Liver Graft Susceptibility during Static Cold Storage and Dynamic Machine Perfusion: DCD versus Fatty Livers

Abstract

We compared static preservation (cold storage, CS, 4 °C) with dynamic preservation (machine perfusion, MP, 20 °C) followed by reperfusion using marginal livers: a model of donation after cardiac death (DCD) livers and two models of fatty livers, the methionine-choline deficient (MCD) diet model, and obese Zucker (fa/fa) rats. CS injury in DCD livers was reversed by an oxygenated washout (OW): hepatic damage, bile flow, and the ATP/ADP ratio in the OW + CS group was comparable with the ratio obtained with MP. Using fatty livers, CS preservation induced a marked release in hepatic and biliary enzymes in obese Zucker rats when compared with the MCD group. The same trend occurred for bile flow. No difference was found when comparing MP in MCD and obese Zucker rats. Fatty acid analysis demonstrated that the total saturated (SFA)/polyunsaturated fatty acid (PUFA) ratio was, respectively, 1.5 and 0.71 in obese Zucker and MCD rats. While preservation damage in DCD livers is associated with the ATP/ADP recovered with OW, injury in fatty livers is linked to fatty acid constituents: livers from obese. Zucker rats, with greater content in saturated FA, might be more prone to CS injury. On the contrary, MCD livers with elevated PUFA content might be less susceptible to hypothermia.

The Effect of Preservation Temperature on Liver, Kidney, and Pancreas Tissue ATP in Animal and Preclinical Human Models

“…It was suggested that subnormothermic temperatures may bridge the gap between metabolic retardation during cold hypothermia and hypoxia at 'hotter' normal physiological temperatures, enabling the maintenance of an approximate 25% of physiological metabolic levels in the liver graft [37]. In a number of animal and preclinical studies [18,[27][28][29][30]38,39] assessing the effects on resynthesis of tissue ATP by SNMP on livers of different extended criteria, DBD or DCD and steatosis were identified (Tables 2-4). Additionally, there are studies of a relatively new perfusion technique, controlled oxygenated rewarming (COR) developed by Minor et al [18] in Essen, Germany.…”

“…Ferrigno [22] Rat, DCD Berendsen [23] Rat, DCD Bruinsma [24] Rat Minor (COR20) [18] Porcine Bruinsma [25] Human, DBD, DCD Ferrigno (20 > 10 > 30 > 37 • C) [24] Rat Bruinsma (DBD/DCD/ steatotic livers) [25] Human von Horn (COR 20 • C > COR 35 • C) [28] Rat, DCD Okamura [39] Rat, steatotic livers Ferrigno [27] Rat, DCD, steatotic livers In the kidneys (Table 12), with fewer published literature on SNMP and NMP to date, HOPE appeared to be most effective in increasing graft ATP resynthesis. Buchs [44] Porcine, DCD Lazeyras [45] Porcine, DCD Ravaioli [47] Human, DBD More evidence is needed on the effects of preservation temperature on donor pancreatic ATP levels (Table 13).…”

Machine Perfusion of Extended Criteria Donor Organs: Immunological Aspects

“…SNMP and NMP significantly ameliorated hepatic damage in DCD livers compared to SCS in animal models (31,39,60,65,68,72). In a porcine model of liver MP, prolonged periods of NMP facilitate a reduction in hepatic steatosis (63), while the supplementation of perfusate with defatting agents significantly reduced the intracellular fat content of perfused rat livers within a few hours (59).…”

Bone marrow mesenchymal stem cells combine with normothermic machine perfusion to improve rat donor liver quality—the important role of hepatic microcirculation in donation after circulatory death

“…Therefore, DCD livers have higher risk of early postoperative allograft dysfunction, primary nonfunction, ischemic cholangiopathy, and vascular embolism than DBD livers, greatly affecting donor liver survival and patient prognosis (Angelico et al 2018 ; DeOliveira et al 2011 ); these problems have not been resolved. Static cold storage (SCS) is subject to some limitations for preserving DCD livers, which may not have sufficient physiological reserves for tolerating SCS-related damage; liver energy metabolism and mitochondrial function are easily impaired, and are particularly sensitive to SCS-related IRI; accordingly, SCS exposure should be restricted (Detelich and Markmann 2018a ; Ferrigno et al 2017 ). Normothermic machine perfusion (NMP) can simulate the normal metabolic state in vivo, can reveal the quality of the liver by assessing bile production and lactate clearance, and store and repair donor livers.…”