Metabolic and lipidomic profiling of steatotic human livers during ex situnormothermic machine perfusion guides resuscitation strategies.

Siavash Raigani,Korkut Uygun,Negin Karimian,Ehab O A Hafiz,Robert J Porte,Viola Huang,Anna M Zhang,Fermin M Fontan,James F Markmann,Martin Yarmush,Sonal Nagpal,Heidi Yeh,Sharon Geerts,Paria Mahboub,Mohamed M Aburawi,Irene Beijert

doi:10.1371/journal.pone.0228011

Abstract

There continues to be a significant shortage of donor livers for transplantation. One impediment is the discard rate of fatty, or steatotic, livers because of their poor post-transplant function. Steatotic livers are prone to significant ischemia-reperfusion injury (IRI) and data regarding how best to improve the quality of steatotic livers is lacking. Herein, we use normothermic (37°C) machine perfusion in combination with metabolic and lipidomic profiling to elucidate deficiencies in metabolic pathways in steatotic livers, and to inform strategies for improving their function. During perfusion, energy cofactors increased in steatotic livers to a similar extent as non-steatotic livers, but there were significant deficits in anti-oxidant capacity, efficient energy utilization, and lipid metabolism. Steatotic livers appeared to oxidize fatty acids at a higher rate but favored ketone body production rather than energy regeneration via the tricyclic acid cycle. As a result, lactate clearance was slower and transaminase levels were higher in steatotic livers. Lipidomic profiling revealed ω-3 polyunsaturated fatty acids increased in non-steatotic livers to a greater extent than in steatotic livers. The novel use of metabolic and lipidomic profiling during ex situ normothermic machine perfusion has the potential to guide the resuscitation and rehabilitation of steatotic livers for transplantation.

Highlights

Liver transplantation remains the only cure for end-stage liver disease
All donor livers were received through New England Donor Services (NEDS); no organs were procured from prisoners
Resuscitating steatotic livers to expand the donor liver pool will be enhanced by knowledge of the metabolic deficiencies specific to these organs

Summary

Introduction

Liver transplantation remains the only cure for end-stage liver disease. there is a significant shortage of donor livers resulting in waitlist mortality rates approaching 20% [1]. Transplantation of livers with moderate (30–60%) and severe (>60%) macrosteatosis is associated with increased rates of primary non-function, early allograft dysfunction (EAD), and decreased graft survival [3, 4]. Poor graft function following transplantation of steatotic livers is attributed to multiple physical and metabolic abnormalities, culminating in decreased ability to tolerate ischemiareperfusion injury (IRI), which occurs during procurement, cold storage, and implantation. The large lipid vesicles seen in macrosteatosis compress adjacent sinusoids resulting in reduced sinusoidal perfusion compared to non-steatotic livers [5]. Normothermic machine perfusion (NMP) has already been demonstrated to decrease organ discard rates and EAD, with equivalent graft survival compared to conventional static cold storage (SCS) in spite of worse donor liver characteristics [12].

Methods

Evaluation of hepatic injury and function

Results

Discussion