Higher thresholds for the utilization of steatotic allografts in liver transplantation: Analysis from a U.S. national database

Steggerda, Justin; Bloom, Matthew B.; Noureddin, Mazen; Brennan, Todd V.; Todo, Tsuyoshi; Nissen, Nicholas N.; Klein, Andrew S.; Kim, Irene

doi:10.1371/journal.pone.0230995

Cited by 16 publications

(16 citation statements)

References 34 publications

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“…With a rising number of new registrants in transplant waitlists, the disparity between allograft availability and waiting candidates remains persistent. To bridge this gap, there has been increasing support for the use of steatotic livers 7,43 . However, accumulating evidences showed that using steatotic grafts for LT is associated with higher risks of complications after LT 44 .…”

Section: Discussionmentioning

confidence: 99%

“…Steatotic liver is a common type of ECD. However, such organs are more prone to preservation injury and graft dysfunction, resulting in a poor prognosis after liver transplantation 6‐8 . It has been proposed that steatotic livers are more susceptible to ischaemia‐reperfusion (I/R) injury, which impairs liver regeneration and is a major cause of liver damage 6,9 .…”

Section: Introductionmentioning

confidence: 99%

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Single‐cell profiling reveals distinct immune phenotypes that contribute to ischaemia‐reperfusion injury after steatotic liver transplantation

Yang

Wang

et al. 2021

Cell Proliferation

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Objectives The discrepancy between supply and demand of organ has led to an increased utilization of steatotic liver for liver transplantation (LT). Hepatic steatosis, however, is a major risk factor for graft failure due to increased susceptibility to ischaemia‐reperfusion (I/R) injury during transplantation. Materials and methods To assess the plasticity and phenotype of immune cells within the microenvironment of steatotic liver graft at single‐cell level, single‐cell RNA‐sequencing (scRNA‐Seq) was carried out on 23 675 cells from transplanted rat livers. Bioinformatic analyses and multiplex immunohistochemistry were performed to assess the functional properties, transcriptional regulation, phenotypic switching and cell‐cell interactions of different cell subtypes. Results We have identified 11 different cell types in transplanted livers and found that the highly complex ecosystem was shaped by myeloid‐derived cell subsets that transit between different states and interact mutually. Notably, a pro‐inflammatory phenotype of Kupffer cells (KCs) with high expression of colony‐stimulating factor 3 (CSF3) that was enriched in transplanted steatotic livers was potentially participated in fatty graft injury. We have also detected a subset of dendritic cells (DCs) with highly expressing XCR1 that was correlated with CD8+ T cells, mediating the severer steatotic liver damage by I/R injury. Conclusions The findings of our study provide new insight into the mechanisms by which steatosis exacerbates liver damage from I/R injury. Interventions based on these observations create opportunities in attenuating fatty liver graft injury and expanding the donor pool.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single‐cell profiling reveals distinct immune phenotypes that contribute to ischaemia‐reperfusion injury after steatotic liver transplantation

Yang

Wang

et al. 2021

Cell Proliferation

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“… 8 Separately, our group showed equivalent 1-y graft survival for liver allografts with up to 50% MaS when used in recipients with model for end-stage liver disease (MELD) scores <33 and up to 40% MaS in higher MELD recipients. 9 Together, these findings support the use of increasingly steatotic allografts with attention to recipient selection.…”

mentioning

confidence: 66%

A Clinical Tool to Guide Selection and Utilization of Marginal Donor Livers With Graft Steatosis in Liver Transplantation

Steggerda

Borja–Cacho

Brennan

et al. 2022

Transplantation Direct

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“…Similarly, Briceño et al were able to show in a clinical study that steatosis over 30% had an influence on IRI development; moreover, steatosis over 30% was the main cause of severe IRI in that study [ 19 ]. In addition, grafts with severe fatty degeneration more often lead to primary non-function [ 26 , 27 ]. Importantly, we found in our study that patients with a marginal transplant who developed an IRI have substantially poorer outcomes, including early mortality.…”

Section: Discussionmentioning

confidence: 99%

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

Eggenhofer

Groell

Junger

et al. 2021

IJMS

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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.

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Higher thresholds for the utilization of steatotic allografts in liver transplantation: Analysis from a U.S. national database

Cited by 16 publications

References 34 publications

Single‐cell profiling reveals distinct immune phenotypes that contribute to ischaemia‐reperfusion injury after steatotic liver transplantation

Single‐cell profiling reveals distinct immune phenotypes that contribute to ischaemia‐reperfusion injury after steatotic liver transplantation

A Clinical Tool to Guide Selection and Utilization of Marginal Donor Livers With Graft Steatosis in Liver Transplantation

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

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