Abstract
Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP—which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion—will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.
Highlights
Liver ischemia-reperfusion injury (IRI) poses a universal risk of adverse clinical outcomes in extended liver resections and orthotopic liver transplantation (OLT)
Normothermic perfusion is most effective when applied during the entire period of organ preservation [53], while end-ischemic applications in marginal DBD and donation after circulatory death (DCD) livers failed to protect from the development of ischemic-type biliary lesions (ITBLs) and subsequent graft loss [54]
Van Leeuwen et al recently reported the clinical experience of the Groningen group with the sequential application of dual hypothermic oxygenated perfusion (HOPE), followed by controlled oxygenated rewarming (COR), and a period of normothermic machine perfusion (NMP) [73]
Summary
Liver ischemia-reperfusion injury (IRI) poses a universal risk of adverse clinical outcomes in extended liver resections and orthotopic liver transplantation (OLT). Based on the critical organ shortage, an increasing number of extended criteria donor (ECD) allografts are utilized today, which were previously considered unsuitable for transplantation [5,6]. Despite the positive impact on waiting list times, the utilization of ECD livers has been linked to inferior posttransplant outcomes due to their increased susceptibility to IRI and a subsequently reduced ability for functional recovery [8,9,10]. In ECD allografts, SCS imposes an increased susceptibility to IRI and allograft related complications; as such, dynamic preservation techniques including machine perfusion (MP) have evolved as important tools to preserve and recondition such livers [6]. Current clinical applications and future perspectives of hypothermic liver perfusion are detailed
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