Machine perfusion in liver transplantation: A step forward, but still on the runway

Abstract

The recent editorial by Parente et al provides a balanced overview of machine perfusion (MP) in liver transplantation. While its potential to improve graft preservation is clear, several challenges hinder routine adoption: High costs, logistical complexity, lack of standardized viability criteria, limited long-term outcome data, and absence of direct comparisons between hypothermic and normothermic MP. From my experience of over 900 liver transplants without MP, and the limited uptake among Korean centers, compelling evidence for its necessity remains lacking. The immunomodulatory effects of MP, particularly in ABO-incompatible or sensitized recipients, remain underexplored. Future research should integrate immune profiling, mechanistic analyses, and biomarker-guided immunosuppression strategies into multicenter trials to clarify its role in tolerance induction and long-term graft protection. Ethical, regulatory, and policy considerations especially in resource-limited settings must also be addressed to ensure equitable access. Robust clinical and mechanistic data are essential before MP can be fully endorsed as standard care.

Key Words: Liver transplantation; Machine perfusion; Immune tolerance; ABO-incompatible; Letter

Core Tip: Machine perfusion (MP) may enhance graft preservation and modulate immune responses, but high costs, logistical barriers, and lack of standardized viability criteria limit its routine use. Long-term outcome data and head-to-head comparisons between perfusion strategies remain scarce, and uptake is low in Korean liver transplant centers. Robust multicenter trials integrating immune profiling and biomarker-guided immunosuppression are needed before MP can be endorsed as standard practice.

TO THE EDITOR

I read with great interest the article by Parente et al[1] published in the World Journal of Gastroenterology. The authors provide a timely and thoughtful overview of current machine perfusion (MP) strategies, underscoring their potential to transform donor organ preservation and improve graft outcomes. As a liver transplant specialist, I applaud the balanced discussion and welcome the spotlight on this rapidly evolving field.

While the editorial makes a compelling argument for the clinical relevance of MP in liver transplantation by synthesizing current evidence and advocating its broader implementation, several areas merit further discussion. Despite its clinical promise, MP in liver transplantation continues to face several unresolved challenges that hinder its routine implementation.

First, while the clinical relevance of MP is increasingly acknowledged, its routine implementation in high-volume transplant programs faces significant barriers. Chief among these are the high costs associated with perfusion devices and consumables, logistical complexity, and the need for specialized personnel and infrastructure. These limitations are particularly acute in resource-constrained settings and smaller transplant centers with limited access to donor organs. Moreover, real-world data on the cost-effectiveness of MP especially in comparison to static cold storage for marginal grafts such as those from donation after circulatory death and extended criteria donors remain insufficient, further hindering widespread adoption.

Second, despite growing interest in viability assessment during normothermic MP, there remains no consensus on standardized criteria. Current clinical trials employ a heterogeneous array of parameters, including lactate clearance, bile production, potential of hydrogen, and glucose metabolism to evaluate graft suitability. However, these thresholds vary widely across centers and protocols, resulting in inconsistencies in decision-making and clinical outcomes. While the authors acknowledge viability assessment as a future objective, this aspect merits stronger emphasis. Emerging data, particularly from viability-guided trials, suggest that dynamic functional markers, such as lactate clearance, bile production, and perfusate metabolomics during normothermic MP may offer predictive insights beyond traditional histological and enzymatic parameters[2]. This is further supported by clinical reviews summarizing multiple trials in which bile output and lactate dynamics were used to guide graft utilization decisions[3]. Moreover, the integration of omics-based technologies into perfusion platforms holds promise for enhancing precision in graft selection and immunological profiling.

Third, while short-term benefits such as reduced ischemia-reperfusion injury are well established, long-term outcome data remain scarce. There is a pressing need for well-designed multicenter trials that extend beyond short-term endpoints and rigorously assess long-term outcomes, including graft and patient survival, the incidence and severity of biliary complications, and the rate of re-transplantation beyond the first postoperative year. Such studies are essential to move beyond anecdotal experience and early-phase evidence, and to establish robust, generalizable data that can inform clinical guidelines, support health policy decisions, and justify broader implementation of MP technologies in diverse healthcare settings.

Fourth, a key limitation in the current literature is the lack of direct comparative evidence between different MP strategies, namely, hypothermic and normothermic MP and their relative advantages in distinct clinical contexts, such as extended criteria donors, donation after circulatory death, and ABO-incompatible liver transplantation. Without head-to-head comparisons, it remains unclear which approach is optimal for specific risk profiles, thereby limiting the development of tailored perfusion protocols and evidence-based decision-making. Table 1 summarizes the comparative features of hypothermic MP and normothermic MP, highlighting differences in metabolic activity, viability assessment, immunomodulatory potential, and logistical considerations[3,4].

Table 1 Comparative features of hypothermic vs normothermic machine perfusion strategies in liver transplantation.

Parameter	Hypothermic MP (HOPE/D-HOPE)	Normothermic MP
Metabolic activity	Suppressed; reduces oxygen demand and cellular stress	Maintained; mimics physiological conditions
Viability assessment	Limited; lacks dynamic functional readouts	Real-time assessment via lactate clearance, bile output, etc.
Biliary protection	Strong evidence for reduced ischemic biliary injury	Mixed results; less consistent protection
Immunomodulatory potential	Underexplored; minimal data on immune modulation	Emerging evidence of Treg induction, cytokine shifts
Logistical complexity	Relatively simple; lower equipment and staffing requirements	More complex; requires specialized devices and trained personnel
Cost	Lower; fewer consumables and infrastructure needs	Higher; expensive devices and perfusate components
Clinical integration	Increasing use, especially in Europe and for marginal grafts	Growing adoption; more common in viability-guided protocols
Limitations	No active metabolism; limited therapeutic intervention window	Risk of overinterpretation of viability markers; cost barriers

MP: Machine perfusion; HOPE: Hypothermic oxygenated perfusion; D-HOPE: Dual hypothermic oxygenated perfusion; Treg: Regulatory T cell.

Finally, recent studies suggest that normothermic MP not only preserves graft function but actively reshapes the immune landscape of the liver prior to transplantation[5-7]. Beyond conventional functional assessment, accumulating evidence suggests that MP may contribute to immunological tolerance through multiple mechanisms, including the induction of regulatory T cells (Tregs), enhanced secretion of anti-inflammatory cytokines such as interleukin-10, and downregulation of pro-inflammatory mediators like tumor necrosis factor-alpha and interleukin-6[8,9]. These immunomodulatory effects highlight the potential of MP to influence post-transplant immune responses and graft acceptance. However, these potential benefits remain controversial (Figure 1). Other reports indicate that perfusing organs before transplantation could result in the depletion of beneficial hematopoietic stem cells and passenger leukocytes, which might otherwise contribute to mixed chimerism and peripheral Treg generation[10,11]. Moreover, experimental models have shown conflicting effects on antigen-presenting cell function and alloantibody responses, suggesting that the immune consequences of MP are highly context-dependent[4].

Figure 1 Immunological pathways modulated by machine perfusion. IL: Interleukin; TNF: Tumor necrosis factor; Treg: Regulatory T cell.

In parallel with these mechanistic insights, recent multicenter experiences have demonstrated tangible clinical benefits of MP. The organ care system liver PROTECT randomized trial showed that normothermic MP significantly reduced early allograft dysfunction and ischemic biliary complications across 20 United States transplant centers[12]. Additionally, the national MP program in Italy has reported successful transplantation of most perfused organs particularly in donation after circulatory death liver transplants thereby expanding the donor pool and improving graft utilization[13]. These examples underscore the growing clinical momentum behind MP and reinforce its translational potential in routine transplant practice.

These divergent findings and emerging clinical data highlight the need for mechanistic studies integrating perfusate immune profiling, graft-infiltrating leukocyte characterization, and longitudinal immune monitoring in recipients. Clinically, modulation of the hepatic immune environment via MP may attenuate alloimmune activation, lowering early rejection risk and potentially improving long-term graft survival. This immunologic “reset” could reduce the need for high-dose immunosuppression, thereby decreasing drug-related complications such as infection, nephrotoxicity, and metabolic syndrome, while alleviating the financial burden of prolonged use of costly immunosuppressants. These hypotheses require validation through well-designed multicenter trials correlating MP-induced immune signatures with safe and effective immunosuppression minimization strategies. Such data would be essential to determine whether MP can reliably induce tolerance or improve long-term immunological outcomes across diverse transplant scenarios.

Based on my institutional experience, I have performed more than 900 Liver transplants without the use of MP, as I have not yet identified a clear clinical need for such equipment in our practice. If MP were unequivocally proven to deliver consistent and substantial benefits, its adoption would be justified regardless of cost. Our outcomes have remained satisfactory without MP and to my knowledge, most liver transplant centers in Korea have not implemented MP because it likely reflects the absence of compelling evidence supporting its routine use. Although numerous studies on MP have emerged in recent years, conclusive proof of its necessity remains lacking. In my view, MP is still in the investigational stage, and widespread adoption should be deferred until robust, high-quality preferably region-specific data demonstrate clear advantages over current standard practice.

The potential of MP to influence long-term immunological tolerance and mitigate biliary injury particularly in ABO-incompatible or sensitized recipients remains a promising yet underexplored area. As MP technologies advance, future research should aim to integrate perfusion metrics not only with graft viability but also with immunologic modulation and individualized risk stratification. To date, few studies have systematically examined how perfusion affects alloimmune activation, regulatory pathways, or the induction of immune tolerance. Incorporating immunologic profiling into perfusion-based trials, such as cytokine signatures, T cell subset characterization, and donor-derived cell-free DNA analysis may uncover novel mechanisms of graft acceptance and inform strategies for minimizing immunosuppression. To fully harness the immunological potential of MP, future research should pursue targeted investigations that integrate mechanistic insights with clinical relevance. Key priorities include the incorporation of immune profiling into MP protocols utilizing techniques such as flow cytometry, multiplex cytokine analysis, and transcriptomic sequencing to characterize graft-specific immune landscapes. Multicenter trials comparing immunologic outcomes across different MP strategies in high-risk recipient populations are needed to establish evidence-based approaches. Additionally, biomarker-guided strategies for immunosuppression minimization, informed by MP-derived data, may enhance personalized transplant management. Finally, longitudinal studies assessing immune tolerance and chronic rejection rates in MP-treated grafts will be essential to define its long-term immunomodulatory impact. Specific research questions that multicenter trials should address include: (1) Can specific cytokine signatures obtained during MP predict the risk of acute or chronic rejection over long-term follow-up? (2) Does integrating perfusate immune profiling with traditional viability markers improve graft allocation accuracy compared with functional criteria alone? (3) In high-risk cohorts (e.g., donation after circulatory death, extended criteria donors, ABO-incompatible), does MP confer differential immunologic or clinical benefits depending on perfusion temperature and modality? (4) Can biomarker-guided immunosuppression minimization, informed by MP-derived data, reduce infection or malignancy rates without increasing rejection? and (5) What are the cost-effectiveness and health-policy impacts of routine MP adoption when stratified by donor type, recipient risk, and regional resource availability?

In addition to scientific and clinical challenges, broader ethical and policy-related considerations must be addressed to ensure equitable and sustainable adoption of MP technologies. Despite the growing enthusiasm for MP technologies, there is a notable absence of discussion around the ethical, regulatory, and policy-related challenges that may impede their equitable implementation. In low-resource settings, the high cost of perfusion devices and consumables raises concerns about distributive justice and access disparities. Ethical dilemmas may arise when advanced technologies are available only to select institutions or patient populations, potentially exacerbating existing inequities in transplant care. Furthermore, regulatory frameworks governing MP use remain fragmented across regions, with limited guidance on standardization, safety oversight, and reimbursement policies. The integration of novel technologies like MP demands proactive policy development, stakeholder engagement, and ethical governance to ensure that innovation translates into inclusive and sustainable clinical practice. In low-resource settings, challenges such as access disparities, fragmented regulatory oversight, and the lack of reimbursement frameworks may significantly hinder implementation.

Although the current discussion is primarily adult-focused, I believe that MP may theoretically offer significant benefits in pediatric liver transplantation particularly by improving graft viability in split grafts and grafts from donors after circulatory death, expanding the donor pool, and reducing cold ischemia time in small-volume recipients.

Addressing these clinical, scientific, logistical, ethical, and policyrelated challenges will be critical to advancing MP from a promising experimental innovation to an established standard of care in liver transplantation.

CONCLUSION

A well-deserved commendation goes to the authors for synthesizing the current landscape of MP and advocating its broader clinical adoption. While MP technologies are steadily evolving and hold clear promise, their potential immunomodulatory benefits particularly in high-risk transplant settings such as donation after circulatory death and ABO-incompatible recipients remain underexplored. By bridging functional recovery with immune modulation, normothermic MP may offer a novel avenue to improve long-term graft outcomes and reduce immunologic complications. However, robust multicenter data encompassing both clinical efficacy and mechanistic insights together with ethical and policy considerations, will be essential before its routine use can be fully endorsed.

ACKNOWLEDGEMENTS

I would like to express my sincere appreciation to all members of our liver transplantation team for their unwavering support and collaboration.