Steatotic Livers Are More Susceptible to Ischemia Reperfusion Damage after Transplantation and Show Increased γδ T Cell Infiltration

Abstract

Liver transplantation (LTx) is often the only possible therapy for many end-stage liver diseases, but successful long-term transplant outcomes are limited by multiple factors, including ischemia reperfusion injury (IRI). This situation is aggravated by a shortage of transplantable organs, thus encouraging the use of inferior quality organs. Here, we have investigated early hepatic IRI in a retrospective, exploratory, monocentric case-control study considering organ marginality. We analyzed standard LTx biopsies from 46 patients taken at the end of cold organ preparation and two hours after reperfusion, and we showed that early IRI was present after two hours in 63% of cases. Looking at our data in general, in accordance with Eurotransplant criteria, a marginal transplant was allocated at our institution in about 54% of cases. We found that patients with a marginal-organ LTx showing evidence of IRI had a significantly worse one-year survival rate (51% vs. 75%). As we saw in our study cohort, the marginality of these livers was almost entirely due to steatosis. In contrast, survival rates in patients receiving a non-marginal transplant were not influenced by the presence or absence of IRI. Poorer outcomes in marginal organs prompted us to examine pre- and post-reperfusion biopsies, and it was revealed that transplants with IRI demonstrated significantly greater T cell infiltration. Molecular analyses showed that higher mRNA expression levels of CXCL-1, CD3 and TCRγ locus genes were found in IRI livers. We therefore conclude that the marginality of an organ, namely steatosis, exacerbates early IRI by enhancing effector immune cell infiltration. Preemptive strategies targeting immune pathways could increase the safety of using marginal organs for LTx.

Defatting of Human Livers during Long-Term ex situ Normothermic Perfusion. Novel Strategy to Rescue Discarded Organs for Transplantation

“…Moreover, the addition of lipid oxidation promoters was likely instrumental in the maintenance of key β-oxidation enzymes over time, a striking finding given the modest changes in lipid oxidation that have been achieved by short-term NMP 24,25,37 . Thus, long-term NMP, as performed here, will be needed to reduce TG content to levels that would enable resistance to ischemia-reperfusion injury and amelioration in metabolic function, both prerequisites for successful transplantation 38,39 . Although there is room for improvement, metabolic zonation was maintained much longer with circadian feeding, providing additional evidence for the preservation of metabolic capacity during long-term NMP 40,41 …”

“…24,25,37 Thus, long-term NMP, as performed here, will be needed to reduce TG content to levels that would enable resistance to ischemia-reperfusion injury and amelioration in metabolic function, both prerequisites for successful transplantation. 38,39 Although there is room for improvement, metabolic zonation was maintained much longer with circadian feeding, providing additional evidence for the preservation of metabolic capacity during long-term NMP. 40,41 Pseudopeliotic steatosis has been observed in biopsies taken early after transplantation of steatotic grafts, followed by spontaneous resolution along with regression of steatosis 3 to 4 weeks after LT. 34,35 Resolution is likely required for successful LT, otherwise, microcirculatory impairment would increase the risk of primary graft nonfunction, in particular endangering the biliary tree and leading to long-term complications (eg, ischemic type biliary lesions).…”

Role of the immune system in liver transplantation and its implications for therapeutic interventions

“…Hepatic IRI is a recognized issue that impacts the success of LT 129 . Factors like age and fatty liver can influence the extent of IRI and trigger AR 129–131 . Hepatic injury linked to ischemia–reperfusion can be categorized into warm IRI and cold IRI 132,133 .…”

Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights into the Immune and Metabolic Compartments

“…In addition, steatotic livers exhibit lower expression of inositol-requiring enzyme 1 and PKR-like endoplasmic reticulum kinase, which may increase the risk of steatotic livers to IRI [ 129 ]. Elke et al [ 130 ] revealed that steatosis exacerbates early IRI by enhancing effector immune cell infiltration, including higher mRNA expression of CXCL-1 and CD3.…”