Hypothermic oxygenated perfusion in extended criteria donor liver transplantation—A randomized clinical trial

Abstract

Hypothermic Oxygenated Perfusion (HOPE) of the liver can reduce the incidence of early allograft dysfunction (EAD) and failure in extended criteria donors (ECD) grafts, although data from prospective studies are very limited. In this monocentric, open‐label study, from December 2018 to January 2021, 110 patients undergoing transplantation of an ECD liver graft were randomized to receive a liver after HOPE or after static cold storage (SCS) alone. The primary endpoint was the incidence of EAD. The secondary endpoints included graft and patient survival, the EASE risk score, and the rate of graft or other graft‐related complications. Patients in the HOPE group had a significantly lower rate of EAD (13% vs. 35%, p = .007) and were more frequently allocated to the intermediate or higher risk group according to the EASE score (2% vs. 11%, p = .05). The survival analysis confirmed that patients in the HOPE group were associated with higher graft survival one year after LT (p = .03, log‐rank test). In addition, patients in the SCS group had a higher re‐admission and overall complication rate at six months, in particular cardio‐vascular adverse events (p = .04 and p = .03, respectively). HOPE of ECD grafts compared to the traditional SCS preservation method is associated with lower dysfunction rates and better graft survival.

Trophism and Homeostasis of Liver Sinusoidal Endothelial Graft Cells during Preservation, with and without Hypothermic Oxygenated Perfusion

“…Notably, the VEGFR-2 increase was significantly higher after HOPE than after SCS: in the present study, the sample size and the low number of main events (two recipient deaths and one graft loss) prevents us from conducting a survival analysis (which was out of the study aims), but our results highlight once more the safety and the efficacy of HOPE at least in restoring LSEC functionality and cellular viability. The efficacy of HOPE in terms of short- and medium-term follow-up was reported in previous studies from our group [ 9 , 10 ].…”

“…In case of discordance between the two biopsies concerning single variables, PP-Biopsy characteristics were chosen, due to the better tissue quality and lack of freezing artifacts [ 28 ]. In the 34 grafts perfused with HOPE, all the perfusion variables concerning the overall procedure were recorded as well, including both the flushing and the perfusion phases, according to the study protocol ( Supplementary Table S1 ) [ 9 ].…”

“…The present study was approved in advance by the local Ethical Committee (code number 65/2018/SPER/AOUBo), and follows the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008); donors are kept anonymous. The study includes donors previously published in the context of a larger open-label, prospective, single-center, randomized clinical trial, where patients were stratified based on the contemporary presence of ECD liver criteria and randomized in a 1:1 ratio to receive a liver preserved with either HOPE after SCS during transportation or with SCS alone [ 9 , 25 ]. Livers undergoing SCS were stored in sterile organ bags with Belzer or Celsior solution, and cooled on ice as previously described and according to the Center policy [ 9 , 10 , 25 ].…”

“…The study includes donors previously published in the context of a larger open-label, prospective, single-center, randomized clinical trial, where patients were stratified based on the contemporary presence of ECD liver criteria and randomized in a 1:1 ratio to receive a liver preserved with either HOPE after SCS during transportation or with SCS alone [ 9 , 25 ]. Livers undergoing SCS were stored in sterile organ bags with Belzer or Celsior solution, and cooled on ice as previously described and according to the Center policy [ 9 , 10 , 25 ]. HOPE was performed through the portal vein at a pressure of 5 mmHg by flushing the organ at low flow values (30 mL/min) with new oxygenated perfusion fluid (Belzer MPS) during back-table preparation with the aim of removing waste products and residual microthrombi, and to provide oxygen.…”

“…The hypothermic oxygenated perfusion (HOPE) allows the redirection from anaerobic metabolism to aerobic metabolism under hypothermic conditions, and protects grafts from species-related oxidative damage. The superiority of HOPE preservation to simple cold storage was reported in clinical liver preservation studies [ 9 , 10 , 11 , 12 ]. LSECs play a key role in the regulation of the venous pressure gradient (at 4 mmHg in normal conditions), by producing vasodilating (nitric oxide synthase, NOS) and vasoconstricting (endothelin-1) factors in response to intrahepatic shear stress [ 13 ]: this is of utmost importance, since one of the protective functions of machine perfusion techniques is the maintenance of adequate shear stress, in order to avoid endothelial damages and the shift in balance toward thrombosis and vasoconstriction [ 14 ].…”