The ex-situ machine perfusion experience in a midvolume liver transplant centre: are we pushing the limits?

Liver transplantation (LT) is the accepted curative treatment for end-stage liver disease, with one and five-year survival of 90% and 70%, respectively1 . With increasing rates of liver disease2 , the supply of transplantable organs is no longer able to meet demand. In UK, despite substantial waiting list mortality (namely 21%), only 63% of deceased donor livers are transplanted. Between January 2018 and December 2019 in Italy, out of 2750 effective donors (i.e. donors from which at least one graft was procured and therefore considered suitable for organ donation) only 2498 (91%) livers turned out to be eligible for transplantation (www.trapianti.salute.gov.it). This resulted in a discard rate during organ procurement of approximately 9% (i.e. N=252 livers were considered at high risk of "non-function" and were therefore not used). In addition, from 2010 to 2019 there was an increasing trend in donor age thus achieving a current median value of 61 years old. These data are in accordance with those reported by the US Organ Procurement and Transplantation Network (OPTN). In fact, in 2018 in the US the organ discard rate (percentage of organs recovered for transplant and not transplanted) was about 8.4%. In particular, the discard rate for donation after brain death organs continued a steady decline, reaching an all-time low of 6.4%. HCV antibody positive donor livers were no more likely to be discarded, reflecting the widespread use of these organs in the DAAs era thus representing a turnabout for what was previously considered a strong risk factor for organ discard (www.srtr.transplant.hrsa.gov). In order to accommodate the growing list of patients awaiting LT, the transplant community has increased efforts to expand the donor pool by utilization of a wide variety of donor organs. The additional donors called Extended Criteria Donors (ECD), tends to be high-risk because of circulatory death (namely DCD donors) as opposed to brain death donors (DBD), or because of elderly with multiple co-morbidities. 6 These marginal grafts generally suffer from a higher risk of early allograft dysfunction (EAD) or primary non-function (PNF), decrease long-term survival with the possibility to lead to later complications, particularly ischaemic cholangiopathy. Higher-risk donor organs represent nowadays an increasing proportion of the current LT practice. The very severe ischaemia-reperfusion related morbidity - that characterizes transplantation of such organs - currently represent the major burden. Relatedly, these organs are often allocated to well compensated recipients thus limiting the access to transplantation for those who suffer from serious clinical conditions who would need "standard" organs. In recent years, the transplant community has explored many strategies to prevent damages after transplantation related to ischemic injury of marginal livers. Novel ex vivo techniques, such as hypothermic, normothermic, and sub-normothermic machine perfusion, have been shown to have a potentially useful role in reducing ischemia-reperfusion liver damage and in “resuscitating” marginal organs. 3,4,5 In particular, several recent studies have reported the feasibility of graft preservation with hypothermic oxygenated perfusion (HOPE) which may permit mitochondrial functional recovery, increasing cellular adenosine trisphosphate (ATP) levels and mitigate the tissue injury that occurs during the rewarming phase6 and the ability of normothermic machine perfusion (NMP) to provide a functional assessment at physiological conditions. 7 This novel strategies have shown to be a promising new modality in the organ preservation field to reduce injury and recover ECD liver grafts