
==== Front
eBioMedicine
EBioMedicine
eBioMedicine
2352-3964
Elsevier

S2352-3964(24)00387-6
10.1016/j.ebiom.2024.105351
105351
Comment
Advanced viability assessment in machine perfusion: what lies ahead?
Nakayama Toshihiro
Sasaki Kazunari sasakik@stanford.edu
∗
Division of Abdominal Transplant, Department of Surgery, Stanford University Medical Center, Stanford, CA, USA
∗ Corresponding author. Division of Abdominal Transplant, Department of Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA. sasakik@stanford.edu
14 9 2024
10 2024
14 9 2024
108 1053512 9 2024
4 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcThe introduction of normothermic machine perfusion (NMP) has revolutionized the landscape of liver transplantation. By enabling the viability assessment and reconditioning of organs, NMP has allowed for the use of previously discarded grafts from extended criteria donors, including those from donation after circulatory death (DCD) donors or macrosteatotic grafts, by mitigating ischemic reperfusion injury (IRI), a significant challenge in the early postoperative period. While the efficacy of NMP in transforming “unusable” organs viable has been demonstrated, the boundaries of this technology remain unclear. How far can we stretch the viability of these organs? Currently, graft viability is evaluated using perfusate or bile acid markers like lactate clearance, bile production, perfusate pH, glucose levels, vascular flows, bile pH, and bicarbonate levels.1, 2, 3, 4 Despite their clinical utility, these markers’ predictive accuracy is limited, prompting the exploration of new methods such as indocyanine green fluorescence imaging, spectroscopy, cell-free microRNA (miRNA), perfusate flavin-mononucleotide (FMN), and metabolomic analyses.5, 6, 7, 8 To date, molecular pathways activated during NMP have not been extensively studied.

In a recent issue of eBioMedicine, Hautz and colleagues explored the potential for predicting graft quality and early graft function through transcriptomic analysis of 50 livers during normothermic perfusion.9 Utilizing bulk RNA sequencing, they identified a 7-gene signature at 6 h NMP that accurately predicted whether grafts would meet the benchmarking criteria for transplantation or be discarded, at a remarkable area under curve of 0.99.10 Among the seven genes, CD274, which encodes PD-L1, was particularly expressed in neutrophils at the end of NMP, suggesting a potential interaction between hepatocytes and immune cells. Furthermore, the expression of the LEAP2 gene at 6 h of NMP and the IFIT1 gene at 20 h of NMP emerged as possible markers for predicting early graft loss. The strengths of the study by Hautz et al. lies in its dynamic analysis of gene expression changes, offering valuable insights into how molecular pathways are involved in graft reconditioning during NMP. Their research uncovered pathways and genes associated with inflammatory responses during liver NMP, which could inform future perfusion protocol optimization.

What does the future hold for viability assessment during NMP? Despite extensive research into identifying viability markers, we still require solid evidence to persuade healthcare policymakers in different countries to support the broader adoption of NMP, given its substantial costs. Due to the time constraints at the time of organ allocation and transplantation, a reliable marker that is straightforward, affordable, and easy to use is necessary. Furthermore, with multiple assessment methods already yielding promising results, we should focus on combining these markers to enhance predictive accuracy and global applicability. Although transcriptomic analyses are not yet cost-effective, they could refine assessment processes by offering a deeper molecular understanding, rather than merely assessing end products like bile production and lactate clearance. Additionally, refining liver function assessment protocols and markers during NMP could extend their application to xenotransplantation or liver resections for malignancies. Though currently speculative, transcriptomic analysis might one day support liver function evaluation before, during, or immediately after surgery, guiding clinical decisions regarding treatment and postoperative care.

In conclusion, the significant contribution by Hautz et al. sheds light on the intricate processes during NMP that affect graft quality, potentially guiding us toward an optimized NMP protocol and improving transplantation outcomes.

Contributors

Participated in research design; TN, KS.

Participated in the writing of the paper; TN, KS.

Participated in the critical review: TN, KS.

Participated in data analysis: TN, KS.

Both authors read and approve the final manuscript.

Declaration of interests

None.

Acknowledgements

None.

The paper is not based on previous communication with a society or meeting.
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