End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Abstract

A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation. Liver Transpl 21:1300-1311, 2015. V C 2015 AASLD.Received March 17, 2015; accepted June 8, 2015.Ischemic cholangiopathy, also known as nonanastomotic biliary strictures (NAS), is one of the most prevalent and troublesome complications after liver transplantation. During NAS formation, in particular, the large (extrahepatic) bile ducts become fibrotic and/or necrotic. Patients with NAS may suffer from recurrent jaundice and episodes of cholangitis, and retransplantation may be the only curative treatment. 1 The combination of ischemia and ischemia/ reperfusion (I/R) injury has been shown to be a major Additional supporting information may be found in the online version of this article.

Peritransplant Energy Changes and Their Correlation to Outcome After Human Liver Transplantation

“…Various parameters have been proposed as predictive biomarkers, ranging from ALT levels in perfusate and bile production 18 , to more complex indices of metabolism shown to correlate to transplant outcome 28,29 . In various experimental machine perfusion models, ATP levels have been shown to correlate to transplant 26,30,31 or reperfusion 32 outcome parameters. Since ATP analysis is arduous, surrogates have also been found and include bile production on reperfusion 33 , and ALT levels during ex vivo perfusion 17 .…”

Hypothermic machine perfusion in liver transplantation

“…The underlying mechanism involves predominantly a mitochondrial repair [22,23]. Accordingly, short periods of hypothermic oxygenated perfusion (HOPE) or hypothermic oxygen persufflation increase ATP significantly in several tissues within 1-2 h [24,25 & ], and decrease radical oxygen species (ROS) and danger-associated molecular patterns (DAMPs) subsequently (HighMobility-Group-Box Protein 1, DNA fragments, and histones) that release during implantation [21,22,26]. Subsequently, several Toll-like receptors 2,4,9 and also receptor for advanced glycation end products on membrane surfaces become less activated [26][27][28], and lead to less release of chemokines (TNFa, CXCL2, and CXCL10) with less immune response [21,23,27,29 ,30,31].…”

Potential approaches to improve the outcomes of donation after cardiac death liver grafts

“…Minor et al [39] suggested that starting reoxygenation in a low temperature could reduce oxidative stress injury during reperfusion, and improve mitochondrial function [40] . Following the previous study Westerkamp et al [41] investigated COR in a rat DCD model. In this study, the rat DCD livers were subjected to SCS at 4 ℃ for 6 h and then subjected to COR, HMP or SNP.…”