Highlights
- The Bridge to HOPE trial (NCT05045794) established the superiority of end-ischemic portal-venous HOPE over static cold storage (SCS), reducing early allograft dysfunction (EAD) from 37.3% to 20.2%.
- HOPE treatment leads to shorter hospital lengths of stay and improved metabolic function scores (MEAF) in recipients of extended criteria donor (ECD) grafts.
- Beyond early function, HOPE improves biliary lipid secretion and reduces bile acid toxicity, potentially mitigating long-term nonanastomotic biliary strictures (NAS).
- Emerging evidence suggests that HOPE possesses immunomodulatory properties, increasing donor-specific regulatory T cells and potentially reducing hepatocellular carcinoma (HCC) recurrence.
Background
Liver transplantation (LT) remains the definitive treatment for end-stage liver disease and hepatocellular carcinoma (HCC). However, the chronic shortage of high-quality donor organs has necessitated the increasing use of extended criteria donor (ECD) grafts, including donation after circulatory death (DCD) and older donation after brain death (DBD) grafts. These “marginal” organs are significantly more susceptible to ischemia-reperfusion injury (IRI), which manifests clinically as early allograft dysfunction (EAD), primary non-function (PNF), and long-term biliary complications such as nonanastomotic biliary strictures (NAS).
Traditional static cold storage (SCS) is a passive preservation method that fails to mitigate the metabolic debt and mitochondrial damage incurred during warm and cold ischemia. Hypothermic oxygenated machine perfusion (HOPE) has emerged as a dynamic preservation strategy designed to “recharge” the cellular energy state (adenosine triphosphate levels) and mitigate the oxidative stress burst upon reperfusion. While European studies have previously suggested benefits, the clinical utility of portal-venous HOPE in the US transplant environment—characterized by longer transport times and distinct donor demographics—remained to be definitively proven until the recent completion of major randomized clinical trials.
Key Content
The Bridge to HOPE Trial: A Landmark US Multicenter Study
The Bridge to HOPE Trial (Reich et al., JAMA Surgery 2026) represents a pivotal shift in US transplant practice. This multicenter, randomized, open-label trial enrolled 219 recipients of ECD livers (both DBD and DCD) across 15 US centers. The study utilized a “back-to-base” approach, where livers were transported via SCS and then underwent portal-venous HOPE for at least two hours prior to implantation using the VitaSmart system.
The primary efficacy endpoint, EAD, was significantly lower in the HOPE group (20.2%) compared to the SCS group (37.3%), achieving both noninferiority and superiority (P = .005). Furthermore, the Model for Early Allograft Function (MEAF) scores were significantly improved in the HOPE cohort (4.28 vs. 4.82, P = .03). Clinical efficiency was also enhanced, with a hazard ratio of 1.32 for shorter hospital length of stay (LOS) in favor of the HOPE group (P = .04). While 1-year survival was comparable, post hoc analyses suggested reduced major complications (Clavien-Dindo ≥IIIa) and lower graft loss due to NAS in the HOPE-treated grafts.
Global Evidence and Comparative RCTs
The US findings are mirrored by the French multicenter randomized controlled trial (NCT03929523) reported in Am J Transplant (2025/2026). In this study of 262 ECD-DBD grafts, HOPE reduced EAD from 30.5% in the SCS control to 17.6% (P = .01). Notably, older recipients receiving grafts with long cold ischemia times (>6 hours) appeared to derive the greatest benefit, with a reduction in severe complications from 72% to 26% (P = .005). Another European trial focusing on routine DBD donors (Ann Surg 2023) suggested that while routine use in low-risk donors might not be necessary, the benefits were significantly pronounced in high-risk donors (Donor Risk Index >1.70).
Mechanistic Insights: Biliary Protection and Metabolic Recovery
One of the most profound benefits of HOPE is its impact on the biliary tree. Biliary epithelial cells (cholangiocytes) are exquisitely sensitive to IRI. Research published in JHEP Reports (2025) involving mass spectrometry analysis of bile composition showed that HOPE-treated livers exhibit improved biliary lipid secretion and a lower biliary bile acid-to-phosphatidylcholine ratio. By promoting the normalization of serum bile acid levels and reducing intrahepatic accumulation, HOPE serves as a protective shield against bile acid toxicity, which is a primary driver of NAS development.
Furthermore, porcine DCD models (Am J Transplant 2026) have compared different perfusion timings, demonstrating that end-ischemic and continuous HOPE are superior to upfront HOPE in enhancing lactate clearance, protecting mitochondrial function, and reducing inflammatory cytokine release.
Immunomodulatory and Oncological Implications
Recent translational research (Liver Transpl 2025) has identified that HOPE significantly alters the immunogenicity of the donor liver. Recipients of HOPE-treated grafts showed a higher frequency of donor-specific CD4+FOXP3+CD127lo regulatory T cells (Tregs) and reduced alloreactivity of CD8+ T cells at three months post-transplant. This molecular recalibration may explain the lower rejection rates observed in various cohorts.
Perhaps most intriguingly, the HOPE-REAL study (JHEP Rep 2026) suggests an oncological benefit. In a matched cohort of 599 patients with HCC, the recurrence rate was only 6.9% for HOPE-treated livers. Compared to a non-perfused external cohort, HOPE-treated recipients had significantly higher 5-year overall survival (84% vs. 74%, P = .034). The ongoing HOPE4Cancer trial (NCT06717919) is currently investigating whether this reduction in the pro-inflammatory milieu of the graft directly inhibits tumor cell seeding and recurrence.
Expert Commentary
The current body of evidence marks the end of the “SCS-only” era for marginal liver grafts. Experts emphasize that the “back-to-base” portal-perfusion model is highly pragmatic. Unlike Normothermic Machine Perfusion (NMP), which often requires specialized equipment and teams to travel to the donor site for “organ-running,” HOPE can be initiated at the recipient center during the recipient’s hepatectomy. This minimizes logistical complexity and cost while maximizing the metabolic recovery window.
However, controversies remain regarding the optimal perfusion duration. While 2 hours is the standard, some centers explore longer periods to accommodate surgical scheduling. Furthermore, while portal-venous HOPE is highly effective, the debate continues over whether dual perfusion (portal vein and hepatic artery) offers additive benefits for DCD grafts, particularly for reducing NAS. Current guidelines are beginning to reflect these trial results, with a paradigm shift toward making machine perfusion the new “gold standard” for ECD organ preservation.
Conclusion
Hypothermic oxygenated perfusion has transitioned from an experimental concept to a clinically validated, pragmatic intervention that directly addresses the challenges of ischemia-reperfusion injury in liver transplantation. The Bridge to HOPE trial provides the definitive evidence needed for widespread adoption in the US, proving that even simple end-ischemic portal-venous perfusion can substantially improve early allograft function and patient recovery. Future research will likely focus on the potential for HOPE to serve as a platform for drug delivery (e.g., cytokine adsorption as seen in pilot studies) and its long-term impact on oncological outcomes. For now, HOPE stands as a vital tool in expanding the donor pool and ensuring the safety of extended-criteria transplantation.
References
- Reich DJ, et al. Portal-Venous Hypothermic Oxygenated Perfusion for Liver Transplant: A Randomized Clinical Trial. JAMA surgery. 2026; PMID: 42201712.
- Schlegel A, et al. Long-term outcomes after hypothermic oxygenated machine perfusion and transplantation of 1,202 donor livers in a real-world setting (HOPE-REAL study). J Hepatol. 2025;82(1):97-106. PMID: 38969242.
- Muller X, et al. A French multicenter randomized controlled trial of hypothermic oxygenated perfusion in extended criteria donor liver transplantation. Am J Transplant. 2026;26(3):607-620. PMID: 41110608.
- Boteon YL, et al. Effects of hypothermic oxygenated machine perfusion on bile composition after liver transplantation – Findings from a randomized controlled trial. JHEP Rep. 2025;8(2):101647. PMID: 41551407.
- Czigany Z, et al. Hypothermic oxygenated machine perfusion influences the immunogenicity of donor livers in humans. Liver Transpl. 2025;31(3):311-322. PMID: 39172015.