a sampling strategy from 14 pharmacokinetic profiles. In phase 2, the bias and precision of the model were evaluated in another 13 pharmacokinetic profiles. The best correlation was achieved at 4 hours after dose (r(2) = 0.790). Stepwise multiple regression analysis determined that the abbreviated AUC at 0, 1, and 4 hours could accurately predict total AUC (r(2) = 0.965). The following formula was developed: AUC = 8.90 + 4.0C0h+ 1.77C1h + 5.47C4h. No significant differences were found between calculated and estimated AUC (165.6 +/- 41.1 and 166.7 +/- 43.2 ng.h/mL, respectively). The mean prediction error (MPE), the relative prediction error (PE), and the mean squared error (MSE) were 0.48 ng.h/mL, 0.16%, and 40.0 ng.h/mL, respectively. The limited sampling with use of the 3 levels at 0, 1, and 4 hours postdose provides accurate, reliable determination of tacrolimus AUC in renal transplant patients.

It is suggested that xanthine content in the donor is able to predict survival after transplantation. Xanthine is significantly involved in the hepatic lesion elicited by warm ischemia and subsequent ischemia-reperfusion associated to liver transplantation from a NHBD.

L-Arginine administration during liver procurement from non heart beating donors prevents liver and biliary tract damage.

The aim of this study was to assess liver viability after different periods of cardiac arrest and the predictive value of two markers of ischemia-reperfusion injury. Methods: A pig liver transplantation model of non-heart-beating donors was studied. Four donor groups were designed; three groups were submitted to different periods of cardiac arrest (20, 30 and 40 min), and the fourth group served as the control group (without cardiac arrest). In the non-heart-beating donor groups, normothermic recirculation was established 30 min prior to total body cooling. Aminotransferase, α-glutathione-S-transferase, and hyaluronic acid determinations as well as liver biopsies, were serially performed. Results: Although hepatocellular function could be preserved after 40 min of cardiac arrest, histological lesions at 5 days were considered irreversible due to the presence of a necrotic biliary tract. An overall significant relationship was found between the time period of cardiac arrest (20, 30 or 40 min) and the levels of hyaluronic acid (p = 0.004) or α-glutathione-S-transferase (p = 0.01) obtained during liver procurement and transplantation. Conclusions: The period of cardiac arrest is the determinant factor of liver viability after liver transplantation from non-heart-beating donors. As early markers of endothelial or hepatocellular damage, hyaluronic acid or α-glutathione-S-transferase levels may help to evaluate the ischemic injury of a potential donor.