Introduction
In 2022, a record 9,527 liver transplants (LTs) were performed in the United States, while a remarkable number of 12,862 additional candidates were added to the waiting list (1, 2). Despite the tremendous disparity between the number of waitlist patients and available organs, donation after circulatory death (DCD) livers remained underutilized compared to donation after brain death (DBD) livers. Only 11.3% of adult liver transplants in 2022 were performed with DCD livers (1, 2). The rates of “recovered but not transplanted” livers, often interpreted as discarded livers, were much higher in DCD compared to DBD (26.8% vs 7.2%) allografts. However, studies have shown that up to 50% of these discarded allografts may be suitable for transplantation (3, 4).
The rationale behind DCD underutilization stems from the concern that DCD allografts are more susceptible to ischemia-reperfusion injury and ischemic biliary complications impacting graft and patient survival, particularly in high-risk recipients (5). A previous cohort study found that DCD LTs in the subgroup of patients with higher MELD have worse graft survival compared to DBD LTs (6). However, with appropriate donor and recipient selection, acceptable outcomes can be achieved as demonstrated in the single-center study by Meier et al (7). The authors compared the outcomes of DCD LT for recipients with MELD ≥35 to a propensity-matched cohort of DBD-LTs. DCD organ acceptance was restricted to high-quality donors with age ≤40 years, graft steatosis ≤10-15%, and warm ischemia time (WIT) of ≤30 minutes. With these predetermined criteria, the 5-year patient survival for the DCD-LT cohort was comparable to DBD LT (85% vs 86%, p=0.843) (7). While noninferiority was demonstrated, only 41 DCD allografts were used compared to 1767 DBD allografts during a 30+ year period. Furthermore, we challenge the clinical implications of this conclusion in addressing the organ shortage given the current shift from static to dynamic liver preservation.
Donor and recipient risk
Extrapolating from the author’s selection criteria, no UK DCD risk-defined “futile” livers were utilized. The DCD allografts that were transplanted would be stratified into low or high-risk groups, which would yield a predicted survival of >85% in selected recipients (8). Furthermore, these allografts were not considered in complex recipients such as those with portal vein thromboses or those requiring retransplantation. It is also important to note that waitlist mortality and dropouts during the study period were not insignificant as illustrated in Supplementary Figure 1 of the original manuscript. Considering that over 80% of candidates who die on the waitlist decline at least one marginal liver offer before death, granular data regarding the number of DCD offers declined for these recipients in the current study would be important in this context (9). Whether to accept a high-risk DCD liver or wait for a potential DBD offer is a difficult decision for transplant providers to make in the real-world clinical setting. In a national registry study, only 56.3% of MELD ≥35 recipients who previously declined a DCD offer ended up getting transplanted with a DBD allograft. The remaining 43% of those patients either died, dropped out, or were removed for other reasons (10). On the contrary, accepting a DCD liver, even from higher-risk donors, as evidenced by the subgroup analysis on DCD livers from donors age≥ 50, BMI≥30, and with a medical history of DM or HTN, lowers mortality risk compared to remaining on the waitlist, with the greatest survival benefit seen in the higher acuity recipients (10, 11).
DCD liver transplantation in the era of machine perfusion
As the authors alluded to, improvements in organ procurement and preservation techniques will have implications in addressing the disparity between organ supply and demand while maintaining acceptable outcomes even in higher risk recipients. Organ perfusion strategies currently applied in the clinical setting include in situ normothermic regional perfusion (NRP), ex-situ hypothermic oxygenated perfusion (HOPE) or ex-situ normothermic machine perfusion (NMP). Compared to static cold storage (SCS), these modalities have all been shown in randomized clinical trials and cohort studies to reduce the incidence of early allograft dysfunction, post-reperfusion syndrome, and ischemic cholangiopathy in DCD-LT (12–17). Furthermore, all modalities provide a platform for viability assessment, allowing for safe transplantation of previously discarded allografts (16, 18, 19).
With amelioration of ischemia-reperfusion injury and its downstream effects, utilization of marginal allografts in high-risk recipients should be considered a viable option in the era of machine perfusion. In the Normothermic Machine Perfusion of the Liver to Enable the high-risk recipients (NAPLES) project, Hann et al. described the short-term outcomes of transplanting suboptimal grafts preserved on NMP into retransplant recipients. No differences were found in 6-month graft and patient survival compared to allografts preserved in SCS (20). Similar conclusions were drawn in another study of recipients age ≥65 years, whereby the NMP group exhibited significantly lower operative time and inpatient complications (21). In clinical practice, historically deemed high-risk or futile DCD allografts preserved on NMP have been utilized for high-risk recipients including those with complex abdominal surgical history, high grade portal vein thrombus, and MELD ≥35, but robust data have yet to be published.
Discussion
Balancing donor and recipient risk while considering the limited availability of organs remains a complex challenge. The authors have demonstrated conservative efforts to improve utilization of DCD grafts for high-risk recipients. Efforts to expand the donor pool will continue to drive the growth of DCD-LT performed in the US, and innovative perfusion technology provides a safe platform for rapid expansion (22).
The highest available evidence has demonstrated with high level certainty that when compared to SCS, HOPE significantly reduces serious complications, retransplantation rates, and improves graft survival and both HOPE and NMP improves overall biliary complications and non-anastomotic biliary strictures (23–25). Most of the trials included in these meta-analyses included extended criteria-DBD or DCD grafts. Currently, no trials have focused on comparing machine perfusion to SCS in high-risk recipients, but ensuring equipoise in such a trial design would be difficult given the evidenced benefits of machine perfusion in liver transplantation. Despite that, differences in regional factors and center policy as well as logistical and financial barriers prevent widespread clinical adoption. Standardized and robust reporting of more granular transplant clinical data as well as collaboration among device companies, clinicians, and regulators will be essential. Addressing these issues will allow centers to learn from the existing experience, and successfully increase utilization of DCD and other marginal donor grafts, ultimately providing timely access to transplant and reduce the waitlist mortality for recipients.
Statements
Author contributions
MN: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. XL: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. KR: Writing – review & editing. AM: Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
KwongAJKimWRLakeJRSchladtDPSchnellingerEMGaunttKet al. OPTN/SRTR 2022 Annual Data Report: Liver. Am J Transplantation. (2024) 24:S176–265. doi: 10.1016/j.ajt.2024.01.014
2
IsraniAKZaunDAGaunttKSchaffhausenCRLozanoCMcKinneyWTet al. OPTN/SRTR 2022 Annual Data Report: Deceased Organ Donation. Am J Transplantation. (2024) 24:S457–88. doi: 10.1016/j.ajt.2024.01.018
3
EdenJSousa Da SilvaRCortes-CerisueloMCroomeKDe CarlisRHessheimerAJet al. Utilization of livers donated after circulatory death for transplantation - An international comparison. J Hepatol. (2023) 78:1007–16. doi: 10.1016/j.jhep.2023.01.025
4
MarconFSchlegelABartlettDCKalisvaartMBishopDMergentalHet al. Utilization of declined liver grafts yields comparable transplant outcomes and previous decline should not be a deterrent to graft Use. Transplantation. (2018) 102:e211–8. doi: 10.1097/TP.0000000000002127
5
FoleyDPFernandezLALeversonGAndersonMMezrichJSollingerHWet al. Biliary complications after liver transplantation from donation after cardiac death donors: an analysis of risk factors and long term outcomes from a single center. Ann Surgery. (2011) 253:817–25. doi: 10.1097/SLA.0b013e3182104784
6
SastryVPandyaKPanlilioMWestCVirtueSWellsMet al. IDDF2019-ABS-0196 Long term outcomes of utilizing donation after circulatory death grafts in liver transplantation – an australian 12-year cohort study. Gut. (2019) 68:A8–8. doi: 10.1136/gutjnl-2019-IDDFAbstracts.14
7
MeierRPHNunezMSyedSMFengSTavakolMFreiseCEet al. DCD liver transplant in patients with a MELD over 35. Front Immunol. (2023) 14:1246867. doi: 10.3389/fimmu.2023.1246867
8
SchlegelAKalisvaartMScaleraILaingRWMergentalHMirzaDFet al. The UK DCD Risk Score: A new proposal to define futility in donation-after-circulatory-death liver transplantation. J Hepatology. (2018) 68:456–64. doi: 10.1016/j.jhep.2017.10.034
9
LaiJCFengSRobertsJP. An examination of liver offers to candidates on the liver transplant wait-list. Gastroenterology. (2012) 143:1261–5. doi: 10.1053/j.gastro.2012.07.105
10
IshaqueTEaglesonMABowringMGMotterJDYuSLuoXet al. Transplant candidate outcomes after declining a DCD liver in the United States. Transplantation. (2023) 107:e339–47. doi: 10.1097/TP.0000000000004777
11
McLeanKACamilleri-BrennanJKnightSRDrakeTMOtsRShawCAet al. Decision modeling in donation after circulatory death liver transplantation. Liver Transplantation. (2017) 23:594. doi: 10.1002/lt.24715
12
van RijnRSchurinkIJde VriesYvan den BergAPCortes CerisueloMDarwish MuradSet al. Hypothermic Machine Perfusion in Liver Transplantation — A Randomized Trial. New Engl J Med. (2021) 384:1391–401. doi: 10.1056/NEJMoa2031532
13
NasrallaDCoussiosCCMergentalHAkhtarMZButlerAJCeresaCDLet al. A randomized trial of normothermic preservation in liver transplantation. Nature. (2018) 557:50–6. doi: 10.1038/s41586-018-0047-9
14
MarkmannJFAbouljoudMSGhobrialRMBhatiCSPelletierSJLuADet al. Impact of portable normothermic blood-based machine perfusion on outcomes of liver transplant. JAMA Surgery. (2022) 157:189–98. doi: 10.1001/jamasurg.2021.6781
15
YamamotoTAtthotaSAgarwalDCrisalliKMacConmaraMNakamuraTet al. Impact of portable normothermic machine perfusion for liver transplantation from adult deceased donors. Ann Surgery. (2023) 278:e922. doi: 10.1097/SLA.0000000000006032
16
SchurinkIJde GoeijFHCHabetsLJMvan de LeemkolkFEMvan DunCAAOniscuGCet al. Salvage of declined extended-criteria dcd livers using in situ normothermic regional perfusion. Ann Surgery. (2022) 276:e223–30. doi: 10.1097/SLA.0000000000005611
17
BrubakerALSellersMTAbtPLCroomeKPMeraniSWallAet al. US liver transplant outcomes after normothermic regional perfusion vs standard super rapid recovery. JAMA Surg. (2024) 159:677–85. doi: 10.1001/jamasurg.2024.0520
18
WatsonCJEGauravRFearCSwiftLSelvesLCeresaCDLet al. Predicting early allograft function after normothermic machine perfusion. Transplantation. (2022) 106:2391–8. doi: 10.1097/TP.0000000000004263
19
MergentalHLaingRWKirkhamAJPereraMTPRBoteonYLAttardJet al. Transplantation of discarded livers following viability testing with normothermic machine perfusion. Nat Commun. (2020) 11:2939. doi: 10.1038/s41467-020-16251-3
20
HannALembachHNutuALembachHNutuADassanayakeBTillakaratneSMcKaySCet al. Outcomes of normothermic machine perfusion of liver grafts in repeat liver transplantation (NAPLES initiative). Br J Surgery. (2022) 109:372–80. doi: 10.1093/bjs/znab475
21
ShubinADFeizpourCAHwangCSHanishSIRaschzokNWangBKet al. Normothermic machine perfusion for older transplant recipients. Artif Organs. (2023) 47:1184–91. doi: 10.1111/aor.14519
22
CroomeKPMaoSTanerCB. The current landscape of liver transplantation after ex situ machine perfusion and normothermic regional perfusion in the united states. Liver Transplantation. (2022) 28:1108. doi: 10.1002/lt.26404
23
ParenteATirottaFPiniAEdenJDondossolaDManziaTMet al. Machine perfusion techniques for liver transplantation - A meta-analysis of the first seven randomized-controlled trials. J Hepatol. (2023) 79:1201–13. doi: 10.1016/j.jhep.2023.05.027
24
TangGZhangLXiaLZhangJWeiZZhouR. Hypothermic oxygenated perfusion in liver transplantation: a meta-analysis of randomized controlled trials and matched studies. Int J Surg. (2024) 110:464–77. doi: 10.1097/JS9.0000000000000784
25
TingleSJDobbinsJJThompsonERFigueiredoRSMahendranBPandanaboyanaSet al. Machine perfusion in liver transplantation. Cochrane Database Syst Rev. (2023) 9:CD014685. doi: 10.1002/14651858.CD014685.pub2
Summary
Keywords
DCD liver transplantation, machine perfusion (MP), high-risk recipients, donor risk index, recipient outcomes
Citation
Nguyen MC, Li X, Reddy KS and Mathur AK (2024) Commentary: DCD liver transplant in patients with a MELD over 35. Front. Immunol. 15:1404948. doi: 10.3389/fimmu.2024.1404948
Received
21 March 2024
Accepted
24 June 2024
Published
11 July 2024
Volume
15 - 2024
Edited by
Jianing Fu, Columbia University, United States
Reviewed by
Naoki Tanimine, National Hospital Organization Kure Medical Center, Japan
Shao-wei Li, Taizhou Hospital Affiliated to Wenzhou Medical University, China
Wenyu Jiao, Tsinghua University, China
Updates
Copyright
© 2024 Nguyen, Li, Reddy and Mathur.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Michelle C. Nguyen, nguyen.michelle3@mayo.edu
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.