Treprostinil Minimizes Ischemia-reperfusion Injury of Liver After Circulatory Death Donation—Evidence Using Normothermic Machine Perfusion

BACKGROUND: Liver transplantation is the treatment of choice for end-stage liver disease. Livers obtained from donation after circulatory death (DCD) are subjected to significant ischemia-reperfusion injury (IRI) and require novel organ preservation measures. The overall objective of our study was to evaluate the protective effect of treprostinil against IRI in DCD livers by using normothermic machine perfusion (NMP). METHODS: Circulatory arrest was induced in male Sprague-Dawley rats, and the organs were subjected to 30 min of warm ischemic time in situ, mimicking the process of DCD liver transplantation. Livers were procured and cold preserved until mounted to ex vivo NMP. DCD livers underwent NMP with or without 20 ng/mL treprostinil in perfusate for 4 h. Perfusate and bile samples were collected to assess hepatic and biliary viability parameters. RESULTS: Treprostinil effectively minimized IRI in rat DCD livers. Levels of alanine aminotransferase and aspartate aminotransferase were significantly higher in DCD-control, whereas treprostinil supplementation during NMP reduced the levels by 50% (P < 0.001) and 30% (P = 0.036) of DCD-control, respectively. The portal venous pressure was higher in DCD-control (10.4 ± 4.3 mm Hg), and significantly lowered in DCD-treprostinil group (4.2 ± 1.0 mm Hg; P < 0.001). Livers perfused with treprostinil produced 1.5-fold (P < 0.01) higher bile volume, compared with DCD-control. The bile pH and lactate dehydrogenase showed improvement in the DCD-treprostinil group compared with the DCD-control and were comparable to naive livers. CONCLUSIONS: Treprostinil supplementation during NMP of DCD livers reduced IRI and improved hepatobiliary function.