American Journal of Transplantation 2014; 14: 1016–1020 Wiley Periodicals Inc.
Personal Viewpoint
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12697
Improving Outcomes in DCDD Liver Transplantation: There Can Only Be Strength in Numbers D. S. Goldberg1,2,* and P. L. Abt3 1
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 2 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 3 Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA Corresponding author: David S. Goldberg, [email protected]
In the United States, liver transplantation using donation after circulatory determination of death (DCDD) donors is challenged by persistently inferior graft survival compared with donation after neurological death (DND), along with declining rates of liver transplantation relative to the total number of DCDD donors. Advances in adult-to-adult living donor liver transplantation graft survival temporally related to the Adult-to-Adult Living Donor Liver Transplantation Cohort Study consortium suggest that a similarly focused collaborative effort may serve to stimulate evolution within DCDD liver transplantation. Without a multi-center consortium to support innovative trials, the current state of DCDD liver transplantation is unlikely to progress. Keywords: A2ALL, donor selection, ex vivo perfusion, living donor liver transplantation, warm ischemia Abbreviations: A2ALL, Adult-to-Adult Living Donor Liver Transplantation Cohort Study; AALDLT, adultto-adult living donor liver transplantation; CMS, Center for Medicare and Medicaid Services; DCDD, donation after circulatory determination of death; DND, donation after neurological death; LDLT, living donor liver transplantation; OPO, organ procurement organization; SRTR, Scientific Registry of Transplant Recipients Received 12 December 2013, revised 21 January 2014 and accepted for publication 04 February 2014
Introduction The persistent mismatch between supply and demand for liver transplantation has led the transplant community to consider expanding the pool of potential organ donors. In 1016
2003, the US Organ Donation Breakthrough Collaborative promulgated transplantation of allografts from donation after circulatory determination of death (DCDD) donors as one potential strategy to increase the donor supply (1). Subsequent to the collaborative, the number of DCDD liver recipients increased fourfold to fivefold, with the overall proportion of transplants from DCDD livers increasing from 1–1.5% to 5–5.5% (2). However, since 2005, the number of transplanted DCDD liver allografts has remained stagnant. There is well-recognized morbidity from DCDD liver transplantation, which includes biliary complications and increased incidence of re-transplantation (3–6). While national data on all US DCDD recipients using data from the Scientific Registry of Transplant Recipients (SRTR) have demonstrated inferior patient and graft survival among DCDD recipients (5), single-center studies from the United States (6,7), the Netherlands (3) and the United Kingdom (8) have demonstrated comparable patient and graft survival in select DCDD recipients. While the potential increased risk of morbidity and mortality associated with DCDD grafts compared with allografts from donation after neurological death (DND) has stymied efforts to broaden consideration of these organs for transplantation, the success of select centers demonstrates that potential exists to utilize these organs as a means to ultimately decrease waitlist mortality (1). We contend that the current state of DCDD liver transplantation will not advance without a focused initiative.
Background/Scope of the Problem Single-center case series have reported variable levels of success (3,4,6,7,9). Nearly all centers report a significantly increased risk of biliary complications, particularly ischemic cholangiopathy, with a 2.4 increased odds of biliary complications, and 10.8 times increased odds of ischemic cholangiopathy (4,5,10–12), yet posttransplant patient and graft survival rates have varied. Several US (6,7) and British (8) centers have reported comparable posttransplant patient and graft survival, while other centers in the United States (5) and the United Kingdom (9) report inferior survival. Delineation of the problems following DCDD liver transplantation has been robust; however, there has only been a modest advancement in our understanding of the contributors to graft failure and biliary complications. Differences in outcomes may be related to differences in donor selection and restrictive donor criteria based on donor age, BMI, hypotension and cold and warm ischemia
DCDD Transplantation
time (3), recipient selection based on factors that include severity of illness at transplantation or history of prior surgeries (7) or varying techniques for in vivo or ex vivo perfusion (13–16). However, without a collaborative, multicenter consortium, the cause of such differences cannot be fully elucidated. This lack of progress is reflected by DCDD graft survival, which has been immutable over the last decade (Figure 1A). The state of the field is also exposed by the increasing rate of DCDD donors from whom a DCDD liver is not transplanted (17) (Figure 2). Many parallels can be drawn to the field of DCDD transplantation today and adult-to-adult living donor liver transplantation (AALDLT) 10–15 years ago. Sample sizes at any one center are limited, national data
lack the granularity to develop effective risk models, donor management practices vary across organ procurement organizations (OPOs) and transplant centers use a diverse set of criteria to select donors and recipients. Without broader cooperation among OPOs, transplant centers and investigators through a centralized mechanism, DCDD liver outcomes and utilization rates are unlikely to advance.
Adult-to-Adult Living Donor Liver Transplantation Cohort Study and the Progress of AALDLT The first reported AALDLT in the United States was in 1998, with early case series drawing from single centers, which were focused on the technical aspects of the donor and
Figure 1: (A) Changes in unadjusted post-DCDD graft survival over time. (B) Changes in unadjusted post-LDLT graft survival over time. DCDD, donation after circulatory determination of death; LDLT, living donor liver transplantation.
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Figure 2: (A) Number of donation after circulatory determination of death (DCDD) liver transplants per year in the United States, 2002–2012. (B) DCDD liver donors per year relative to all DCDD donors.
recipient operation. Initial retrospective multi-center series from the United States demonstrated inferior outcomes in right lobe grafts from living donors compared with whole grafts from deceased donors (18,19). The limited number of AALDLTs at individual centers and inadequate granularity among data collected by the United Network for Organ Sharing stood as impediments to the advancement of AALDLT. Due to these recognized limitations of national data, and the need to address several important questions, including the risks of the procedure for the donor, donor and recipient quality of life, ethics of the procedure and the science of hepatic regeneration, the National Institute of Diabetes and Digestive and Kidney Diseases published a 1018
request for applications to fund a multi-center cohort study that was the genesis of Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) (20). The governing structure of A2ALL consists of a central oversight committee with multiple subcommittees that meet regularly to review research proposals and monitor ongoing studies. The initial cohort included nine centers, with data collected retrospectively from each center. Subsequently, data accrual became prospective, and the number of centers expanded to include 13 in North America (21). Investigations by A2ALL have covered multiple topics, prominent among them being: (1) recipient American Journal of Transplantation 2014; 14: 1016–1020
DCDD Transplantation
selection and surgical complications; (2) identification of recipient survival benefit in relation to the Model for EndStage Liver Disease score; (3) donor selection; (4) donor quality of life; and (5) technical aspects of both recipient and donor operations. Ongoing studies will enhance an understanding of the molecular events surrounding liver regeneration and the pathophysiology of small-for-size syndrome. Findings derived from the A2ALL consortium have been distributed to the transplant community in scientific forums, 22 peer-reviewed publications and through the A2ALL website (21). Substantial progress in outcomes among AALDLT recipients in the United States over the last 10 years is evident (Figure 1B), although direct quantification of the role of A2ALL in advancing and contributing to this success is not possible. However, these advances have occurred against a backdrop of decreased utilization of living donor liver transplantations (LDLTs) nationally. The decreased use of LDLTs is most likely attributable to three well-publicized donor deaths since 2002, coupled with growing concern over donor safety, and unrelated to the A2ALL consortium. Nonetheless, improved outcomes may have come at the expense of overall decreased usage of LDLTs secondary to a more conservative stance by transplant centers. A focus of any DCDD consortium should be to optimize the current pool of DCDD grafts, while also developing techniques to utilize the increasing proportion of discarded organs. One potential mechanism might be to conduct several clinical trials within the context of the consortium with provisions by Center for Medicare and Medicaid Services (CMS) and the SRTR that outcomes derived from patients enrolled in these trials would not contribute to center-specific reports. In doing so, scientific exploration and examination of different medical and surgical techniques can be fostered without concern of flagging by regulatory bodies such as CMS or the SRTR.
Potential Research Agenda and Proposal High rates of DCDD liver discard, stagnant numbers of DCDD transplants and inferior graft outcomes when juxtaposed to DND transplantation evidence the necessity for focused research and exploration on several topics. These potential research areas can be grouped into several areas (Table 1), broadly focusing on optimizing donor graft management both in vivo and ex vivo, shared best practices and selecting appropriate recipients for DCDD transplants. Additional policy considerations that should be explored by the consortium would be ethical issues of management of potential DCDD donors, and benchmarking of center and OPO performance. These research areas overlap in many ways, and must be integrated with one another. For example, while a major goal should be to test new predonation and postdonation techniques to improve graft function, these must be coupled with exploration into donor-recipient matching and identification of the ideal recipients for such DCDD donors. Akin to AALDLT and the development of the A2ALL consortium, we suggest the creation of a National Institutes of Health–funded multi-center study group consisting of OPOs, transplant centers and investigators knowledgeable in DCDD with the singular goal of advancing the field of DCDD liver transplantation. The consortium would have a governing board with broad representation from the donation and transplant community, which would establish research priorities, consortium goals and review proposals. Mechanisms to further the mission of the consortium could include the establishment of a retrospective and subsequently prospective database with a level of granularity not available from the Organ Procurement and Transplantation Network, and the conduct of prospective hypothesis-driven trials developed to optimize utilization and outcomes of DCDD livers. A multi-center consortium similar to the ONE
Table 1: Areas of research and policy investigation for proposed DCDD consortium Category Optimizing donor management
Recipient selection and management Policy issues
Research/policy areas Donor selection Quantification of the dynamic aspects of donor warm ischemic time and association with allograft outcomes The science of ischemia and reperfusion injury in DCDD The role of in vivo or ex vivo mechanical perfusion to assess allograft function and ameliorate ischemia reperfusion injury Identification of recipients who will benefit from DCDD Management of biliary complications Defining acceptable ischemic cholangiopathy rates Defining expected graft and patient survival rates; parameters for flagging of program Cost of DCDD procurements and comparison to DNDs Benchmark ratio DCDD to DND transplants Best practices to optimize OPO procurement rates Selection and prioritization of DCDD retransplant candidates
DCDD, donation after circulatory determination of death; DND, donation after neurological death; OPO, organ procurement organization.
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Study (22), with standardized data collection and measurement techniques, would allow for a consortia to support innovative studies across centers, with an adaptive trial design to quickly and serially evaluate various interventions and therapies. Given the experience and expertise of centers outside of the United States, for example, the United Kingdom, consideration of an international consortium should be given depending on the funding mechanism that would be pursued by the consortium. At the minimum, experts from such centers should serve as consultants and/or collaborators to the research network.
Conclusion For well over a decade DCDD liver transplantation has been recognized and espoused as a mechanism to bridge the organ demand–supply mismatch. Significant and welldocumented impediments underlie broader utilization of DCDD for liver transplantation. Although maximizing DCDD transplantation will not allow the transplant community to fully meet the current organ demand (23), without a resolute multi-center effort the field will remain dormant and we will not have fulfilled an ethical obligation to our patients to help bridge the gap between organ supply and demand.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References 1. U.S. Department of Health and Human Services; Health Resources and Services Administration; Office of Special Programs DoT. The Organ Donation Breakthrough Collaborative: Best Practices Final Report. Available at: http://www.lewin.com//media/lewin/ site_sections/publications/organdonationbreakthroughcollaborative. pdf. Accessed November 19, 2013. 2. Organ Procurement and Transplantation Network. According to OPTN/UNOS data as of June 3, 2013. 3. Dubbeld J, Hoekstra H, Farid W, et al. Similar liver transplantation survival with selected cardiac death donors and brain death donors. Br J Surg 2010; 97: 744–753. 4. Foley DP, Fernandez LA, Leverson G, et 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 Surg 2011; 253: 817–825. 5. Jay C, Ladner D, Wang E, et al. A comprehensive risk assessment of mortality following donation after cardiac death liver transplant—An analysis of the national registry. J Hepatol 2011; 55: 808–813.
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6. Fujita S, Mizuno S, Fujikawa T, et al. Liver transplantation from donation after cardiac death: A single center experience. Transplantation 2007; 84: 46–49. 7. Grewal HP, Willingham DL, Nguyen J, et al. Liver transplantation using controlled donation after cardiac death donors: An analysis of a large single-center experience. Liver Transpl 2009; 15: 1028– 1035. 8. Davila D, Ciria R, Jassem W, et al. Prediction models of donor arrest and graft utilization in liver transplantation from maastricht-3 donors after circulatory death. Am J Transplant 2012; 12: 3414– 3424. 9. Pine JK, Aldouri A, Young AL, et al. Liver transplantation following donation after cardiac death: An analysis using matched pairs. Liver Transpl 2009; 15: 1072–1082. 10. Abecassis MM, Fisher RA, Olthoff KM, et al. Complications of living donor hepatic lobectomy—A comprehensive report. Am J Transplant 2012; 12: 1208–1217. 11. Jay CL, Lyuksemburg V, Ladner DP, et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: A meta-analysis. Ann Surg 2011; 253: 259–264. 12. Skaro AI, Jay CL, Baker TB, et al. The impact of ischemic cholangiopathy in liver transplantation using donors after cardiac death: The untold story. Surgery 2009; 146: 543–552, discussion 552–543. 13. Abt PL, Praestgaard J, West S, Hasz R. The donor hemodynamic profile presages graft survival in donation after cardiac death liver transplantation. Liver Transpl 2013; 18: 165–172. 14. Boehnert MU, Yeung JC, Knaak JM, Selzner N, Selzner M. Normothermic a cellular ex vivo liver perfusion (NEVLP) reduces liver and bile duct in DCD liver grafts. Am J Transplant 2013; 13: 3290. 15. Fondevila C, Hessheimer AJ, Maathuis MH, et al. Hypothermic oxygenated machine perfusion in porcine donation after circulatory determination of death liver transplant. Transplantation 2012; 94: 22–29. 16. Schlegel A, Graf R, Clavien PA, Dutkowski P. Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation. J Hepatol 2013; 59: 984–991. 17. Orman ES, St Barritt A, Wheeler SB, Hayashi PH. Declining liver utilization for transplantation in the United States and the impact of donation after cardiac death. Liver Transpl 2013; 19: 59–68. 18. Abt PL, Mange KC, Olthoff KM, Markmann JF, Reddy KR, Shaked A. Allograft survival following adult-to-adult living donor liver transplantation. Am J Transplant 2004; 4: 1302–1307. 19. Patt CH, Thuluvath PJ. Adult living donor liver transplantation. MedGenMed 2003; 5: 26. 20. Shiffman ML, Brown RS Jr, Olthoff KM, et al. Living donor liver transplantation: Summary of a conference at the National Institutes of Health. Liver Transpl 2002; 8: 174–188. 21. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Available at: http://www.nih-a2all.org/. Accessed November 26, 2013. 22. ONE Study. Available at: http://www.onestudy.org/participants. html. Accessed December 8, 2013. 23. Halpern SD, Barnes B, Hasz RD, Abt PL. Estimated supply of organ donors after circulatory determination of death: A populationbased cohort study. JAMA 2010; 304: 2592–2594.
American Journal of Transplantation 2014; 14: 1016–1020
Personal Viewpoint
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12697
Improving Outcomes in DCDD Liver Transplantation: There Can Only Be Strength in Numbers D. S. Goldberg1,2,* and P. L. Abt3 1
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 2 Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 3 Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA Corresponding author: David S. Goldberg, [email protected]
In the United States, liver transplantation using donation after circulatory determination of death (DCDD) donors is challenged by persistently inferior graft survival compared with donation after neurological death (DND), along with declining rates of liver transplantation relative to the total number of DCDD donors. Advances in adult-to-adult living donor liver transplantation graft survival temporally related to the Adult-to-Adult Living Donor Liver Transplantation Cohort Study consortium suggest that a similarly focused collaborative effort may serve to stimulate evolution within DCDD liver transplantation. Without a multi-center consortium to support innovative trials, the current state of DCDD liver transplantation is unlikely to progress. Keywords: A2ALL, donor selection, ex vivo perfusion, living donor liver transplantation, warm ischemia Abbreviations: A2ALL, Adult-to-Adult Living Donor Liver Transplantation Cohort Study; AALDLT, adultto-adult living donor liver transplantation; CMS, Center for Medicare and Medicaid Services; DCDD, donation after circulatory determination of death; DND, donation after neurological death; LDLT, living donor liver transplantation; OPO, organ procurement organization; SRTR, Scientific Registry of Transplant Recipients Received 12 December 2013, revised 21 January 2014 and accepted for publication 04 February 2014
Introduction The persistent mismatch between supply and demand for liver transplantation has led the transplant community to consider expanding the pool of potential organ donors. In 1016
2003, the US Organ Donation Breakthrough Collaborative promulgated transplantation of allografts from donation after circulatory determination of death (DCDD) donors as one potential strategy to increase the donor supply (1). Subsequent to the collaborative, the number of DCDD liver recipients increased fourfold to fivefold, with the overall proportion of transplants from DCDD livers increasing from 1–1.5% to 5–5.5% (2). However, since 2005, the number of transplanted DCDD liver allografts has remained stagnant. There is well-recognized morbidity from DCDD liver transplantation, which includes biliary complications and increased incidence of re-transplantation (3–6). While national data on all US DCDD recipients using data from the Scientific Registry of Transplant Recipients (SRTR) have demonstrated inferior patient and graft survival among DCDD recipients (5), single-center studies from the United States (6,7), the Netherlands (3) and the United Kingdom (8) have demonstrated comparable patient and graft survival in select DCDD recipients. While the potential increased risk of morbidity and mortality associated with DCDD grafts compared with allografts from donation after neurological death (DND) has stymied efforts to broaden consideration of these organs for transplantation, the success of select centers demonstrates that potential exists to utilize these organs as a means to ultimately decrease waitlist mortality (1). We contend that the current state of DCDD liver transplantation will not advance without a focused initiative.
Background/Scope of the Problem Single-center case series have reported variable levels of success (3,4,6,7,9). Nearly all centers report a significantly increased risk of biliary complications, particularly ischemic cholangiopathy, with a 2.4 increased odds of biliary complications, and 10.8 times increased odds of ischemic cholangiopathy (4,5,10–12), yet posttransplant patient and graft survival rates have varied. Several US (6,7) and British (8) centers have reported comparable posttransplant patient and graft survival, while other centers in the United States (5) and the United Kingdom (9) report inferior survival. Delineation of the problems following DCDD liver transplantation has been robust; however, there has only been a modest advancement in our understanding of the contributors to graft failure and biliary complications. Differences in outcomes may be related to differences in donor selection and restrictive donor criteria based on donor age, BMI, hypotension and cold and warm ischemia
DCDD Transplantation
time (3), recipient selection based on factors that include severity of illness at transplantation or history of prior surgeries (7) or varying techniques for in vivo or ex vivo perfusion (13–16). However, without a collaborative, multicenter consortium, the cause of such differences cannot be fully elucidated. This lack of progress is reflected by DCDD graft survival, which has been immutable over the last decade (Figure 1A). The state of the field is also exposed by the increasing rate of DCDD donors from whom a DCDD liver is not transplanted (17) (Figure 2). Many parallels can be drawn to the field of DCDD transplantation today and adult-to-adult living donor liver transplantation (AALDLT) 10–15 years ago. Sample sizes at any one center are limited, national data
lack the granularity to develop effective risk models, donor management practices vary across organ procurement organizations (OPOs) and transplant centers use a diverse set of criteria to select donors and recipients. Without broader cooperation among OPOs, transplant centers and investigators through a centralized mechanism, DCDD liver outcomes and utilization rates are unlikely to advance.
Adult-to-Adult Living Donor Liver Transplantation Cohort Study and the Progress of AALDLT The first reported AALDLT in the United States was in 1998, with early case series drawing from single centers, which were focused on the technical aspects of the donor and
Figure 1: (A) Changes in unadjusted post-DCDD graft survival over time. (B) Changes in unadjusted post-LDLT graft survival over time. DCDD, donation after circulatory determination of death; LDLT, living donor liver transplantation.
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Figure 2: (A) Number of donation after circulatory determination of death (DCDD) liver transplants per year in the United States, 2002–2012. (B) DCDD liver donors per year relative to all DCDD donors.
recipient operation. Initial retrospective multi-center series from the United States demonstrated inferior outcomes in right lobe grafts from living donors compared with whole grafts from deceased donors (18,19). The limited number of AALDLTs at individual centers and inadequate granularity among data collected by the United Network for Organ Sharing stood as impediments to the advancement of AALDLT. Due to these recognized limitations of national data, and the need to address several important questions, including the risks of the procedure for the donor, donor and recipient quality of life, ethics of the procedure and the science of hepatic regeneration, the National Institute of Diabetes and Digestive and Kidney Diseases published a 1018
request for applications to fund a multi-center cohort study that was the genesis of Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) (20). The governing structure of A2ALL consists of a central oversight committee with multiple subcommittees that meet regularly to review research proposals and monitor ongoing studies. The initial cohort included nine centers, with data collected retrospectively from each center. Subsequently, data accrual became prospective, and the number of centers expanded to include 13 in North America (21). Investigations by A2ALL have covered multiple topics, prominent among them being: (1) recipient American Journal of Transplantation 2014; 14: 1016–1020
DCDD Transplantation
selection and surgical complications; (2) identification of recipient survival benefit in relation to the Model for EndStage Liver Disease score; (3) donor selection; (4) donor quality of life; and (5) technical aspects of both recipient and donor operations. Ongoing studies will enhance an understanding of the molecular events surrounding liver regeneration and the pathophysiology of small-for-size syndrome. Findings derived from the A2ALL consortium have been distributed to the transplant community in scientific forums, 22 peer-reviewed publications and through the A2ALL website (21). Substantial progress in outcomes among AALDLT recipients in the United States over the last 10 years is evident (Figure 1B), although direct quantification of the role of A2ALL in advancing and contributing to this success is not possible. However, these advances have occurred against a backdrop of decreased utilization of living donor liver transplantations (LDLTs) nationally. The decreased use of LDLTs is most likely attributable to three well-publicized donor deaths since 2002, coupled with growing concern over donor safety, and unrelated to the A2ALL consortium. Nonetheless, improved outcomes may have come at the expense of overall decreased usage of LDLTs secondary to a more conservative stance by transplant centers. A focus of any DCDD consortium should be to optimize the current pool of DCDD grafts, while also developing techniques to utilize the increasing proportion of discarded organs. One potential mechanism might be to conduct several clinical trials within the context of the consortium with provisions by Center for Medicare and Medicaid Services (CMS) and the SRTR that outcomes derived from patients enrolled in these trials would not contribute to center-specific reports. In doing so, scientific exploration and examination of different medical and surgical techniques can be fostered without concern of flagging by regulatory bodies such as CMS or the SRTR.
Potential Research Agenda and Proposal High rates of DCDD liver discard, stagnant numbers of DCDD transplants and inferior graft outcomes when juxtaposed to DND transplantation evidence the necessity for focused research and exploration on several topics. These potential research areas can be grouped into several areas (Table 1), broadly focusing on optimizing donor graft management both in vivo and ex vivo, shared best practices and selecting appropriate recipients for DCDD transplants. Additional policy considerations that should be explored by the consortium would be ethical issues of management of potential DCDD donors, and benchmarking of center and OPO performance. These research areas overlap in many ways, and must be integrated with one another. For example, while a major goal should be to test new predonation and postdonation techniques to improve graft function, these must be coupled with exploration into donor-recipient matching and identification of the ideal recipients for such DCDD donors. Akin to AALDLT and the development of the A2ALL consortium, we suggest the creation of a National Institutes of Health–funded multi-center study group consisting of OPOs, transplant centers and investigators knowledgeable in DCDD with the singular goal of advancing the field of DCDD liver transplantation. The consortium would have a governing board with broad representation from the donation and transplant community, which would establish research priorities, consortium goals and review proposals. Mechanisms to further the mission of the consortium could include the establishment of a retrospective and subsequently prospective database with a level of granularity not available from the Organ Procurement and Transplantation Network, and the conduct of prospective hypothesis-driven trials developed to optimize utilization and outcomes of DCDD livers. A multi-center consortium similar to the ONE
Table 1: Areas of research and policy investigation for proposed DCDD consortium Category Optimizing donor management
Recipient selection and management Policy issues
Research/policy areas Donor selection Quantification of the dynamic aspects of donor warm ischemic time and association with allograft outcomes The science of ischemia and reperfusion injury in DCDD The role of in vivo or ex vivo mechanical perfusion to assess allograft function and ameliorate ischemia reperfusion injury Identification of recipients who will benefit from DCDD Management of biliary complications Defining acceptable ischemic cholangiopathy rates Defining expected graft and patient survival rates; parameters for flagging of program Cost of DCDD procurements and comparison to DNDs Benchmark ratio DCDD to DND transplants Best practices to optimize OPO procurement rates Selection and prioritization of DCDD retransplant candidates
DCDD, donation after circulatory determination of death; DND, donation after neurological death; OPO, organ procurement organization.
American Journal of Transplantation 2014; 14: 1016–1020
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Study (22), with standardized data collection and measurement techniques, would allow for a consortia to support innovative studies across centers, with an adaptive trial design to quickly and serially evaluate various interventions and therapies. Given the experience and expertise of centers outside of the United States, for example, the United Kingdom, consideration of an international consortium should be given depending on the funding mechanism that would be pursued by the consortium. At the minimum, experts from such centers should serve as consultants and/or collaborators to the research network.
Conclusion For well over a decade DCDD liver transplantation has been recognized and espoused as a mechanism to bridge the organ demand–supply mismatch. Significant and welldocumented impediments underlie broader utilization of DCDD for liver transplantation. Although maximizing DCDD transplantation will not allow the transplant community to fully meet the current organ demand (23), without a resolute multi-center effort the field will remain dormant and we will not have fulfilled an ethical obligation to our patients to help bridge the gap between organ supply and demand.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References 1. U.S. Department of Health and Human Services; Health Resources and Services Administration; Office of Special Programs DoT. The Organ Donation Breakthrough Collaborative: Best Practices Final Report. Available at: http://www.lewin.com//media/lewin/ site_sections/publications/organdonationbreakthroughcollaborative. pdf. Accessed November 19, 2013. 2. Organ Procurement and Transplantation Network. According to OPTN/UNOS data as of June 3, 2013. 3. Dubbeld J, Hoekstra H, Farid W, et al. Similar liver transplantation survival with selected cardiac death donors and brain death donors. Br J Surg 2010; 97: 744–753. 4. Foley DP, Fernandez LA, Leverson G, et 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 Surg 2011; 253: 817–825. 5. Jay C, Ladner D, Wang E, et al. A comprehensive risk assessment of mortality following donation after cardiac death liver transplant—An analysis of the national registry. J Hepatol 2011; 55: 808–813.
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6. Fujita S, Mizuno S, Fujikawa T, et al. Liver transplantation from donation after cardiac death: A single center experience. Transplantation 2007; 84: 46–49. 7. Grewal HP, Willingham DL, Nguyen J, et al. Liver transplantation using controlled donation after cardiac death donors: An analysis of a large single-center experience. Liver Transpl 2009; 15: 1028– 1035. 8. Davila D, Ciria R, Jassem W, et al. Prediction models of donor arrest and graft utilization in liver transplantation from maastricht-3 donors after circulatory death. Am J Transplant 2012; 12: 3414– 3424. 9. Pine JK, Aldouri A, Young AL, et al. Liver transplantation following donation after cardiac death: An analysis using matched pairs. Liver Transpl 2009; 15: 1072–1082. 10. Abecassis MM, Fisher RA, Olthoff KM, et al. Complications of living donor hepatic lobectomy—A comprehensive report. Am J Transplant 2012; 12: 1208–1217. 11. Jay CL, Lyuksemburg V, Ladner DP, et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: A meta-analysis. Ann Surg 2011; 253: 259–264. 12. Skaro AI, Jay CL, Baker TB, et al. The impact of ischemic cholangiopathy in liver transplantation using donors after cardiac death: The untold story. Surgery 2009; 146: 543–552, discussion 552–543. 13. Abt PL, Praestgaard J, West S, Hasz R. The donor hemodynamic profile presages graft survival in donation after cardiac death liver transplantation. Liver Transpl 2013; 18: 165–172. 14. Boehnert MU, Yeung JC, Knaak JM, Selzner N, Selzner M. Normothermic a cellular ex vivo liver perfusion (NEVLP) reduces liver and bile duct in DCD liver grafts. Am J Transplant 2013; 13: 3290. 15. Fondevila C, Hessheimer AJ, Maathuis MH, et al. Hypothermic oxygenated machine perfusion in porcine donation after circulatory determination of death liver transplant. Transplantation 2012; 94: 22–29. 16. Schlegel A, Graf R, Clavien PA, Dutkowski P. Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation. J Hepatol 2013; 59: 984–991. 17. Orman ES, St Barritt A, Wheeler SB, Hayashi PH. Declining liver utilization for transplantation in the United States and the impact of donation after cardiac death. Liver Transpl 2013; 19: 59–68. 18. Abt PL, Mange KC, Olthoff KM, Markmann JF, Reddy KR, Shaked A. Allograft survival following adult-to-adult living donor liver transplantation. Am J Transplant 2004; 4: 1302–1307. 19. Patt CH, Thuluvath PJ. Adult living donor liver transplantation. MedGenMed 2003; 5: 26. 20. Shiffman ML, Brown RS Jr, Olthoff KM, et al. Living donor liver transplantation: Summary of a conference at the National Institutes of Health. Liver Transpl 2002; 8: 174–188. 21. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Available at: http://www.nih-a2all.org/. Accessed November 26, 2013. 22. ONE Study. Available at: http://www.onestudy.org/participants. html. Accessed December 8, 2013. 23. Halpern SD, Barnes B, Hasz RD, Abt PL. Estimated supply of organ donors after circulatory determination of death: A populationbased cohort study. JAMA 2010; 304: 2592–2594.
American Journal of Transplantation 2014; 14: 1016–1020
