Metabonomic Profile of Macrosteatotic Allografts for Orthotopic Liver Transplantation in Patients With Initial Poor Function: Mechanistic Investigation and Prognostic Prediction.

Zhengtao Liu,Haiyang Xie,Wenchao Wang,Shusen Zheng,Feng Zhang,Junjie Qian,Lin Zhou,Shuai Wang,Hai Zhu,Jian Yu,Jun Xu,Shengyong Yin,Shuping Que,Lei Geng,Li Zhuang

doi:10.3389/fcell.2020.00826

Abstract

BackgroundOur previous study revealled amplified hazardous effects of macrosteatosis (MaS) on graft failure (GF) in recipients with severe liver damage in short post-operative days, with vague mechanism inside.AimWe aimed to uncover the molecular mechanism of donor MaS on GF, and construct the predictive model to monitor post-transplant prognosis based on “omics” perspective.MethodsUltra-performance liquid chromatography coupled to mass spectrometry metabolomic analysis was performed in allograft tissues from 82 patients with initial poor function (IPF) from multi-liver transplant (LT) centers. Pathway analysis was performed by on-line toolkit Metaboanalyst (v 3.0). Predictive model was constructed based on combinative metabonomic and clinical data extracted by stepwised cox proportional analysis.ResultsPrinciple component analysis (PCA) analysis revealled stratification on metabolic feature in organs classified by MaS status. Differential metabolits both associated with MaS and GF were significantly enriched on pathway of glycerophospholipid metabolism (P < 0.05). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) involved in glycerophospholipid metabolism was significantly decreased in cases with MaS donors and GF (P < 0.05). Better prediction was observed on graft survival by combinative model (area under the curve = 0.91) and confirmed by internal validation.ConclusionMetabonomic features of allografts can be clearly distinguished by MaS status in patients with IPF. Dysfunction on glycerophospholipid metabolism was culprit to link donor MaS and final GF. Decrement on PC and PE exerted the fatal effects of MaS on organ failure. Metabonomic data might help for monitoring long-term graft survival after LT.

Highlights

Orthotopic liver transplantation (OLT) is one of the most effective therapeutic strategy for end-stage liver disease, hepatobiliary malignancy, and acute/chronic hepatic failure (Oleary et al, 2008)
In accordance with development of machine perfusion (MP) for organ perservation (Nasralla et al, 2018), this study provided prospective knowledge for better assessment of MaS grafts with provision of meaningful metabolites as potential targets for further improvement of allograft quality
2https://www.metaboanalyst.ca/MetaboAnalyst/home.xhtml allografts was significantly increased from 15% in 2015 to more than one quarter in 2019 (P < 0.05, Supplementary Figure S2)

Summary

Introduction

Orthotopic liver transplantation (OLT) is one of the most effective therapeutic strategy for end-stage liver disease, hepatobiliary malignancy, and acute/chronic hepatic failure (Oleary et al, 2008). Macrosteatosis (MaS) was considered as an profound risk component for exceeded criteria donor (ECD), with positive impacts on inferior post-transplant survival and complications (Spitzer et al, 2010; Vodkin and Kuo, 2017; Moosburner et al, 2018). As one of prominent sign for extended criteria donor (ECD) livers, MaS was proved to be a risk predictor on adverse prognosis including severer liver injury, increased peri-operative complications, higher posttransplant mortality and graft loss (De Graaf et al, 2012; Croome et al, 2019). Our previous study revealled amplified hazardous effects of macrosteatosis (MaS) on graft failure (GF) in recipients with severe liver damage in short post-operative days, with vague mechanism inside

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