Mitochondrial injury during normothermic regional perfusion (NRP) and hypothermic oxygenated perfusion (HOPE) in a rodent model of DCD liver transplantation

Background Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking.Methods A rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 degrees C (NRP) or with oxygenated Belzer-MPS at 10 degrees C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury.Findings Healthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mito-chondrial injury and inflammation as measured by increased perfusate Lactate, FMN-and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%).Interpretation High-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results.Funding Funding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.Copyright (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).