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Hif-1a Expression Influences Recipient Clinical Outcomes in Liver Transplant Patients

K. Kadono, T. Ito, H. Kojima, K. Nakamura, H. Hirao, S. Kageyama, K. J. Dery, A. Murray, R. W. Busutill, F. Kaldas, J. W. Kupiec-Weglinski

Liver Transplant Surgery, UCLA, Los Angeles, CA

Meeting: 2020 American Transplant Congress

Abstract number: A-304

Keywords: Biopsy, Graft function, Ischemia, Liver transplantation

Session Information

Session Name: Poster Session A: Biomarkers, Immune Assessment and Clinical Outcomes

Session Type: Poster Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:00pm

 Presentation Time: 3:30pm-4:00pm

Location: Virtual

*Purpose: Liver ischemia-reperfusion injury (IRI), an innate-immune dominated hepatocellular damage, is a risk factor for early allograft dysfunction (EAD) and rejection crises in liver transplantation (LT). Although hypoxia-inducible factor 1-alpha (Hif-1α) is considered a key mediator of the cellular response to hypoxia, its role in clinical LT remains elusive. Here, we analyzed human LT biopsies (Bx) to investigate the impact of graft Hif-1α expression on clinical outcomes.

*Methods: Hepatic Bx were obtained after cold storage and at 2h post-reperfusion from human LT recipients (n=52) recruited under IRB protocol. Bx were retrospectively analyzed by RT-PCR (Pre-transplant Bx: Hif-1α; Post-transplant Bx: Hif-1α/CD80/CD86/ CD68/CD154/ Cathepsin G/CD4/CD28/TLR-2/TLR-4), while human LT recipients were split evenly into low-Hif-1α (n=26) vs high-Hif-1α (n=26) expression groups. In addition, 41 liver Bx samples were screened for lipid droplet cells (HE stain).

*Results: Compared with low-Hif-1α expression cohort, high-Hif-1α cases were characterized by: 1/ improved hepatocellular function, evidenced by decreased levels of sALT/sAST at POD1-7; 2/ depressed macrophage activation, i.e., suppressed mRNA levels coding for TLR2 (0.13±0.09 vs 0.28±0.18, p=0.034), TLR4 (0.12±0.09 vs 0.17±0.13, p=0.029), CD80 (0.34±0.35 vs 0.53±0.48, p=0.014), and CD68 (0.16±0.12 vs 0.30±0.24, p=0.003); 3/ depressed neutrophil activation, i.e., decreased levels of Cathepsin G (0.15±0.12 vs 0.25±0.22, p=0.036); 4/ suppressed T cell activation, i.e., CD4 (0.72±0.07 vs 1.00±0.13, p=0.008), CD28 (0.83±0.07 vs 1.00±0.09, p=0.049), and CD154 (0.17±0.16 vs 0.25±0.23, p=0.039); 4/ lower frequency of large droplet cell>10% (0% vs 26.1%, p=0.019); 5/ lower incidence of early allograft dysfunction (EAD; 11.5% vs 34.6%); as well as 6/ improved LT graft survival at 3-years (96.2% vs 69.2%, p=0.030). Classification by Hif-1α in post-transplant Bx samples also showed high- Hif-1α group was associated with the superior post-LT graft survival (100% vs 75.0%, p=0.055), suppressed innate/adaptive immune cell markers (TLR-2, TLR-4, CD80, CD68, Cathepsin G, CD4, CD28, CD154, p<0.01) and reduced fatty liver incidence (p=0.027).

*Conclusions: This study demonstrated that increased hepatic Hif-1α expression in human LT patients mitigated IR-stress and improved hepatocellular graft function. These beneficial effects were associated with suppressed innate/adaptive immune activation, lower incidence of fatty liver disease and preferable LT clinical outcomes. Hence, Hif-1α activation may not only serve as a potential biomarker of IR stress resistance but may also represent a novel therapeutic target to ameliorate IRI in LT recipients.

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To cite this abstract in AMA style:

Kadono K, Ito T, Kojima H, Nakamura K, Hirao H, Kageyama S, Dery KJ, Murray A, Busutill RW, Kaldas F, Kupiec-Weglinski JW. Hif-1a Expression Influences Recipient Clinical Outcomes in Liver Transplant Patients [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/hif-1a-expression-influences-recipient-clinical-outcomes-in-liver-transplant-patients/. Accessed May 11, 2025.

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