Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation.

Tamara Horváth,Bálint Baráth,Mihály Boros,Marietta Zita Poles,Petra Hartmann,Dávid Kurszán Jász

doi:10.3390/ijms22062816

Tamara Horváth, Bálint Baráth + Show 4 more

Open Access

https://doi.org/10.3390/ijms22062816

Copy DOI

Abstract

Allograft ischemia during liver transplantation (LT) adversely affects the function of mitochondria, resulting in impairment of oxidative phosphorylation and compromised post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. This study aimed to summarize the available data on mitochondrial effects of graft preservation methods in preclinical models of LT. Furthermore, a network meta-analysis was conducted to determine if any of these treatments provide a superior benefit, suggesting that they might be used on humans. A systematic search was conducted using electronic databases (EMBASE, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science) for controlled animal studies using preservation methods for LT. The ATP content of the graft was the primary outcome, as this is an indicator overall mitochondrial function. Secondary outcomes were the respiratory activity of mitochondrial complexes, cytochrome c and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were used. After a comprehensive search of the databases, 25 studies were enrolled in the analysis. Treatments that had the most significant protective effect on ATP content included hypothermic and subnormothermic machine perfusion (HMP and SNMP) (MD = −1.0, 95% CI: (−2.3, 0.3) and MD = −1.1, 95% CI: (−3.2, 1.02)), while the effects of warm ischemia (WI) without cold storage (WI) and normothermic machine perfusion (NMP) were less pronounced (MD = −1.8, 95% CI: (−2.9, −0.7) and MD = −2.1 MD; CI: (−4.6; 0.4)). The subgroup of static cold storage (SCS) with shorter preservation time (< 12 h) yielded better results than SCS ≥ 12 h, NMP and WI, in terms of ATP preservation and the respiratory capacity of complexes. HMP and SNMP stand out in terms of mitochondrial protection when compared to other treatments for LT in animals. The shorter storage time at lower temperatures, together with the dynamic preservation, provided superior protection for the grafts in terms of mitochondrial function. Additional clinical studies on human patients including marginal donors and longer ischemia times are needed to confirm any superiority of preservation methods with respect to mitochondrial function.

Highlights

Human clinical results have strengthened the association between disturbances in mitochondrial bioenergetics and the acute rejection process, raising the possibility of establishing a rejection score containing data predictive of mitochondrial function [14,15,16,17,18,19,20]
The current state-of-the-art method for diagnosis of cellular rejection is performed by core needle biopsy and is analyzed under a light microscope using the grading scale of the Banff Schema, which is added to a final rejection index (RAI) [72]
The correlation of graft performance and mitochondrial functional analyses of the OxPhos and ETC systems in the included experimental studies indicates the potential of high-resolution respirometry for quantitative assessment of allograft injury upon transplantation, providing a basis for diagnostic approaches and evaluation of improved preservation techniques for liver grafts [16,46]

Summary

Introduction

Liver transplantation (LT) is the treatment of choice for patients with end-stage liver disease. From the first human LT performed by Thomas Starzl in 1963, advances in surgical technology and effective immunosuppressive agents have increased the five-year survival of transplanted patients by over 75% [1]. The success of LT, is limited by a shortage of donor organs compared to waiting list demand. Efforts to expand the donor pool have included the use of suboptimal, so-called extended criteria donor (ECD) grafts, which were previously considered unsuitable for transplantation, allowing the use of organs after prolonged cold ischemia times (CIT), inclusion of older donors, donation after cardiac death (DCD) or hepatic steatosis [2] (Table 1).

Methods

Discussion

Conclusion