Standardization is needed in reporting risk and outcomes of machine perfusion in liver transplantation

We congratulate Yamamoto et al. on their study “Impact of Portable Normothermic Machine Perfusion for Liver Transplantation from Adult Deceased Donors” (1). The surge of interest in normothermic machine perfusion (NMP) in the United States (US) has generated considerable enthusiasm. The authors present generally exciting results from their single-center analysis of 541 liver transplantations. Among these, 469 were from donors after brain dead (DBD); 58 (12.4%) received NMP and 411 static cold storage (SCS, 87.6%). Seventy-two transplants were from donors after circulatory death (DCD); 52 (72.2%) received NMP (device-to-donor) vs. 20 SCS (27.8%). This retrospective study compared outcomes between device-to-donor NMP and traditional SCS, stratifying for donor type to account for different risk profiles. Both DBD and DCD liver recipients with upfront NMP demonstrated a reduced rate of early allograft dysfunction (EAD) and post-reperfusion syndrome (PRS). Additionally, the authors describe lower ischemic cholangiopathy (IC) rates in DCD grafts when upfront NMP was used. Overall and major biliary complications, such as non-anastomotic biliary strictures (NAS), which Yamamoto et al. defined as IC, are highly relevant and often the primary factors limiting the higher utilization of DCD livers. Despite the growing excitement, it is key to delve into “real world” outcomes of NMP in clinical practice to fully understand its implications and optimize its use.

Yamamoto et al.’s findings echo previous studies, affirming the potential of NMP, both upfront and back-to-base (i.e., NMP after SCS during transport), to mitigate EAD and improve other 3-month outcomes (2-5). However, we harbor reservations regarding the methodologies employed in this study and propose avenues for future scientific exploration.

Primarily, the study would have benefited from more standardized reporting of results. Yamamoto et al. compared 1-, 3- and 5-year outcomes between SCS and upfront NMP approaches, using the TransMedics OCS^® system (1). Discrepancies exist in exposure times to post-operative complications between the study groups, with OCS^® cases inherently conducted later in the study period. At time of publication, many cases may have conceivably had less than 1 year posttransplant follow-up, as the TransMedics OCS^® was not approved for clinical use until late 2021 (6). This temporal imbalance could skew results, notably impacting the NMP cohort. Finally, the sample size in the DCD cohort was quite small, particularly the control cohort (DCD-SCS n=20). Thus, drawing definite conclusions about the impact of NMP is challenging (Table 1).

Furthermore, the study lacks standardized reporting of complications using validated metrics, including the Clavien-Dindo Classification or Comprehensive Complications Index (12-14).

Prior works have emphasized these metrics specifically in machine perfusion research, as they are directly linked to long-term outcomes and costs of medical care. This concern is pivotal in navigating the advancement of this promising yet costly technology (15). Standardized reporting of donor/recipient risk and outcomes would facilitate cross-study comparisons.

In addition, incorporating liver transplantation-specific metrics, so called Core Outcome Sets (COS), defined in previous benchmarking studies could enrich posttransplant outcome assessment (16,17). Detailed reporting of complications, including anastomotic strictures (AS), NAS, vascular complications, post-transplant renal-replacement therapy, and acute rejection would enhance reproducibility and comparability across studies with different preservation techniques.

For instance, NAS represents an objective and clinically-relevant outcome directly linked to donor and graft risk. Its inclusion in reporting with enough detail would enhance comparability with future studies. While Yamamoto et al. reported IC rates, it does not distinguish them from bile leaks, complicating interpretation. Moreover, although graft loss is documented, the specific causes are not detailed, which would provide valuable insight. This critique aims not to question the validity of the findings, but to underscore the challenge to replicate research lacking standardized definitions and relying on panel judgement. This study is not alone in its variable outcome reporting; indeed, all available 11 randomized controlled trials (RCTs) on machine perfusion have reported different sets of “most important” outcomes for liver transplantation, assessed at varying time-points (2-4,18-26). We encourage Yamamoto et al. to conduct an updated analysis incorporating benchmark outcomes to facilitate comparisons with future research endeavors.

Despite the study’s focus on standard risk cohorts within benchmark criteria, elucidating outcomes comparisons between groups is challenging due to inherent differences in patient characteristics and procedural factors (16,17).

The authors assert that OCS enables them to transplant higher-risk livers (both extended-criteria DBD and DCDs), citing previous trials supporting this claim. However, the data from this study indicate that both groups generally fall within benchmark criteria.

Given the differences between study groups (SCS vs. NMP), including preservation time, hepatitis C status, distance from hospital (DCD-grafts) and high-risk donor status, it is difficult to make reasonable comparisons. Additional risk scores for donor and recipient risk [Donor Risk Index (DRI) (27), balance-of-risk (BAR) (28,29), or UK-DCD (30)] and/or propensity score matching (or similar) could help ensure equal risk distribution among study cohorts.

While the findings in this study are intriguing, they also raise concerns about resource utilization. TransMedics OCS^® offers various “service packages”, including organ recovery specialists. Were these utilized in the study? Additionally, the authors do not address the cost of these services, which is a significant limitation for many hospitals nationwide. Recent work using a risk-matched approach has demonstrated that back-to-base NMP is associated with improved short-term outcomes without increasing medical care costs (5). We encourage the authors to conduct a thorough cost analysis comparing care under SCS and upfront NMP. Such an analysis has not yet been published and should compare short- and long-term cost viability of different NMP approaches.

Given that both arms of the study demonstrated similar graft and patient survival, a less costly approach might be necessary for most hospitals. EAD is commonly used yet is not strongly linked to definitive patient outcomes. Thus, a more expensive approach to NMP that improves EAD but does not affect long term outcomes, might not be cost-justified. Dutkowski et al. noted that surrogate markers of liver injury such as transaminase release should not be used as primary endpoint, because their correlation with outcomes, especially in DCD liver grafts, is inconsistent (15). They also stated that “defining liver graft dysfunction based on peak transaminases combined with later (e.g., 7-day) single levels of the international normalized ratio and bilirubin at arbitrary cut-off points must be avoided in perfusion trials” (15). The Boston group should be commended for their approach in the PROTECT trial, which investigated the association of EAD with longer-term outcomes (2). However, since EAD frequently resolves, improving EAD alone might not lead to significantly better patient outcomes and could be quite costly depending on the specific NMP technique applied. Therefore, conducting a cost analysis would be highly beneficial, and we encourage the authors to pursue this as described.

The Yamamoto study advocates that upfront NMP can improve outcomes, particularly NAS, while end-ischemic NMP cannot (1). They cite a case involving 3,000 miles of travel to procure a liver graft, noting it was only feasible due to the device-to-donor aspect (upfront NMP). However, to date, only two studies comparing upfront and end-ischemic NMP with subsequent liver transplantation have been published, which showed no difference in outcomes for within-benchmark liver grafts (8,9). The assertion that upfront outperforms end-ischemic NMP is based on extrapolations of biliary complication rates from studies involving different donor and recipient risk and allocation systems on different continents. Additionally, these studies have had varied outcome measures and follow-up periods. We believe this conclusion is problematic, as it may influence national practice based on comparisons of fundamentally dissimilar studies.

The discussion of NMP outcomes (upfront/device-to-donor vs. back-to-base) raises questions about the future of perfusion with the potential advent of hypothermic oxygenated perfusion (HOPE). Studies from the US and Europe have demonstrated that HOPE can reduce NAS-rates despite equivalent cold ischemic time (CIT) in the SCS and HOPE groups (7,22,31). This occurs secondary to the protective effect of oxygen reintroduction at hypothermic temperatures, which reduces reactive oxygen species (ROS) and protects from mitochondrial damage. Such a protective mechanism has not been demonstrated in NMP, leaving the reason for a reduction in NAS unclear. The authors hypothesize that this is secondary to a reduction in CIT between groups. We argue that this study does not provide clear evidence that OCS offers benefits other than reducing CIT, which is certainly valuable. We encourage future studies to compare transplants with OCS and SCS with similar CIT, to assess whether ischemic time, perfusion, or both impact clinical outcomes.

The study raises the intriguing point regarding graft “non-use” due to rising perfusate lactate levels (n=5) and other concerning viability testing. We commend the authors for reporting this and for their willingness to discard grafts during perfusion, as viability assessment is one of the most promising benefits of machine perfusion. It is also important to note that the discarded grafts were from DCD donors, pointing towards increased risk and reperfusion injury despite short SCS prior to NMP. We also emphasize the need for robust markers for viability assessment as they are generally lacking. Of note, primary nonfunction and graft loss due to NAS were reported by others despite passing all traditional viability tests (including lactate clearance), particularly when risk factors exceeded benchmark criteria (10,11,32,33). Developing and validating both traditional and new markers will enable the safe increase in the use of organs traditionally deemed unsuitable.

Flavin-mononucleotide (FMN), a marker of mitochondrial injury, has been described for viability assessment during machine perfusion (34,35). Other clinical, perfusate and bile parameters have also been described, but few have been validated. Only the VITTAL trial has prospectively used most of such traditional criteria to assess liver injury (10,11,34-42). These studies highlight that factors beyond warm and CITs play a role, such as the underlying metabolic quality of the liver, which affects its resistance to transplant injury. This inherent quality is often unmeasured and underappreciated in most studies on machine perfusion, potentially explaining why the “ideal” CIT contributing to NAS varies widely between studies (4, 6 and even 8 hours), as livers likely have different levels of tolerable ischemic injury. Yamamoto et al. are in an excellent position to lead the field of viability assessment given their extensive experience with NMP. We hope that future studies from this group will advance this specific field to the next generation.

In summary, we thank and commend the Boston group for their ongoing hard work on this challenging but critical topic. We look forward to follow-up studies addressing further important points, including cost-effectiveness, viability assessment, and more. We hope that future or adjunct studies will employ techniques for risk-matching, as current comparisons have not involved groups with similar known risk factors. Additionally, they might consider assessing the impact of the OCS device in outside-benchmark cases, and reporting outcomes using a more standardized and rigorous approach. Upfront and back-to-base perfusion are both highly interesting topics, and we are eager to see how the field develops in the coming years. Along with the introduction of HOPE technology, each study raises new questions, and ongoing re-assessment is key to improving patient care.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-301/coif). A.S. is a consultant to Bridge to Life Inc. to support participating centers during the randomized controlled trial on hypothermic oxygenated perfusion in liver transplantation. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Yamamoto T, Atthota S, Agarwal D, et al. Impact of Portable Normothermic Machine Perfusion for Liver Transplantation From Adult Deceased Donors. Ann Surg 2023;278:e922-9. [Crossref] [PubMed]
2. Markmann JF, Abouljoud MS, Ghobrial RM, et al. Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial. JAMA Surg 2022;157:189-98. [Crossref] [PubMed]
3. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018;557:50-6. [Crossref] [PubMed]
4. Chapman WC, Barbas AS, D'Alessandro AM, et al. Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States: A Randomized Controlled Trial. Ann Surg 2023;278:e912-21. [Crossref] [PubMed]
5. Wehrle CJ, Zhang M, Khalil M, et al. Impact of Back-to-Base Normothermic Machine Perfusion on Complications and Costs: A Multi-Center, Real-World Risk-Matched Analysis. Ann Surg 2024; Epub ahead of print. [Crossref] [PubMed]
6. Premarket Approval (PMA) - Organ Care System (OCS™) Liver, in Normothermic machine perfusion system for the preservation of donor livers prior to transplantation, U.F.a.D. Administration, Editor. 2021: Product Code QQK. available online: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P200031
7. Parente A, Tirotta F, Pini A, et al. Machine perfusion techniques for liver transplantation - A meta-analysis of the first seven randomized-controlled trials. J Hepatol 2023;79:1201-13. [Crossref] [PubMed]
8. Bral M, Dajani K, Leon Izquierdo D, et al. A Back-to-Base Experience of Human Normothermic Ex Situ Liver Perfusion: Does the Chill Kill? Liver Transpl 2019;25:848-58. [Crossref] [PubMed]
9. Ceresa CDL, Nasralla D, Watson CJE, et al. Transient Cold Storage Prior to Normothermic Liver Perfusion May Facilitate Adoption of a Novel Technology. Liver Transpl 2019;25:1503-13. [Crossref] [PubMed]
10. Mergental H, Laing RW, Kirkham AJ, et al. Discarded livers tested by normothermic machine perfusion in the VITTAL trial: Secondary end points and 5-year outcomes. Liver Transpl 2024;30:30-45. [Crossref] [PubMed]
11. Mergental H, Laing RW, Kirkham AJ, et al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun 2020;11:2939. [Crossref] [PubMed]
12. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187-96. [Crossref] [PubMed]
13. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13. [Crossref] [PubMed]
14. Slankamenac K, Graf R, Barkun J, et al. The comprehensive complication index: a novel continuous scale to measure surgical morbidity. Ann Surg 2013;258:1-7. [Crossref] [PubMed]
15. Dutkowski P, Guarrera JV, de Jonge J, et al. Evolving Trends in Machine Perfusion for Liver Transplantation. Gastroenterology 2019;156:1542-7. [Crossref] [PubMed]
16. Muller X, Marcon F, Sapisochin G, et al. Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results. Ann Surg 2018;267:419-25. [Crossref] [PubMed]
17. Schlegel A, van Reeven M, Croome K, et al. A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation. J Hepatol 2022;76:371-82. [Crossref] [PubMed]
18. Ghinolfi D, Rreka E, De Tata V, et al. Pilot, Open, Randomized, Prospective Trial for Normothermic Machine Perfusion Evaluation in Liver Transplantation From Older Donors. Liver Transpl 2019;25:436-49. [Crossref] [PubMed]
19. van Rijn R, Schurink IJ, de Vries Y, et al. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial. N Engl J Med 2021;384:1391-401. [Crossref] [PubMed]
20. Czigany Z, Pratschke J, Froněk J, et al. Hypothermic Oxygenated Machine Perfusion Reduces Early Allograft Injury and Improves Post-transplant Outcomes in Extended Criteria Donation Liver Transplantation From Donation After Brain Death: Results From a Multicenter Randomized Controlled Trial (HOPE ECD-DBD). Ann Surg 2021;274:705-12. [Crossref] [PubMed]
21. Ravaioli M, Germinario G, Dajti G, et al. Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial. Am J Transplant 2022;22:2401-8. [Crossref] [PubMed]
22. Schlegel A, Mueller M, Muller X, et al. A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation. J Hepatol 2023;78:783-93. [Crossref] [PubMed]
23. Brüggenwirth IMA, Lantinga VA, Lascaris B, et al. Prolonged hypothermic machine perfusion enables daytime liver transplantation - an IDEAL stage 2 prospective clinical trial. EClinicalMedicine 2024;68:102411. [Crossref] [PubMed]
24. Panayotova GG, Lunsford KE, Quillin RC 3rd, et al. Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial. Hepatology 2024;79:1033-47. [Crossref] [PubMed]
25. Grąt M, Morawski M, Zhylko A, et al. Routine End-ischemic Hypothermic Oxygenated Machine Perfusion in Liver Transplantation From Donors After Brain Death: A Randomized Controlled Trial. Ann Surg 2023;278:662-8. [Crossref] [PubMed]
26. Czigany Z, Uluk D, Pavicevic S, et al. Improved outcomes after hypothermic oxygenated machine perfusion in liver transplantation-Long-term follow-up of a multicenter randomized controlled trial. Hepatol Commun 2024;8:e0376. [Crossref] [PubMed]
27. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6:783-90. [Crossref] [PubMed]
28. Dutkowski P, Oberkofler CE, Slankamenac K, et al. Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the model for end-stage liver disease era. Ann Surg 2011;254:745-53; discussion 753. [Crossref] [PubMed]
29. Dutkowski P, Schlegel A, Slankamenac K, et al. The use of fatty liver grafts in modern allocation systems: risk assessment by the balance of risk (BAR) score. Ann Surg 2012;256:861-8; discussion 868-9. [Crossref] [PubMed]
30. Schlegel A, Kalisvaart M, Scalera I, et al. The UK DCD Risk Score: A new proposal to define futility in donation-after-circulatory-death liver transplantation. J Hepatol 2018;68:456-64. [Crossref] [PubMed]
31. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation facilitates successful transplantation of "orphan" extended criteria donor livers. Am J Transplant 2015;15:161-9. [Crossref] [PubMed]
32. Patrono D, De Carlis R, Gambella A, et al. Viability assessment and transplantation of fatty liver grafts using end-ischemic normothermic machine perfusion. Liver Transpl 2023;29:508-20. [Crossref] [PubMed]
33. Watson CJE, Gaurav R, Swift L, et al. Bile Chemistry During Ex Situ Normothermic Liver Perfusion Does Not Always Predict Cholangiopathy. Transplantation 2024;108:1383-93. [Crossref] [PubMed]
34. Eden J, Breuer E, Birrer D, et al. Screening for mitochondrial function before use-routine liver assessment during hypothermic oxygenated perfusion impacts liver utilization. EBioMedicine 2023;98:104857. [Crossref] [PubMed]
35. Schlegel A, Muller X, Mueller M, et al. Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation. EBioMedicine 2020;60:103014. [Crossref] [PubMed]
36. Sutton ME. Criteria for viability assessment of discarded human donor livers during ex vivo normothermic machine perfusion. PLoS One 2014;9:e110642. [Crossref] [PubMed]
37. Watson CJE, Kosmoliaptsis V, Pley C, et al. Observations on the ex situ perfusion of livers for transplantation. Am J Transplant 2018;18:2005-20. [Crossref] [PubMed]
38. Matton APM, de Vries Y, Burlage LC, et al. Biliary Bicarbonate, pH, and Glucose Are Suitable Biomarkers of Biliary Viability During Ex Situ Normothermic Machine Perfusion of Human Donor Livers. Transplantation 2019;103:1405-13. [Crossref] [PubMed]
39. van Leeuwen OB, de Vries Y, Fujiyoshi M, et al. Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion: A Prospective Clinical Trial. Ann Surg 2019;270:906-14. [Crossref] [PubMed]
40. Thorne AM, Wolters JC, Lascaris B, et al. Bile proteome reveals biliary regeneration during normothermic preservation of human donor livers. Nat Commun 2023;14:7880. [Crossref] [PubMed]
41. Muller X, Schlegel A, Kron P, et al. Novel Real-time Prediction of Liver Graft Function During Hypothermic Oxygenated Machine Perfusion Before Liver Transplantation. Ann Surg 2019;270:783-90. [Crossref] [PubMed]
42. Sousa Da Silva RX, Darius T, Mancina L, et al. Real-time assessment of kidney allografts during HOPE using flavin mononucleotide (FMN) — a preclinical study. Front Transplant 2023;2:1132673. [Crossref] [PubMed]