Influence of hepatic ischemia-reperfusion injury on tacrolimus acute renal toxicity in pigs

Abstract

H T E DEVELOPMENT of new immunosuppressants has been a determining factor in the recent surge in organ transplants. Tacrolimus, which was introduced in clinical practice by Starzl in 1989, has proved to be useful for prevention and treatment of rejection.1-5 Among its side effects, nephrotoxicity is of particular importance. The precipitating causes of acute nephrotoxicity (ANT), which may affect 35% to 45% of liver transplant patients are uncertain, 5-8 but possibly include early graft malfunction, a phenomenon related to ischemia and reperfusion injuries, which result at least in part from shortcomings in the organ preservation. [5][6][7][8][9] To shed light on the relationship between ischemic liver injury and ANT caused by tacrolimus, we designed a comparative experimental study of the kidney damage generated in two experimental models of hepatic ischemia-reperfusion injury: non-heart-beating donor and an ischemia-reperfusion model with the organ in situ. MATERIAL AND METHODS Experimental DesignThirteen large white Landrace pigs weighing around 30 kg were divided among three experimental groups.(1) Liver Transplant From Donor With Cardiac Arrest (LT group, n = 5) Once the hepatic pedicle (HEP) structures had been dissected, we administered 90 mg of calcium heparin IV, and 10 minutes later 40 mg of potassium chloride which caused the animal's death. After 60 minutes, we clamped the thoracic aorta and proceeded to perform perfusion with 1 I of University of Wisconsin solution (4°C) via the infrarenal aorta in retrograde fashion. During backtable surgery, we perfused 1 I of University of Wisconsin solution through the porta. The organ was stored at 2 to 4°C for 60 minutes. The implants were performed according to the procedure described by Starzl using shunting of the portal flow by a passive portojugular shunt. The biliary drainage reconstructed using an end-to-end choledocho-choledochostomy.(2) In Situ Ischemia Group Nontreated With Tacrolimus (IS Group, n = 4) We dissected the HEP structures and the left external jugular vein, and freed the splenic vein close to the hilar area, after insertion of heparinized Gott no. 22 cannulae in the splenic and left external jugular veins to construct a passive splenojugular shunt. We then proceeded immediately to clamp the elements of the hepatic pedicle and infrahepatic vena cava (IHVC) at a point proximal to the renal veins. The flow in the IHVC was maintained without interruption for 60 minutes (mean duration of the anhepatic phase in the liver transplantation model), whereas the clamp was kept on the HEP for 160 minutes.

Comparison between two warm ischemic models in experimental liver transplantation in pigs

“…Both experimental models have been used by our group in previous studies. [4][5][6] The comparisons included a group control in which the graft liver experienced no ischemia. …”