Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications

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.

Polyethylene Glycol 35 as a Perfusate Additive for Mitochondrial and Glycocalyx Protection in HOPE Liver Preservation

“…As a consequence, in the last decade, the hypothermic oxygenated perfusion (HOPE) has been implemented as a complementary tool to improve graft preservation [36][37][38][39]. This strategy combines the benefits of cold preservation conditions with the presence of a transient oxygen supply to the organ in a perfusion system, with the purpose to help the mitochondrial system to sustain a basic level of oxidative phosphorylation, which in turn will provide the organ with better conditions to face the unavoidable reperfusion [36][37][38][39]. In contrast to static preservation, the fluid dynamics that intrinsically occurs in any fluid-applying forces in a vascular section, as it happens in HOPE (or any kind of reperfusion), is responsible for generating the phenomenon known as shear stress [40].…”

“…As the same formulation is used throughout this article, we refer to them generically as Belzer MPS. This solution was designed for kidney MP and then extended to liver HOPE strategies [36][37][38][39]. However, the use of Belzer MPS-like solutions in liver MP has some limitations.…”

“…Nowadays, with the advance in innovation, their design is more portable and efficient. HOPE is the modality that embraces a dynamic perfusion at the range of 4-11 • C with active oxygenation of the perfusate [36][37][38][39].…”

Hesperidin ameliorates liver ischemia/reperfusion injury via activation of the Akt pathway

“…Ischemia-reperfusion (IR) injury remains a key medical challenge because it relates to organ transplantation and alterations in vascular perfusion (1)(2)(3). Liver I/R injury frequently occurs as a result of liver transplantation, partial hepatectomy, hemorrhagic shock, trauma, severe infection and metabolic disorder (1,4).…”

The Role of Metabolomics in Current Concepts of Organ Preservation

“…The allograft, metabolically impaired during warm and cold ischemia (WI and CI), is further damaged by a paradox reperfusion injury after revascularization and re-oxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function (DGF) and even immune activation have been associated with IRI [ 5 , 8 ].…”