Normothermic Machine Perfusion (NMP) Inhibits Proinflammatory Responses in the Liver and Promotes Regeneration

Abstract

Liver transplantation (LT) is a successful treatment for patients with liver failure. However, organ shortage results in over 11% of patients losing their chance of a transplant attributed to liver decompensation (LD) and death. Ischemia/reperfusion injury (IRI) following conventional cold storage (CS) is a major cause of injury leading to graft loss after LT. Normothermic machine perfusion (NMP), a method of organ preservation, provides oxygen and nutrition during preservation and allows aerobic metabolism. NMP has recently been shown to enable improved organ utilization and posttransplant outcomes following a phase I and a phase III randomized trial. The aim of the present study is to assess the impact of NMP on reducing IRI and to define the underlying mechanisms. We transplanted and compared 12 NMP with 27 CS‐preserved livers by performing gene microarray, immunoprofiling of hepatic lymphocytes, and immunochemistry staining of liver tissues for assessing necrosis, platelet deposition, and neutrophil infiltration, and the status of steatosis after NMP or CS prereperfusion and postreperfusion. Recipients receiving NMP grafts showed significantly lower peak aspartate aminotransferase (AST) levels than those receiving CS grafts. NMP altered gene‐expression profiles of liver tissue from proinflammation to prohealing and regeneration. NMP also reduced the number of interferon gamma (IFN‐γ) and interleukin (IL)‐17–producing T cells and enlarged the CD4posCD25highCD127negFOXP3pos regulatory T cell (Treg) pool. NMP liver tissues showed less necrosis and apoptosis in the parenchyma and fewer neutrophil infiltration compared to CS liver tissues. Conclusion: Reduced IRI in NMP recipients was the consequence of the combination of inhibiting inflammation and promoting graft regeneration.

A Back‐to‐Base Experience of Human Normothermic Ex Situ Liver Perfusion: Does the Chill Kill?

“…This landmark study clearly demonstrated less graft injury with NMP, despite much longer preservation times, with overall higher graft‐use rates . These positive findings may be attributed to reduced ischemia/reperfusion injury during NMP as a consequence of the combination of inflammation inhibition and up‐regulation of a regenerative profile of gene expression by the perfused graft . In most prior clinical NMP studies, machine perfusion was initiated as early as possible at the donor center using a preservation machine perfusion strategy in order to derive maximal benefit from ex situ NMP conditions .…”

“…(14) These positive findings may be attributed to reduced ischemia/reperfusion injury during NMP as a consequence of the combination of inflammation inhibition and up-regulation of a regenerative profile of gene expression by the perfused graft. (15) In most prior clinical NMP studies, machine perfusion was initiated as early as possible at the donor center using a preservation machine perfusion strategy in order to derive maximal benefit from ex situ NMP conditions. (11)(12)(13)(14)16) This required transportation of the device with a technical team to and from the donor center as well as maintenance of NMP throughout transportation back to the recipient center.…”

The future of organ perfusion and re‐conditioning

“…Normothermic machine perfusion has been the subject of most interest in liver transplantation and recently, Jassem et al . have provided a much needed mechanistic insight into NMP in liver transplantation by demonstrating an altered gene expression profile in NMP compared with cold‐stored livers from pro‐inflammation to pro‐healing and regeneration. It's safety and feasibility was first demonstrated in 2016 by the Oxford group and the first randomized controlled trial by the same group was recently published .…”

“…It is estimated that steatosis exists in 13–28% of deceased donor livers and therefore salvaging these livers for transplantation may help bridge the gap between organ supply and demand. NMP provides the potential to reduce IRI by avoiding the deleterious effects of cooling possibly by inhibiting inflammation and promoting graft regeneration . NMP also provides a platform to treat the liver ex situ in an attempt to remove the fat during preservation which may further improve outcomes.…”

Pumping new life into old ideas: Preservation and rehabilitation of the liver using ex situ machine perfusion

“…Additionally, viability assessment would increase utilization rates of a significant number of grafts that would have been discarded for a combination of traditional risk factors such as advanced donor age, warm ischemia, steatosis, and social history. At the same time, grafts undergoing machine perfusion have the benefit of receiving oxygenated circulation and various nutrients, allowing regeneration of ATP, washout of accumulated metabolic waste products, and modulation of pro‐inflammatory pathways that result during procurement and cold storage. These benefits become obvious when high‐risk or previously discarded grafts are resuscitated and successfully transplanted after machine perfusion.…”