Implications For Liver Transplantation Research Articles

Exogenous melatonin enhances bile flow and ATP levels after cold storage and reperfusion in rat liver: implications for liver transplantation

Although the use of melatonin in the transplantation field has been suggested, it has not been previously tested in a liver cold-storage model. We used a rat liver model to study (a) the dose-dependent effect of melatonin on bile production, and (b) the potential of melatonin to improve liver function after cold-storage. Male Wistar rats were perfused with Krebs-Henseleit bicarbonate buffer (KHB) at 37 degrees C without or with 25, 50, 100 and 200 microM melatonin. Each dose of melatonin stimulated bile production. For cold-storage studies, livers were flushed with either University of Wisconsin (UW) or Celsior solution and stored for 20 hr at 4 degrees C. Reperfusion (120 min) was performed with KHB at 37 degrees C. In subsequent studies, 100 microM melatonin were added to the perfusate during the reperfusion period. ATP and melatonin levels in the tissue were measured. Bile analysis was performed by measuring melatonin, bilirubin and gamma-glutamyl transpeptidase (gamma-GT) levels in the fluid. A dose-dependent increase in bile secretion, associated with an enhanced melatonin and bilirubin levels in the bile were observed. Also, tissue levels of melatonin increased in a dose-dependent manner. When melatonin was added during the reperfusion period, bile production and bile bilirubin levels increased both with UW and Celsior solutions. The analysis of gamma-GT in the bile showed an increase in the Celsior-preserved liver and the addition of melatonin to the perfusate reduced this effect. Tissue ATP levels were higher when melatonin was added to the perfusion medium. Higher levels of melatonin in bile than in tissue were found. In conclusion, we demonstrate that melatonin improves significantly the restoration of liver function after cold-storage and reperfusion.

Persistent anastomosis between proper hepatic and replaced right hepatic artery: implications in liver transplantation

Persistent anastomosis between proper hepatic and replaced right hepatic artery: implications in liver transplantation

FTY720 Pretreatment Reduces Warm Hepatic Ischemia Reperfusion Injury Through Inhibition of T-Lymphocyte Infiltration

Ischemia and reperfusion (IR) injury remains a significant problem in clinical liver transplantation. We investigated the effects of lymphocyte depletion with FTY720 in models of warm hepatic IR. Using 60-min partial warm hepatic IR, three groups of rats were studied: Sham--laparotomy alone; Control--water p.o. x 3 d before ischemia; Treatment--FTY720 p.o. x 3 d before ischemia. Animals were sacrificed for analysis at 6 h and 24 h post reperfusion. The effect of FTY720 pretreatment on survival was also studied using 150 min total hepatic IR with portojugular shunt. FTY720 treatment significantly reduced serum glutamic pyruvic transaminase and peripheral blood lymphocytes compared to controls at 6h and 24h (p < 0.0005). Histological grade was significantly improved in treated livers vs. controls (p < 0.05). CD3 immunocytochemical analysis revealed a significant reduction in T-cell infiltration in FTY720-treated livers (p < 0.0002). No difference in tissue myeloperoxidase levels was observed. Seven-day survival was significantly improved in treated rats vs. controls following total hepatic ischemia (p < 0.05). In conclusion, FTY720 ameliorates the biochemical and histological manifestations of hepatic IR by preventing T-lymphocyte infiltration and prolongs survival following a more severe ischemic insult. Myeloperoxidase data suggest this mechanism is independent of neutrophil activation. These results indicate that T lymphocytes are pivotal mediators in hepatic IR and may have important implications in liver transplantation.

Pathophysiology of renal disease associated with liver disorders: implications for liver transplantation. Part I.

Renal and hepatic function are often intertwined through both the existence of associated primary organ diseases and hemodynamic interrelationships. This connection occasionally results in the chronic failure of both organs, necessitating combined liver-kidney transplantation (LKT). Since 1988, more than 850 patients in the United States have received such transplants, with patient survival somewhat less than that for patients receiving either organ alone. Patients with renal failure caused by acute injury or hepatorenal syndrome have classically not been included as candidates for combined transplantation because of the reversibility of renal dysfunction after liver transplantation. However, the rate and duration of renal failure before liver transplantation is increasing in association with prolonged waiting list times. Thus, the issue of acquired permanent renal damage in the setting of hepatic failure continues to confront the transplant community. The following article and its sequel (Part II, to be published in vol 8, no 3 of this journal) attempt to review the problem of primary and secondary renal disease in patients with end-stage liver disease, elements involved in renal disease progression and recovery, the impact of renal disease on liver transplant outcome, and results of combined LKT; outline the steps in the pretransplantation renal evaluation; and provide the beginnings of an algorithm for making the decision for combined LKT.

Impaired liver function tests in patients treated with antithymocyte globulin: implication for liver transplantation.

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day -1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 +/- 37.7 U/l pre-treatment to 1394.4 +/- 488.7 U/l 3 days post-treatment (n = 16; p < 0.029), and then declined to 561.4 +/- 61.3 U/l 10 days post-treatment (n = 16; p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 +/- 11.3 U to 184.6 +/- 74.6 U (n = 16; p < 0.036), and then declined to 121.9 +/- 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 + 5.7 U to 152.0 +/- 67.0 U (n = 16; p < 0.44) and then declined to 46.0 +/- 14 (n = 16; p < 0.049). The mean tau-glutamyltransferase (GTP) levels increased from 93.0 +/- 34 to 188.0 +/- 36 (n = 16; p < 0.02), and were 168.0 +/- 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 +/- 1.9 microM l(-1) to 22.7 +/- 2.8 (n = 16); NS), at day +3 and to 31.9 +/- 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.