1
|
Royo-Villanova M, Miñambres E, Coll E, Domínguez-Gil B. Normothermic Regional Perfusion in Controlled Donation After the Circulatory Determination of Death: Understanding Where the Benefit Lies. Transplantation 2025; 109:428-439. [PMID: 39049104 DOI: 10.1097/tp.0000000000005143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 07/27/2024]
Abstract
Controlled donation after the circulatory determination of death (cDCDD) has emerged as a strategy to increase the availability of organs for clinical use. Traditionally, organs from cDCDD donors have been subject to standard rapid recovery (SRR) with poor posttransplant outcomes of abdominal organs, particularly the liver, and limited organ utilization. Normothermic regional perfusion (NRP), based on the use of extracorporeal membrane oxygenation devices, consists of the in situ perfusion of organs that will be subject to transplantation with oxygenated blood under normothermic conditions after the declaration of death and before organ recovery. NRP is a potential solution to address the limitations of traditional recovery methods. It has become normal practice in several European countries and has been recently introduced in the United States. The increased use of NRP in cDCDD has occurred as a result of a growing body of evidence on its association with improved posttransplant outcomes and organ utilization compared with SRR. However, the expansion of NRP is precluded by obstacles of an organizational, legal, and ethical nature. This article details the technique of both abdominal and thoracoabdominal NRP. Based on the available evidence, it describes its benefits in terms of posttransplant outcomes of abdominal and thoracic organs and organ utilization. It addresses cost-effectiveness aspects of NRP, as well as logistical and ethical obstacles that limit the implementation of this innovative preservation strategy.
Collapse
Affiliation(s)
- Mario Royo-Villanova
- Transplant Coordination Unit and Service of Intensive Care, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Eduardo Miñambres
- Transplant Coordination Unit and Service of Intensive Care, University Hospital Marqués de Valdecilla-IDIVAL, School of Medicine, Universidad de Cantabria, Santander, Spain
| | | | | |
Collapse
|
2
|
Blondeel J, van Leeuwen OB, Schurink IJ, Lantinga VA, Gilbo N, de Goeij FHC, Pirenne J, Huurman VAL, de Meijer VE, de Jonge J, Porte RJ, Monbaliu D. Dynamic Preservation of Donation After Circulatory Death Liver Grafts From Donors Aged 60 y and Older. Transplantation 2024:00007890-990000000-00961. [PMID: 39702514 DOI: 10.1097/tp.0000000000005297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/21/2024]
Abstract
BACKGROUND Donor livers from older donation after circulatory death (DCD) donors are frequently discarded for transplantation because of the high risk of graft failure. It is unknown whether DCD livers from older donors benefit from dynamic preservation. METHODS In a multicenter study, we retrospectively compared graft and patient outcomes after transplantation of livers from DCD donors older than 60 y, preserved with either static cold storage (SCS), ex situ sequential dual hypothermic perfusion, controlled oxygenated rewarming, and normothermic perfusion (DHOPE-COR-NMP), or in situ abdominal normothermic regional perfusion (aNRP). RESULTS Fifty-six liver transplants were included in the SCS cohort, 33 in the DHOPE-COR-NMP cohort, and 27 in the aNRP cohort. Donor warm ischemia time was significantly shorter in the SCS group than in DHOPE-COR-NMP (P < 0.001) and aNRP (P < 0.001) groups. Cold ischemia times were similar. One-year incidence of nonanastomotic biliary strictures was lower after DHOPE-COR-NMP (3%, P = 0.03) or aNRP (7%, P = 0.13), compared with SCS alone (21%). Anastomotic strictures were less frequent in aNRP (19%) compared with DHOPE-COR-NMP (52%; P = 0.015). One-year graft and patient survival were similar. CONCLUSIONS Dynamic preservation allows safe transplantation of livers from DCD donors aged 60 y or older. The risk of nonanastomotic strictures was significantly lower after DHOPE-COR-NMP than after SCS, despite longer donor warm ischemia times.
Collapse
Affiliation(s)
- Joris Blondeel
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Otto B van Leeuwen
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ivo J Schurink
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Veerle A Lantinga
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Nicholas Gilbo
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Surgery and Transplantation, CHU Liege, Liege, Belgium
| | - Femke H C de Goeij
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Jacques Pirenne
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Volkert A L Huurman
- Department of Surgery, Leiden University Medical Center Transplant Center, Leiden University Medical Center, Leiden, the Netherlands
| | - Vincent E de Meijer
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jeroen de Jonge
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Robert J Porte
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Diethard Monbaliu
- Laboratory of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation Surgery and Coordination, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
3
|
Samuel D. EASL Clinical Practice Guidelines on liver transplantation. J Hepatol 2024; 81:1040-1086. [PMID: 39487043 DOI: 10.1016/j.jhep.2024.07.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 11/04/2024]
Abstract
Liver transplantation (LT) is an established life-saving procedure. The field of LT has changed in the past 10 years from several perspectives, with the expansion of indications, transplantation of patients with acute-on-chronic liver failure, evolution of transplant oncology, the use of donations after cardiac death, new surgical techniques, and prioritisation of recipients on the waiting list. In addition, the advent of organ perfusion machines, the recognition of new forms of rejection, and the attention paid to the transition from paediatric to adult patients, have all improved the management of LT recipients. The purpose of the EASL guidelines presented here is not to cover all aspects of LT but to focus on developments since the previous EASL guidelines published in 2016.
Collapse
|
4
|
Finotti M, Romano M, Grossi U, Dalla Bona E, Pelizzo P, Piccino M, Scopelliti M, Zanatta P, Zanus G. Innovations in Liver Preservation Techniques for Transplants from Donors after Circulatory Death: A Special Focus on Transplant Oncology. J Clin Med 2024; 13:5371. [PMID: 39336858 PMCID: PMC11432009 DOI: 10.3390/jcm13185371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/18/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
Liver transplantation is the preferred treatment for end-stage liver disease. Emerging evidence suggests a potential role for liver transplantation in treating liver tumors such as colorectal liver metastases and cholangiocarcinoma. However, due to a limited donor pool, the use of marginal grafts from donation after circulatory death (DCD) donors is increasing to meet demand. Machine perfusion is crucial in this context for improving graft acceptance rates and reducing ischemia-reperfusion injury. Few studies have evaluated the role of machine perfusion in the context of transplant oncology. Perfusion machines can be utilized in situ (normothermic regional perfusion-NRP) or ex situ (hypothermic and normothermic machine perfusion), either in combination or as a complement to conventional in situ cold flush and static cold storage. The objective of this analysis is to provide an up-to-date overview of perfusion machines and their function in donation after circulatory death with particular attention to their current and likely potential effects on transplant oncology. A literature review comparing standard cold storage to machine perfusion methods showed that, so far, there is no evidence that these devices can reduce the tumor recurrence rate. However, some evidence suggests that these innovative perfusion techniques can improve graft function, reduce ischemia-reperfusion injury, and, based on this mechanism, may lead to future improvements in cancer recurrence.
Collapse
Affiliation(s)
- Michele Finotti
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
- Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX 75246, USA
| | - Maurizio Romano
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Ugo Grossi
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Enrico Dalla Bona
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Patrizia Pelizzo
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Marco Piccino
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Michele Scopelliti
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| | - Paolo Zanatta
- Department of Anesthesiology and Critical Care, Treviso Regional Hospital AULSS 2 Marca Trevigiana, 31100 Treviso, Italy
| | - Giacomo Zanus
- Hepatobiliary and General Surgery Unit, Regional Hospital Treviso, Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche (DISCOG), University of Padua, 35128 Padua, Italy
| |
Collapse
|
5
|
Schurink IJ, de Goeij FHC, van der Heijden FJ, van Rooden RM, van Dijk MC, Polak WG, van der Laan LJW, Huurman VAL, de Jonge J. Liver function maximum capacity test during normothermic regional perfusion predicts graft function after transplantation. EPMA J 2024; 15:545-558. [PMID: 39239110 PMCID: PMC11372035 DOI: 10.1007/s13167-024-00371-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/04/2024] [Accepted: 06/29/2024] [Indexed: 09/07/2024]
Abstract
Purpose In an effort to reduce waitlist mortality, extended criteria donor organs, including those from donation after circulatory death (DCD), are being used with increasing frequency. These donors carry an increased risk for postoperative complications, and balancing donor-recipient risks is currently based on generalized nomograms. Abdominal normothermic regional perfusion (aNRP) enables individual evaluation of DCD organs, but a gold standard to determine suitability for transplantation is lacking. This study aimed to incorporate individualized and predictive measurements of the liver maximum capacity (LiMAx) test to objectively grade liver function during aNRP and prevent post-op complications. Methods aNRP was performed to salvage 18 DCD liver grafts, otherwise discarded. Continuous variables were presented as the median with the interquartile range. Results The liver function maximum capacity (LiMAx) test was successfully performed within the aNRP circuit in 17 aNRPs (94%). Donor livers with good lactate clearance during aNRP demonstrated significantly higher LiMAx scores (396 (301-451) µg/kg/h versus those who did not 105 (70-158) µg/kg/h; P = 0.006). This was also true for manifesting stress hyperglycemia > 20 mmol/l (P = 0.032). LiMAx score correlated with alanine aminotransferase (ALT; R = - 0.755) and aspartate transaminase (AST; R = - 0.800) levels during perfusion and distinguished livers that were selected for transplantation (397 (346-453) µg/kg/h) from those who were discarded (155 (87-206) µg/kg/h; P < 0.001). Twelve livers were accepted for transplantation, blinded for LiMAx results, and all had LiMAx scores of > 241 µg/kg/h. Postoperatively, LiMAx during aNRP displayed correlation with 24-h lactate levels. Conclusions This study shows for the first time the feasibility to assess liver function during aNRP in individual donor livers. LiMAx presents an objective tool to predict donor liver function and risk of complications in the recipient, thus enabling individualized matching of donor livers for an individual recipient. The LiMAx test may present a valuable test for the prediction of donor liver function, preventing post-transplant complication, and personalizing the selection of donor livers for individual recipients. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-024-00371-7.
Collapse
Affiliation(s)
- Ivo J Schurink
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, Zuid Holland The Netherlands
| | - Femke H C de Goeij
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, Zuid Holland The Netherlands
| | - Fenna J van der Heijden
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, Zuid Holland The Netherlands
| | - Rutger M van Rooden
- LUMC Transplant Center, Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Madeleine C van Dijk
- LUMC Transplant Center, Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Wojciech G Polak
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, Zuid Holland The Netherlands
| | - Luc J W van der Laan
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, Zuid Holland The Netherlands
| | - Volkert A L Huurman
- LUMC Transplant Center, Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeroen de Jonge
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, Zuid Holland The Netherlands
| |
Collapse
|
6
|
Prudhomme T, Mesnard B, Branchereau J, Roumiguié M, Maulat C, Muscari F, Kamar N, Soulié M, Gamé X, Sallusto F, Timsit MO, Drouin S. Simultaneous liver-kidney transplantation: future perspective. World J Urol 2024; 42:489. [PMID: 39162870 PMCID: PMC11335780 DOI: 10.1007/s00345-024-05174-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/22/2023] [Accepted: 07/11/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND The aims of this narrative review were (i) to describe the current indications of SLKT, (ii) to report evolution of SLKT activity, (iii) to report the outcomes of SLKT, (iv) to explain the immune-protective effect of liver transplant on kidney transplant, (v) to explain the interest of delay kidney transplantation, using hypothermic machine perfusion (HMP), (vi) to report kidney after liver transplantation (KALT) indications and (vii) to describe the value of the increase in the use of extended criteria donors (ECD) and particular controlled donation after circulatory death (cDCD) transplant, thanks to the development of new organ preservation strategies. METHOD Electronic databases were screened using the keywords "Simultaneous", "Combined", "kidney transplantation" and "liver transplantation". The methodological and clinical heterogeneity of the included studies meant that meta-analysis was inappropriate. RESULTS A total of 1,917 publications were identified in the literature search. Two reviewers screened all study abstracts independently and 1,107 of these were excluded. Thus, a total of 79 full text articles were assessed for eligibility. Of these, 21 were excluded. In total, 58 studies were included in this systematic review. CONCLUSIONS Simultaneous liver-kidney transplantation has made a significant contribution for patients with dual-organ disease. The optimization of indication and selection of SLKT patients will reduce futile transplantation. Moreover, increasing the use of transplants from extended criteria donors, in particular cDCD, should be encouraged, thanks to the development of new modalities of organ preservation.
Collapse
Affiliation(s)
- Thomas Prudhomme
- Department of Urology, Kidney Transplantation and Andrology, TSA 50032 Rangueil Hospital, Toulouse Cedex 9, 31059, France.
- Center for Research in Transplantation and Translational Immunology, Nantes Université, INSERM, UMR 1064, Nantes, 44000, France.
| | - Benoit Mesnard
- Center for Research in Transplantation and Translational Immunology, Nantes Université, INSERM, UMR 1064, Nantes, 44000, France
- Department of Urology, University Hospital of Nantes, Nantes, France
| | - Julien Branchereau
- Center for Research in Transplantation and Translational Immunology, Nantes Université, INSERM, UMR 1064, Nantes, 44000, France
- Department of Urology, University Hospital of Nantes, Nantes, France
| | - Mathieu Roumiguié
- Department of Urology, Kidney Transplantation and Andrology, TSA 50032 Rangueil Hospital, Toulouse Cedex 9, 31059, France
| | - Charlotte Maulat
- Department of Digestive Surgery, University Hospital of Rangueil, Toulouse, France
| | - Fabrice Muscari
- Department of Digestive Surgery, University Hospital of Rangueil, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, University Hospital of Rangueil, Toulouse, France
| | - Michel Soulié
- Department of Urology, Kidney Transplantation and Andrology, TSA 50032 Rangueil Hospital, Toulouse Cedex 9, 31059, France
| | - Xavier Gamé
- Department of Urology, Kidney Transplantation and Andrology, TSA 50032 Rangueil Hospital, Toulouse Cedex 9, 31059, France
| | - Federico Sallusto
- Department of Urology, Kidney Transplantation and Andrology, TSA 50032 Rangueil Hospital, Toulouse Cedex 9, 31059, France
| | - Marc Olivier Timsit
- Department of Urology, Hôpital Européen Georges Pompidou, APHP-Centre, Paris, France
| | - Sarah Drouin
- Service Médico-Chirurgical de Transplantation Rénale, APHP Sorbonne-Université, Hôpital Pitié-Salpêtrière, Paris, Île-de-France, France
| |
Collapse
|
7
|
Croome K, Bababekov Y, Brubaker A, Montenovo M, Mao S, Sellers M, Foley D, Pomfret E, Abt P. American Society of Transplant Surgeons Normothermic Regional Perfusion Standards: Abdominal. Transplantation 2024; 108:1660-1668. [PMID: 39012956 DOI: 10.1097/tp.0000000000005114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 07/18/2024]
Abstract
BACKGROUND Normothermic regional perfusion (NRP) has emerged as a vital technique in organ procurement, particularly in donation after circulatory death (DCD) cases, offering the potential to optimize organ utilization and improve posttransplant outcomes. Recognizing its significance, the American Society of Transplant Surgeons (ASTS) convened a work group to develop standardized recommendations for abdominal NRP in the United States. METHODS The workgroup, comprising experts in NRP, DCD, and transplantation, formulated recommendations through a collaborative process involving revisions and approvals by relevant committees and the ASTS council. Four key areas were identified for standardization: Preprocedure communication, NRP procedure, Terminology and documentation, and Mentorship/credentialing. RESULTS The recommendations encompass a range of considerations, including preprocedure communication protocols to facilitate informed decision-making by transplant centers and organ procurement organizations, procedural guidelines for NRP teams, uniform terminology to clarify the NRP process, and standards for mentorship and credentialing of NRP practitioners. Specific recommendations address logistical concerns, procedural nuances, documentation requirements, and the importance of ongoing quality assurance. CONCLUSIONS The standardized recommendations for abdominal NRP presented in this article aim to ensure consistency, safety, and efficacy in the organ procurement process. By establishing clear protocols and guidelines, the ASTS seeks to enhance organ utilization, honor donor wishes, and uphold public trust in the donation process. Implementation of these recommendations can contribute to the advancement of NRP practices and improve outcomes for transplant recipients.
Collapse
Affiliation(s)
| | - Yanik Bababekov
- Division of Transplant Surgery, Department of Surgery, University of Colorado, Aurora, CO
| | - Aleah Brubaker
- Division of Transplant and Hepatobiliary Surgery, Department of Surgery, University of California San Diego, La Jolla, CA
| | | | - Shennen Mao
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL
| | | | - David Foley
- Department of Surgery, University of Wisconsin, Madison, WI
| | - Elizabeth Pomfret
- Division of Transplant Surgery, Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, CO
| | - Peter Abt
- Transplant Division, Department of Surgery, University of Pennsylvania, Philadelphia, PA
| |
Collapse
|
8
|
Brubaker AL, Sellers MT, Abt PL, Croome KP, Merani S, Wall A, Abreu P, Alebrahim M, Baskin R, Bohorquez H, Cannon RM, Cederquist K, Edwards J, Huerter BG, Hobeika MJ, Kautzman L, Langnas AN, Lee DD, Manzi J, Nassar A, Neidlinger N, Nydam TL, Schnickel GT, Siddiqui F, Suah A, Taj R, Taner CB, Testa G, Vianna R, Vyas F, Montenovo MI. US Liver Transplant Outcomes After Normothermic Regional Perfusion vs Standard Super Rapid Recovery. JAMA Surg 2024; 159:677-685. [PMID: 38568597 PMCID: PMC10993160 DOI: 10.1001/jamasurg.2024.0520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/15/2023] [Accepted: 01/06/2024] [Indexed: 04/06/2024]
Abstract
Importance Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). Objective To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. Design, Setting, and Participants This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. Exposures cDCD livers were recovered by either NRP or SRR. Main Outcomes and Measures The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. Results A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. Conclusion and Relevance There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.
Collapse
Affiliation(s)
- Aleah L. Brubaker
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, University of California San Diego, La Jolla, California
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
| | - Marty T. Sellers
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
- Tennessee Donor Services, Nashville
| | - Peter L. Abt
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
- Department of Surgery, Transplant Division, University of Pennsylvania, Philadelphia
| | - Kristopher P. Croome
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
- Department of Transplant, Mayo Clinic Florida, Jacksonville
| | - Shaheed Merani
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
- Department of Surgery, University of Nebraska Medical Center, Omaha
| | - Anji Wall
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas
| | - Phillipe Abreu
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, Florida
| | | | - Roy Baskin
- Methodist Transplant Specialists, Dallas, Texas
| | - Humberto Bohorquez
- Department of Surgery, Ochsner School of Medicine, New Orleans, Louisiana
| | - Robert M. Cannon
- Department of Surgery, University of Alabama at Birmingham, Birmingham
| | - Kelly Cederquist
- Department of Surgery, Transplant Division, University of Pennsylvania, Philadelphia
| | - John Edwards
- Gift of Life Donor Program, Philadelphia, Pennsylvania
| | | | - Mark J. Hobeika
- J.C. Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas
| | | | - Alan N. Langnas
- Department of Surgery, University of Nebraska Medical Center, Omaha
| | - David D. Lee
- Department of Surgery, Loyola University, Chicago, Illinois
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Joao Manzi
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, Florida
| | - Ahmed Nassar
- Department of Surgery, Emory University, Atlanta, Georgia
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, Michigan
| | | | - Trevor L. Nydam
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
- Department of Surgery, Division of Transplant Surgery, University of Colorado, Aurora
| | - Gabriel T. Schnickel
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, University of California San Diego, La Jolla, California
| | - Farjad Siddiqui
- Department of Surgery, The Ohio State University, Columbus
- Department of Surgery, Emory University, Atlanta, Georgia
| | - Ashley Suah
- Department of Surgery, Emory University, Atlanta, Georgia
- Department of Surgery, University of Chicago, Chicago, Illinois
| | - Raeda Taj
- Department of Surgery, Division of Transplant and Hepatobiliary Surgery, University of California San Diego, La Jolla, California
- Department of Surgery, Transplant Division, University of Pennsylvania, Philadelphia
| | | | - Giuliano Testa
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas
| | - Rodrigo Vianna
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, Florida
| | - Frederick Vyas
- Department of Surgery, Transplant Division, University of Pennsylvania, Philadelphia
| | - Martin I. Montenovo
- CONCORD: Consortium for Donation after Circulatory Death and Normothermic Regional Perfusion Outcomes Research and Development
- Department of Surgery, Vanderbilt University, Nashville, Tennessee
| |
Collapse
|
9
|
Merani S, Urban M, Westphal SG, Dong J, Miles CD, Maskin A, Hoffman A, Langnas AN. Improved Early Post-Transplant Outcomes and Organ Use in Kidney Transplant Using Normothermic Regional Perfusion for Donation after Circulatory Death: National Experience in the US. J Am Coll Surg 2024; 238:107-118. [PMID: 37772721 DOI: 10.1097/xcs.0000000000000880] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 09/30/2023]
Abstract
BACKGROUND Normothermic regional perfusion (NRP) is a technique that is intended to enhance organ transplant outcomes from donation circulatory death (DCD) donors. STUDY DESIGN A retrospective analysis of data from the Scientific Registry of Transplant Recipients was performed. DCD donors were screened for inclusion based on date of donation 2020 or later, and whether the heart was also recovered for transplantation. We grouped donors as either donation after brain death or DCD. DCD donors were further divided into groups including those in which the heart was not recovered for transplant (Non-Heart DCD) and those in which it was, based on recovery technique (thoracoabdominal-NRP [TA-NRP] Heart DCD and Super Rapid Recovery Heart DCD). RESULTS A total of 219 kidney transplant recipients receiving organs from TA-NRP Heart DCD donors were compared to 436 SRR Super Rapid Recovery DCD, 10,630 Super Rapid Recovery non-heart DCD, and 27,820 donations after brain death recipients. Kidney transplant recipients of TA-NRP DCD allografts experienced shorter length of stay, lower rates of delayed graft function, and lower serum creatinine at the time of discharge when compared with recipients of other DCD allografts. CONCLUSIONS Our analysis demonstrates superior early kidney allograft function when TA-NRP is used for DCD organ recovery.
Collapse
Affiliation(s)
- Shaheed Merani
- From the Division of Transplant, Department of Surgery (Merani, Maskin, Hoffman, Langnas), University of Nebraska Medical Center, Omaha, NE
| | - Marian Urban
- Division of Cardiothoracic Surgery, Department of Surgery (Urban), University of Nebraska Medical Center, Omaha, NE
| | - Scott G Westphal
- Division of Nephrology Department of Medicine (Westphal, Dong, Miles), University of Nebraska Medical Center, Omaha, NE
| | - James Dong
- Division of Nephrology Department of Medicine (Westphal, Dong, Miles), University of Nebraska Medical Center, Omaha, NE
- Department of Biostatistics (Dong), University of Nebraska Medical Center, Omaha, NE
| | - Clifford D Miles
- Division of Nephrology Department of Medicine (Westphal, Dong, Miles), University of Nebraska Medical Center, Omaha, NE
| | - Alexander Maskin
- From the Division of Transplant, Department of Surgery (Merani, Maskin, Hoffman, Langnas), University of Nebraska Medical Center, Omaha, NE
| | - Arika Hoffman
- From the Division of Transplant, Department of Surgery (Merani, Maskin, Hoffman, Langnas), University of Nebraska Medical Center, Omaha, NE
| | - Alan N Langnas
- From the Division of Transplant, Department of Surgery (Merani, Maskin, Hoffman, Langnas), University of Nebraska Medical Center, Omaha, NE
| |
Collapse
|
10
|
Panconesi R, Carvalho MF, Eden J, Fazi M, Ansari F, Mancina L, Navari N, Sousa Da Silva RX, Dondossola D, Borrego LB, Pietzke M, Peris A, Meierhofer D, Muiesan P, Galkin A, Marra F, Dutkowski P, Schlegel A. Mitochondrial injury during normothermic regional perfusion (NRP) and hypothermic oxygenated perfusion (HOPE) in a rodent model of DCD liver transplantation. EBioMedicine 2023; 98:104861. [PMID: 37924707 PMCID: PMC10660010 DOI: 10.1016/j.ebiom.2023.104861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/04/2023] [Revised: 10/15/2023] [Accepted: 10/16/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking. METHODS A rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 °C (NRP) or with oxygenated Belzer-MPS at 10 °C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury. FINDINGS Healthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mitochondrial injury and inflammation as measured by increased perfusate Lactate, FMN- and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%). INTERPRETATION High-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results. FUNDING Funding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.
Collapse
Affiliation(s)
- Rebecca Panconesi
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, 10124, Turin, Italy; Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | | | - Janina Eden
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Marilena Fazi
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fariha Ansari
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - Leandro Mancina
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Nadia Navari
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Richard Xavier Sousa Da Silva
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Centre of Preclinical Research, 20122, Italy
| | - Lucia Bautista Borrego
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Matthias Pietzke
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, 14195, Berlin, Germany
| | - Adriano Peris
- Tuscany Regional Transplant Authority, Centro Regionale Allocazione Organi e Tessuti (CRAOT), Florence, Italy
| | - David Meierhofer
- Max Planck Institute for Molecular Genetics, Mass Spectrometry Facility, 14195, Berlin, Germany
| | - Paolo Muiesan
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - Alexander Galkin
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Center for Research, High Education and Transfer DENOThe, University of Florence, Florence, Italy
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Andrea Schlegel
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland; General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Centre of Preclinical Research, 20122, Italy; Transplantation Center, Digestive Disease and Surgery Institute and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
| |
Collapse
|
11
|
Secanella L, Alconchel F, López-Monclús J, Toledo-Martínez E, Barrios O, Ramírez P, Jiménez-Garrido MC, Rodríguez-Sanjuán JC, Royo-Villanova M, Moreno-González G, Lladó L. Outcomes of liver transplantation with thoracoabdominal normothermic regional perfusion: a matched-controlled initial experience in Spain. FRONTIERS IN TRANSPLANTATION 2023; 2:1280454. [PMID: 38993919 PMCID: PMC11235216 DOI: 10.3389/frtra.2023.1280454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 08/20/2023] [Accepted: 10/16/2023] [Indexed: 07/13/2024]
Abstract
Thoracoabdominal (TA) normothermic regional perfusion (NRP) should allow the safe recovery of heart and liver grafts simultaneously in the context of controlled donation after circulatory death (cDCD). We present the initial results of cDCD liver transplantation with simultaneous liver and heart procurement in Spain until October 2021. Outcomes were compared with a matched cohort of cDCD with abdominal NRP (A-NRP) from participating institutions. Primary endpoints comprised early allograft dysfunction (EAD) or primary non-function (PNF), and the development of ischemic-type biliary lesions (ITBL). Six transplants were performed using cDCD with TA-NRP during the study period. Donors were significantly younger in the TA-NRP group than in the A-NRP group (median 45.6 years and 62.9 years respectively, p = 0.011), with a median functional warm ischemia time of 12.5 min in the study group and 13 min in the control group. Patient characteristics, procurement times, and surgical baseline characteristics did not differ significantly between groups. No patient in the study group developed EAD or PNF, and over a median follow-up of 9.8 months, none developed ITBL or graft loss. Extending A-NRP to TA-NRP for cardiac procurement may be technically challenging, but it is both feasible and safe, showing comparable postoperative outcomes to A-NRP.
Collapse
Affiliation(s)
- Luis Secanella
- Unidad HPB y Trasplante Hepático, Servicio de Cirugía General y Digestiva, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Felipe Alconchel
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Clínico Universitario Virgen de la Arrixaca (IMIB-Virgen de la Arrixaca), Murcia, Spain
| | - Javier López-Monclús
- Servicio de Cirugía General y del Aparato Digestivo, Unidad de Trasplante Hepático, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Enrique Toledo-Martínez
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Oriana Barrios
- Unidad HPB y Trasplante Hepático, Servicio de Cirugía General y Digestiva, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Pablo Ramírez
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Clínico Universitario Virgen de la Arrixaca (IMIB-Virgen de la Arrixaca), Murcia, Spain
| | - Manuel Cecilio Jiménez-Garrido
- Servicio de Cirugía General y del Aparato Digestivo, Unidad de Trasplante Hepático, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain
| | | | - Mario Royo-Villanova
- Servicio de Medicina Intensiva, Coordinación de Trasplantes, Hospital Clínico Universitario Virgen de la Arrixaca (IMIB-Virgen de la Arrixaca), Murcia, Spain
| | - Gabriel Moreno-González
- Servicio de Medicina Intensiva, Coordinación de Trasplantes, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Laura Lladó
- Unidad HPB y Trasplante Hepático, Servicio de Cirugía General y Digestiva, Hospital Universitari de Bellvitge, Barcelona, Spain
| |
Collapse
|
12
|
Parente A, Tirotta F, Pini A, Eden J, Dondossola D, Manzia TM, Dutkowski P, Schlegel A. Machine perfusion techniques for liver transplantation - A meta-analysis of the first seven randomized-controlled trials. J Hepatol 2023; 79:1201-1213. [PMID: 37302578 DOI: 10.1016/j.jhep.2023.05.027] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/29/2023] [Revised: 05/02/2023] [Accepted: 05/19/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND & AIMS Machine perfusion is increasingly being tested in clinical transplantation. Despite this, the number of large prospective clinical trials remains limited. The aim of this study was to compare the impact of machine perfusion vs. static cold storage (SCS) on outcomes after liver transplantation. METHODS A systematic search of MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted to identify randomized-controlled trials (RCTs) comparing "post-transplant" outcomes following machine perfusion vs. SCS. Data were pooled using random effect models. Risk ratios (RRs) were calculated for relevant outcomes. The quality of evidence was rated using the GRADE-framework. RESULTS Seven RCTs were identified (four on hypothermic oxygenated [HOPE] and three on normothermic machine perfusion [NMP]), including a total number of 1,017 patients. Both techniques were associated with significantly lower rates of early allograft dysfunction (NMP: n = 41/282, SCS: n = 74/253, RR 0.50, 95% CI 0.30-0.86, p = 0.01, I2 = 39%; HOPE: n = 45/241, SCS: n = 97/241, RR 0.48, 95% CI 0.35-0.65, p < 0.00001, I2 = 5%). The HOPE approach led to a significant reduction in major complications (Clavien Grade ≥IIIb; HOPE: n = 90/241; SCS: n = 117/241, RR 0.76, 95% CI 0.63-0.93, p = 0.006, I2 = 0%), "re-transplantation" (HOPE: n = 1/163; SCS: n = 11/163; RR 0.21, 95% CI 0.04-0.96, p = 0.04; I2 = 0%) and graft loss (HOPE: n = 7/163; SCS: n = 19/163; RR 0.40, 95% CI 0.17-0.95, p = 0.04; I2 = 0%). Both perfusion techniques were found to 'likely' reduce overall biliary complications and non-anastomotic strictures. CONCLUSIONS Although this study provides the highest current evidence on the role of machine perfusion, outcomes remain limited to a 1-year follow-up after liver transplantation. Comparative RCTs and large real-world cohort studies with longer follow-up are required to enhance the robustness of the data further, thereby supporting the introduction of perfusion technologies into routine clinical practice. PROSPERO-REGISTRATION CRD42022355252. IMPACT AND IMPLICATIONS For a decade, two dynamic perfusion concepts have increasingly been tested in several transplant centres worldwide. We undertook the first systematic review and meta-analysis and identified seven published RCTs, including 1,017 patients, evaluating the effect of machine perfusion (hypothermic and normothermic perfusion techniques) compared to static cold storage in liver transplantation. Both perfusion techniques were associated with lower rates of early allograft dysfunction in the first week after liver transplantation. Hypothermic oxygenated perfusion led to a reduction in major complications, lower "re-transplantation" rates and better graft survival. Both perfusion strategies were found to 'likely' reduce overall biliary complications and non-anastomotic biliary strictures. This study provides the highest current evidence on the role of machine perfusion. Outcomes remain limited to a 1-year post-transplant follow-up. Larger cohort studies with longer follow-up and clinical trials comparing the perfusion techniques are required. This is especially relevant to provide clarity and optimise implementation processes further to support the commissioning of this technology worldwide.
Collapse
Affiliation(s)
- Alessandro Parente
- HPB and Transplant Unit, Department of Surgical Science, University of Rome Tor Vergata, Rome, Italy
| | - Fabio Tirotta
- Department of Surgery, Queen Elizabeth Hospital Birmingham, University Hospital Birmingham NHS Trust, Birmingham, United Kingdom
| | - Alessia Pini
- Department of Statistical Sciences, Università Cattolica del Sacro Cuore, Milan, Italy
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
| | - Daniele Dondossola
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, General and Liver Transplant Surgery Unit, Milan, 20122, Italy; Department of Pathophysiology and Transplantation Università degli Studi di Milano, Italy
| | - Tommaso M Manzia
- HPB and Transplant Unit, Department of Surgical Science, University of Rome Tor Vergata, Rome, Italy
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
| | - Andrea Schlegel
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, General and Liver Transplant Surgery Unit, Milan, 20122, Italy; Transplantation Center, Digestive Disease and Surgery Institute and Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
| |
Collapse
|
13
|
Wall A, Rosenzweig M, McKenna GJ, Ma TW, Asrani SK, Testa G. Six-month abdominal transplant recipient outcomes from donation after circulatory death heart donors: A retrospective analysis by procurement technique. Am J Transplant 2023; 23:987-995. [PMID: 37088143 DOI: 10.1016/j.ajt.2023.04.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/25/2022] [Revised: 04/07/2023] [Accepted: 04/19/2023] [Indexed: 04/25/2023]
Abstract
Standard US practice for donation after circulatory death (DCD) abdominal organ procurement is superrapid recovery (SRR). A newer approach using thoracoabdominal normothermic regional perfusion (TA-NRP) shows promise for better recipient outcomes for all organs, but there are few reports of abdominal recipient outcomes from TA-NRP donors. We used the United Network for Organ Sharing data to identify all cardiac DCD donors from October 1, 2020, to May 20, 2022, and categorized them by recovery procedure (SRR vs TA-NRP). We then identified all liver, kidney, and pancreas recipients of these donors for whom 6-month outcome data were available and compared patient and graft survival, kidney delayed graft function (DGF), and biliary complications between TA-NRP DCD and SRR DCD organ recipients. Patient and graft survival did not differ significantly between groups for either kidney or liver recipients. Significantly fewer TA-NRP kidney recipients developed DGF (12.7% [15/118] vs 42.0% [84/200], P <.001), and TA-NRP and pumped kidneys had lower odds for DGF on multivariate analysis. No liver recipients in either group had biliary complications or were relisted for transplantation for ischemic cholangiopathy. Although long-term outcomes need to be investigated, our early results show similar outcomes for recipients of TA-NRP DCD abdominal organs versus recipients of SRR DCD abdominal organs. We believe that TA-NRP is an effective approach to expand the use of DCD organs.
Collapse
Affiliation(s)
- Anji Wall
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA.
| | - Matthew Rosenzweig
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Gregory J McKenna
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Tsung-Wei Ma
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Sumeet K Asrani
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Giuliano Testa
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| |
Collapse
|
14
|
Durán M, Calleja R, Hann A, Clarke G, Ciria R, Nutu A, Sanabria-Mateos R, Ayllón MD, López-Cillero P, Mergental H, Briceño J, Perera MTPR. Machine perfusion and the prevention of ischemic type biliary lesions following liver transplant: What is the evidence? World J Gastroenterol 2023; 29:3066-3083. [PMID: 37346149 PMCID: PMC10280793 DOI: 10.3748/wjg.v29.i20.3066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/26/2023] [Revised: 03/01/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
The widespread uptake of different machine perfusion (MP) strategies for liver transplant has been driven by an effort to minimize graft injury. Damage to the cholangiocytes during the liver donation, preservation, or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage. This problem continues to trouble clinicians, and may have catastrophic consequences for the graft and patient. Ischemic injury, as a result of compromised hepatic artery flow, is a well-known cause of biliary strictures, sepsis, and graft failure. However, very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions (ITBL) that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise. Both the warm and cold ischemic period duration appear to influence the onset of ITBL. All of the commonly used MP techniques deliver oxygen to the graft cells, and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL. As clinical experience and published evidence grows for these modalities, the impact they have on ITBL rates is important to consider. In this review, the evidence for the three commonly used MP strategies (abdominal normothermic regional perfusion [A-NRP], hypothermic oxygenated perfusion [HOPE], and normothermic machine perfusion [NMP] for ITBL prevention has been critically reviewed. Inconsistencies with ITBL definitions used in trials, coupled with variations in techniques of MP, make interpretation challenging. Overall, the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage. The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak.
Collapse
Affiliation(s)
- Manuel Durán
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Rafael Calleja
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - George Clarke
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Ruben Ciria
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Anisa Nutu
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | | | - María Dolores Ayllón
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Pedro López-Cillero
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - Hynek Mergental
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Javier Briceño
- Department of Liver Transplantation, Reina Sofía University Hospital, Córdoba 14004, Spain
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| |
Collapse
|
15
|
Staubli SM, Ceresa CDL, Pollok JM. The Current Role and Future Applications of Machine Perfusion in Liver Transplantation. Bioengineering (Basel) 2023; 10:bioengineering10050593. [PMID: 37237663 DOI: 10.3390/bioengineering10050593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2023] [Revised: 04/07/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
The relative paucity of donor livers suitable for transplantation has sparked innovations to preserve and recondition organs to expand the pool of transplantable organs. Currently, machine perfusion techniques have led to the improvement of the quality of marginal livers and to prolonged cold ischemia time and have allowed for the prediction of graft function through the analysis of the organ during perfusion, improving the rate of organ use. In the future, the implementation of organ modulation might expand the scope of machine perfusion beyond its current usage. The aim of this review was to provide an overview of the current clinical use of machine perfusion devices in liver transplantation and to provide a perspective for future clinical use, including therapeutic interventions in perfused donor liver grafts.
Collapse
Affiliation(s)
- Sebastian M Staubli
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
| | - Carlo D L Ceresa
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
- Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxfordshire OX3 9DU, UK
| | - Joerg M Pollok
- HPB and Liver Transplantation Service, Royal Free London NHS Foundation Trust, Pond Street, London NW3 QG, UK
- Division of Surgery & Interventional Science, University College London, London WC1E 6BT, UK
| |
Collapse
|
16
|
Liu L, Xiao F, Sun J, Wang Q, Wang A, Zhang F, Li Z, Wang X, Fang Z, Qiao Y. Hepatocyte-derived extracellular vesicles miR-122-5p promotes hepatic ischemia reperfusion injury by regulating Kupffer cell polarization. Int Immunopharmacol 2023; 119:110060. [PMID: 37044034 DOI: 10.1016/j.intimp.2023.110060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/15/2022] [Revised: 03/17/2023] [Accepted: 03/17/2023] [Indexed: 04/14/2023]
Abstract
Ischemia reperfusion injury remains a major barrier to liver transplantation, especially using grafts from donation after circulatory death, and it is also a pressing issue to be solved in clinical practice. Kupffer cell polarization toward a proinflammatory M1 phenotype is an early trigger of liver ischemia-reperfusion injury. However, the molecular mechanism regulating Kupffer cell polarization has not yet been fully elucidated. We induced liver ischemia reperfusion injury in mice and obtained samples from patients undergoing liver transplantation, serum and hepatocytes-derived extracellular vesicles were isolated by differential ultracentrifugation. Kupffer cell polarization was examined by flow cytometry and immunofluorescence histochemistry. RNA-seq was conducted to detect the differentially expressed miRNAs in extracellular vesicles. The role and mechanism of exosomal miR-122-5p in liver ischemia-reperfusion injury were determined both in vitro and in vivo. We identified ischemia reperfusion induced extracellular vesicles as a major cause of hepatic inflammation and tissue damage using adoptive transfer and release inhibition. The study also demonstrated that hepatocyte-derived exosomal miR-122-5p mediates liver ischemia reperfusion injury by polarizing Kupffer cell via PPARδ down-regulation and NF-κB pathway activation using profiling and functional analysis. Moreover, inhibiting miR-122-5p with antagomir suppressed Kupffer cell M1 polarization and attenuated liver ischemia reperfusion injury. Overall, our study demonstrated that hepatocyte-derived exosomal miR-122-5p played a critical role in promoting hepatic ischemia reperfusion injury through modulating PPARδ signaling and NF-κB pathway to introduce M1 polarization of Kupffer cell. Inhibition of miR-122-5p exhibited a protective effect against liver ischemia reperfusion injury, suggesting a potential therapeutic target for liver transplantation.
Collapse
Affiliation(s)
- Long Liu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, Zhejiang 317000, China
| | - Fei Xiao
- Department of Organ Transplantation, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China
| | - Jie Sun
- Medical Records Department, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China
| | - Qi Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Aidong Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China.
| | - Fabiao Zhang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Zhu Li
- Department of Organ Transplantation, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China
| | - Xuequan Wang
- Department of Radiation Oncology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, Zhejiang 317000, China; Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China.
| | - Yingli Qiao
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang 317000, China.
| |
Collapse
|
17
|
Quandahl R, Vanneman MW, Wilke TJ, Kassel CA. 2022 Clinical Updates in Liver Transplantation. J Cardiothorac Vasc Anesth 2023:S1053-0770(23)00116-7. [PMID: 36964080 DOI: 10.1053/j.jvca.2023.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 02/25/2023]
Affiliation(s)
- Rachel Quandahl
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE
| | - Matthew W Vanneman
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA
| | - Trevor J Wilke
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE
| | - Cale A Kassel
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE.
| |
Collapse
|
18
|
Oniscu GC, Mehew J, Butler AJ, Sutherland A, Gaurav R, Hogg R, Currie I, Jones M, Watson CJE. Improved Organ Utilization and Better Transplant Outcomes With In Situ Normothermic Regional Perfusion in Controlled Donation After Circulatory Death. Transplantation 2023; 107:438-448. [PMID: 35993664 DOI: 10.1097/tp.0000000000004280] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND . We evaluated whether the use of normothermic regional perfusion (NRP) was associated with increased organ recovery and improved transplant outcomes from controlled donation after circulatory death (cDCD). METHODS . This is a retrospective analysis of UK adult cDCD donors' where at least 1 abdominal organ was accepted for transplantation between January 1, 2011, and December 31, 2019. RESULTS . A mean of 3.3 organs was transplanted when NRP was used compared with 2.6 organs per donor when NRP was not used. When adjusting for organ-specific donor risk profiles, the use of NRP increased the odds of all abdominal organs being transplanted by 3-fold for liver ( P < 0.0001; 95% confidence interval [CI], 2.20-4.29), 1.5-fold for kidney ( P = 0.12; 95% CI, 0.87-2.58), and 1.6-fold for pancreas ( P = 0.0611; 95% CI, 0.98-2.64). Twelve-mo liver transplant survival was superior for recipients of a cDCD NRP graft with a 51% lower risk-adjusted hazard of transplant failure (HR = 0.494). In risk-adjusted analyses, NRP kidneys had a 35% lower chance of developing delayed graft function than non-NRP kidneys (odds ratio, 0.65; 95% CI, 0.465-0.901)' and the expected 12-mo estimated glomerular filtration rate was 6.3 mL/min/1.73 m 2 better if abdominal NRP was used ( P < 0.0001). CONCLUSIONS . The use of NRP during DCD organ recovery leads to increased organ utilization and improved transplant outcomes compared with conventional organ recovery.
Collapse
Affiliation(s)
- Gabriel C Oniscu
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, United Kingdom
- Department of Clinical Surgery, University of Edinburgh, Edinburgh, United Kingdom
| | - Jennifer Mehew
- Statistics and Clinical Studies, NHS Blood and Transplant, Bristol, United Kingdom
| | - Andrew J Butler
- University of Cambridge Department of Surgery, Addenbrooke's Hospital, Cambridge, the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), London, United Kingdom
- Cambridge Transplant Unit, Cambridge University Hospitals NHS Trust, Addenbrooke's Hospital, Bristol, United Kingdom
| | - Andrew Sutherland
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, United Kingdom
- Department of Clinical Surgery, University of Edinburgh, Edinburgh, United Kingdom
| | - Rohit Gaurav
- Cambridge Transplant Unit, Cambridge University Hospitals NHS Trust, Addenbrooke's Hospital, Bristol, United Kingdom
| | - Rachel Hogg
- Statistics and Clinical Studies, NHS Blood and Transplant, Bristol, United Kingdom
| | - Ian Currie
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, United Kingdom
- Department of Clinical Surgery, University of Edinburgh, Edinburgh, United Kingdom
| | - Mark Jones
- Statistics and Clinical Studies, NHS Blood and Transplant, Bristol, United Kingdom
| | - Christopher J E Watson
- University of Cambridge Department of Surgery, Addenbrooke's Hospital, Cambridge, the National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT), London, United Kingdom
- Cambridge Transplant Unit, Cambridge University Hospitals NHS Trust, Addenbrooke's Hospital, Bristol, United Kingdom
| |
Collapse
|
19
|
Abdominal Organ Preservation Solutions in the Age of Machine Perfusion. Transplantation 2023; 107:326-340. [PMID: 35939388 DOI: 10.1097/tp.0000000000004269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/28/2023]
Abstract
The past decade has been the foreground for a radical revolution in the field of preservation in abdominal organ transplantation. Perfusion has increasingly replaced static cold storage as the preferred and even gold standard preservation method for marginal-quality organs. Perfusion is dynamic and offers several advantages in comparison with static cold storage. These include the ability to provide a continuous supply of new metabolic substrates, clear metabolic waste products, and perform some degree of organ viability assessment before actual transplantation in the recipient. At the same time, the ongoing importance of static cold storage cannot be overlooked, in particular when it comes to logistical and technical convenience and cost, not to mention the fact that it continues to work well for the majority of transplant allografts. The present review article provides an overview of the fundamental concepts of organ preservation, providing a brief history of static cold preservation and description of the principles behind and basic components of cold preservation solutions. An evaluation of current evidence supporting the use of different preservation solutions in abdominal organ transplantation is provided. As well, the range of solutions used for machine perfusion of abdominal organs is described, as are variations in their compositions related to changing metabolic needs paralleling the raising of the temperature of the perfusate from hypothermic to normothermic range. Finally, appraisal of new preservation solutions that are on the horizon is provided.
Collapse
|
20
|
Where are we today with machine perfusion of liver in donation after circulatory death liver transplantation? TRANSPLANTATION REPORTS 2022. [DOI: 10.1016/j.tpr.2022.100111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/24/2022] Open
|
21
|
Lepoittevin M, Giraud S, Kerforne T, Allain G, Thuillier R, Hauet T. How to improve results after DCD (donation after circulation death). Presse Med 2022; 51:104143. [PMID: 36216034 DOI: 10.1016/j.lpm.2022.104143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/31/2021] [Accepted: 09/29/2022] [Indexed: 11/09/2022] Open
Abstract
The shortage of organs for transplantation has led health professionals to look for alternative sources of donors. One of the avenues concerns donors who have died after circulatory arrest. This is a special situation because the organs from these donors are exposed to warm ischaemia-reperfusion lesions that are unavoidable during the journey of the organs from the donor to the moment of transplantation in the recipient. We will address and discuss the key issues from the perspective of team organization, legislation and its evolution, and the ethical framework. In a second part, the avenues to improve the quality of organs will be presented following the itinerary of the organs between the donor and the recipient. The important moments from the point of view of therapeutic strategy will be put into perspective. New connections between key players involved in pathophysiological mechanisms and implications for innate immunity and injury processes are among the avenues to explore. Technological developments to improve the quality of organs from these recipients will be analyzed, such as perfusion techniques with new modalities of temperatures and oxygenation. New molecules are being investigated for their potential role in protecting these organs and an analysis of potential prospects will be proposed. Finally, the important perspectives that seem to be favored will be discussed in order to reposition the use of deceased donors after circulatory arrest. The use of these organs has become a routine procedure and improving their quality and providing the means for their evaluation is absolutely inevitable.
Collapse
Affiliation(s)
- Maryne Lepoittevin
- Unité UMR U1082, F-86000 Poitiers, France; Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France
| | - Sébastien Giraud
- Unité UMR U1082, F-86000 Poitiers, France; Service de Biochimie, Pôle Biospharm, Centre Hospitalier Universitaire, 2 rue de la Milétrie, CS 90577, 86021 Poitiers Cedex, France
| | - Thomas Kerforne
- Unité UMR U1082, F-86000 Poitiers, France; Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France; CHU Poitiers, Service de Réanimation Chirurgie Cardio-Thoracique et Vasculaire, Coordination des P.M.O., F-86021 Poitiers, France
| | - Géraldine Allain
- Unité UMR U1082, F-86000 Poitiers, France; Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France; CHU Poitiers, Service de Chirurgie Cardiothoracique et Vasculaire, F-86021 Poitiers, France
| | - Raphaël Thuillier
- Unité UMR U1082, F-86000 Poitiers, France; Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France; Service de Biochimie, Pôle Biospharm, Centre Hospitalier Universitaire, 2 rue de la Milétrie, CS 90577, 86021 Poitiers Cedex, France
| | - Thierry Hauet
- Unité UMR U1082, F-86000 Poitiers, France; Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France; Fédération Hospitalo-Universitaire « Survival Optimization in Organ Transplantation », CHU de Poitiers, 2 rue de la Milétrie - CS 90577, 86021 Poitiers Cedex, France.
| |
Collapse
|
22
|
Mohkam K, Nasralla D, Mergental H, Muller X, Butler A, Jassem W, Imber C, Monbaliu D, Perera MTPR, Laing RW, García‐Valdecasas JC, Paul A, Dondero F, Cauchy F, Savier E, Scatton O, Robin F, Sulpice L, Bucur P, Salamé E, Pittau G, Allard M, Pradat P, Rossignol G, Mabrut J, Ploeg RJ, Friend PJ, Mirza DF, Lesurtel M. In situ normothermic regional perfusion versus ex situ normothermic machine perfusion in liver transplantation from donation after circulatory death. Liver Transpl 2022; 28:1716-1725. [PMID: 35662403 PMCID: PMC9796010 DOI: 10.1002/lt.26522] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/18/2021] [Revised: 03/14/2022] [Accepted: 03/19/2022] [Indexed: 12/30/2022]
Abstract
In situ normothermic regional perfusion (NRP) and ex situ normothermic machine perfusion (NMP) aim to improve the outcomes of liver transplantation (LT) using controlled donation after circulatory death (cDCD). NRP and NMP have not yet been compared directly. In this international observational study, outcomes of LT performed between 2015 and 2019 for organs procured from cDCD donors subjected to NRP or NMP commenced at the donor center were compared using propensity score matching (PSM). Of the 224 cDCD donations in the NRP cohort that proceeded to asystole, 193 livers were procured, resulting in 157 transplants. In the NMP cohort, perfusion was commenced in all 40 cases and resulted in 34 transplants (use rates: 70% vs. 85% [p = 0.052], respectively). After PSM, 34 NMP liver recipients were matched with 68 NRP liver recipients. The two cohorts were similar for donor functional warm ischemia time (21 min after NRP vs. 20 min after NMP; p = 0.17), UK-Donation After Circulatory Death risk score (5 vs. 5 points; p = 0.38), and laboratory Model for End-Stage Liver Disease scores (12 vs. 12 points; p = 0.83). The incidence of nonanastomotic biliary strictures (1.5% vs. 2.9%; p > 0.99), early allograft dysfunction (20.6% vs. 8.8%; p = 0.13), and 30-day graft loss (4.4% vs. 8.8%; p = 0.40) were similar, although peak posttransplant aspartate aminotransferase levels were higher in the NRP cohort (872 vs. 344 IU/L; p < 0.001). NRP livers were more frequently allocated to recipients suffering from hepatocellular carcinoma (HCC; 60.3% vs. 20.6%; p < 0.001). HCC-censored 2-year graft and patient survival rates were 91.5% versus 88.2% (p = 0.52) and 97.9% versus 94.1% (p = 0.25) after NRP and NMP, respectively. Both perfusion techniques achieved similar outcomes and appeared to match benchmarks expected for donation after brain death livers. This study may inform the design of a definitive trial.
Collapse
Affiliation(s)
- Kayvan Mohkam
- Department of Digestive Surgery & Liver Transplantation, Croix‐Rousse Hospital, Hospices Civils de LyonClaude Bernard Lyon 1 UniversityLyonFrance
| | - David Nasralla
- Department of Hepatopancreatobiliary and Liver Transplant SurgeryRoyal Free HospitalLondonUK
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth HospitalUniversity Hospitals BirminghamBirminghamUK
| | - Xavier Muller
- Department of Digestive Surgery & Liver Transplantation, Croix‐Rousse Hospital, Hospices Civils de LyonClaude Bernard Lyon 1 UniversityLyonFrance
| | - Andrew Butler
- Department of Surgery, Addenbrooke's HospitalUniversity of CambridgeCambridgeUK
| | - Wayel Jassem
- Institute of Liver StudiesKing's College HospitalLondonUK
| | - Charles Imber
- Department of Hepatopancreatobiliary and Liver Transplant SurgeryRoyal Free HospitalLondonUK
| | - Diethard Monbaliu
- Abdominal Transplant Surgery Unit, Department of SurgeryUniversity Hospitals LeuvenLeuvenBelgium
| | | | - Richard W. Laing
- Liver Unit, Queen Elizabeth HospitalUniversity Hospitals BirminghamBirminghamUK
| | | | - Andreas Paul
- Department of General, Visceral and Transplantation SurgeryUniversity Hospital EssenEssenGermany
| | - Federica Dondero
- Department of Hepatobiliopancreatic SurgeryDepartment of Hepatopancreatobiliary Surgery and Liver TransplantationBeaujon Hospital, Assitance Publique‐Hôpitaux de Paris (AP‐HP), University Paris CitéClichyFrance
| | - François Cauchy
- Department of Hepatobiliopancreatic SurgeryDepartment of Hepatopancreatobiliary Surgery and Liver TransplantationBeaujon Hospital, Assitance Publique‐Hôpitaux de Paris (AP‐HP), University Paris CitéClichyFrance
| | - Eric Savier
- Department of Hepatobiliary Surgery and Liver Transplantation, Pitié‐Salpêtrière HospitalSorbonne UniversityParisFrance
| | - Olivier Scatton
- Department of Hepatobiliary Surgery and Liver Transplantation, Pitié‐Salpêtrière HospitalSorbonne UniversityParisFrance
| | - Fabien Robin
- Department of Hepatobiliary and Digestive SurgeryPontchaillou University HospitalRennesFrance
| | - Laurent Sulpice
- Department of Hepatobiliary and Digestive SurgeryPontchaillou University HospitalRennesFrance
| | - Petru Bucur
- Department of Digestive, Oncological, Endocrine, Hepato‐Biliary, Pancreatic and Liver Transplant SurgeryTrousseau HospitalToursFrance
| | - Ephrem Salamé
- Department of Digestive, Oncological, Endocrine, Hepato‐Biliary, Pancreatic and Liver Transplant SurgeryTrousseau HospitalToursFrance
| | - Gabriella Pittau
- Centre Hépato‐Biliaire, Hôpital Paul Brousse, Assistance Publique‐Hôpitaux de Paris (AP‐HP)Université Paris SudVillejuifFrance
| | - Marc‐Antoine Allard
- Centre Hépato‐Biliaire, Hôpital Paul Brousse, Assistance Publique‐Hôpitaux de Paris (AP‐HP)Université Paris SudVillejuifFrance
| | - Pierre Pradat
- Clinical Research Centre, Hospices Civils de LyonClaude Bernard Lyon 1 UniversityLyonFrance
| | - Guillaume Rossignol
- Department of Digestive Surgery & Liver Transplantation, Croix‐Rousse Hospital, Hospices Civils de LyonClaude Bernard Lyon 1 UniversityLyonFrance
| | - Jean‐Yves Mabrut
- Department of Digestive Surgery & Liver Transplantation, Croix‐Rousse Hospital, Hospices Civils de LyonClaude Bernard Lyon 1 UniversityLyonFrance
| | - Rutger J. Ploeg
- Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
| | - Peter J. Friend
- Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
| | - Darius F. Mirza
- Liver Unit, Queen Elizabeth HospitalUniversity Hospitals BirminghamBirminghamUK
| | - Mickaël Lesurtel
- Department of Digestive Surgery & Liver Transplantation, Croix‐Rousse Hospital, Hospices Civils de LyonClaude Bernard Lyon 1 UniversityLyonFrance
| | | |
Collapse
|
23
|
Normothermic Regional Perfusion Provides a Great Opportunity to Maximize Organ Procurement in Donation After the Circulatory Determination of Death. Crit Care Med 2022; 50:1649-1653. [PMID: 36227033 DOI: 10.1097/ccm.0000000000005645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/26/2022]
|
24
|
Schurink IJ, van de Leemkolk FEM, Fondevila C, De Carlis R, Savier E, Oniscu GC, Huurman VAL, de Jonge J. Donor eligibility criteria and liver graft acceptance criteria during normothermic regional perfusion: A systematic review. Liver Transpl 2022; 28:1563-1575. [PMID: 35603445 PMCID: PMC9796375 DOI: 10.1002/lt.26512] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 11/16/2021] [Revised: 04/23/2022] [Accepted: 05/12/2022] [Indexed: 01/01/2023]
Abstract
Acceptance of liver grafts from donations after circulatory death (DCD) largely remains a "black box," particularly due to the unpredictability of the agonal phase. Abdominal normothermic regional perfusion (aNRP) can reverse ischemic injury early during the procurement procedure, and it simultaneously enables graft viability testing to unravel this black box. This review evaluates current protocols for liver viability assessment to decide upon acceptance or decline during aNRP. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was used, and relevant literature databases were searched. The primary outcome consisted of criteria for liver graft viability assessment. Secondary outcomes included survival, primary nonfunction (PNF), early dysfunction, and biliary complications. A total of 14 articles were included in the analysis. In all protocols, a combination of criteria was used to assess suitability of the liver for transplantation. As many as 12 studies (86%) used macroscopic assessment, 12 studies (86%) used alanine transaminase (ALT) levels in perfusate, 9 studies (64%) used microscopic assessment, and 7 studies (50%) used lactate levels as assessment criteria. The organ utilization rate (OUR) was 16% for uncontrolled donation after circulatory death (uDCD) and 64% for controlled donation after circulatory death (cDCD). The most used acceptation criterion in uDCD is ALT level (31%), while in cDCD macroscopic aspect (48%) is most used. Regarding postoperative complications, PNF occurred in 13% (6%-25%) of uDCD livers and 3% (2%-4%) of cDCD livers. In uDCD, the 1-year graft and patient survival rates were 75% (66%-82%) and 82% (75%-88%). In cDCD, the 1-year graft and patient survival rates were 91% (89%-93%) and 93% (91%-94%), respectively. In conclusion, the currently used assessment criteria consist of macroscopic aspect and transaminase levels. The acceptance criteria should be tailored according to donor type to prevent an unacceptable PNF rate in uDCD and to increase the relatively modest OUR in cDCD.
Collapse
Affiliation(s)
- Ivo J. Schurink
- Department of SurgeryErasmus MC Transplant InstituteRotterdamThe Netherlands
| | | | | | - Riccardo De Carlis
- Department of Surgery and TransplantationASST Grande Ospedale Metropolitano NiguardaMilanItaly
| | - Eric Savier
- Department of Hepato‐Biliary and Pancreatic Surgery and Liver TransplantationPitie‐Salpetriere Hospital, Assistance Publique‐Hôpitaux de Paris (AP‐HP), Sorbonne UniversityParisFrance
| | | | - Volkert A. L. Huurman
- Department of Surgery, Transplant CenterLeiden University Medical CenterLeidenThe Netherlands
| | - Jeroen de Jonge
- Department of SurgeryErasmus MC Transplant InstituteRotterdamThe Netherlands
| |
Collapse
|
25
|
Muller X, Rossignol G, Mohkam K, Mabrut JY. Novel strategies in liver graft preservation - The French perspective. J Visc Surg 2022; 159:389-398. [PMID: 36109331 DOI: 10.1016/j.jviscsurg.2022.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/14/2022]
Abstract
Given the increasing graft shortage, the transplant community is forced to use so called marginal liver grafts with a higher susceptibility to ischemia-reperfusion injury. This exposes the recipient to a higher risk of graft failure and post-transplant complications. While static cold storage remains the gold standard in low-risk transplant scenarios, dynamic preservation strategies may allow to improve outcomes after transplantation of marginal liver grafts. Two dynamic preservation strategies, end-ischemic hypothermic oxygenated perfusion (HOPE) and continuous normothermic machine perfusion (cNMP), have been evaluated in randomized clinical trials. The results show improved preservation of liver grafts after cNMP and reduction of post-transplant biliary complications after HOPE. In comparison to cNMP, HOPE has the advantage of requiring less logistics and expertise with the possibility to return to default static cold storage. Both strategies allow to assess graft viability prior to transplantation and may thus contribute to optimizing graft selection and reducing discard rates. The use of dynamic preservation is rapidly increasing in France and results from a national randomized trial on the use of HOPE in marginal grafts will soon be available. Future applications should focus on controlled donation after circulatory death liver grafts, split grafts and graft treatment during perfusion. The final aim of dynamic liver graft preservation is to improve post-transplant outcomes, increase the number of transplanted grafts and allow expansion of transplant indications.
Collapse
Affiliation(s)
- X Muller
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France; ED 340 BMIC, Claude-Bernard Lyon 1 University, 69622 Villeurbanne, France.
| | - G Rossignol
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France; ED 340 BMIC, Claude-Bernard Lyon 1 University, 69622 Villeurbanne, France; Department of Pediatric Surgery and Liver Transplantation, Femme-Mère-Enfant University Hospital, Hospices Civils de Lyon, Lyon, France
| | - K Mohkam
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France; Department of Pediatric Surgery and Liver Transplantation, Femme-Mère-Enfant University Hospital, Hospices Civils de Lyon, Lyon, France
| | - J Y Mabrut
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France; The Lyon Cancer Research Centre, Inserm U1052 UMR 5286, Lyon, France
| |
Collapse
|
26
|
Abstract
PURPOSE OF REVIEW This review describes recent developments in the field of liver perfusion techniques. RECENT FINDINGS Dynamic preservation techniques are increasingly tested due to the urgent need to improve the overall poor donor utilization. With their exposure to warm ischemia, livers from donors after circulatory death (DCD) transmit additional risk for severe complications after transplantation. Although the superiority of dynamic approaches compared to static-cold-storage is widely accepted, the number of good quality studies remains limited. Most risk factors, particularly donor warm ischemia, and accepted thresholds are inconsistently reported, leading to difficulties to assess the impact of new preservation technologies. Normothermic regional perfusion (NRP) leads to good outcomes after DCD liver transplantation, with however short ischemia times. While randomized controlled trials (RCT) with NRP are lacking, results from the first RCTs with ex-situ perfusion were reported. Hypothermic oxygenated perfusion was shown to protect DCD liver recipients from ischemic cholangiopathy. In contrast, endischemic normothermic perfusion seems to not impact on the development of biliary complications, although this evidence is only available from retrospective studies. SUMMARY Dynamic perfusion strategies impact posttransplant outcomes and are increasingly commissioned in various countries along with more evidence from RCTs. Transparent reporting of risk and utilization with uniform definitions is required to compare the role of different preservation strategies in DCD livers with prolonged ischemia times.
Collapse
|
27
|
Rossignol G, Muller X, Mohkam K, Dubois R, Lesurtel M, Mabrut JY. Full left/full right liver graft ex situ split during hypothermic oxygenated perfusion. Pediatr Transplant 2022; 26:e14284. [PMID: 35437884 DOI: 10.1111/petr.14284] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/30/2021] [Revised: 02/17/2022] [Accepted: 03/28/2022] [Indexed: 12/21/2022]
Abstract
BACKGROUND Ex vivo split liver transplantation in pediatric recipients has shown inferior results compared with whole grafts. One factor among others contributing to split grafts being considered as marginal is the prolonged static cold storage time related to ex vivo liver splitting. End ischemic hypothermic oxygenated perfusion is a validated strategy to improve outcomes of marginal whole grafts and may thus also benefit split liver grafts. METHOD We present the first case of full left/full right split procedure performed during hypothermic oxygenated perfusion. RESULTS We present a standardized surgical two-step approach where parenchymal transection was performed during end ischemic hypothermic oxygenated perfusion via the portal vein to shorten static cold storage duration. Both split grafts were successfully transplanted in a 4-year-old pediatric and a 38-year-old adult recipient. Despite high-risk procedure (retransplantation), extended donor criteria including a prolonged cardiac arrest and high donor risk index (2,25), both grafts showed early recovery of hepatic function and low serum transaminase release. At 6 months, both recipients were alive with a normal liver biology and a functioning graft. CONCLUSION Although challenging, full left/full right liver split procedure during end ischemic hypothermic oxygenated perfusion can be successfully performed and is a promising strategy to improve post-transplant outcomes.
Collapse
Affiliation(s)
- Guillaume Rossignol
- Department of Pediatric Surgery and Liver Transplantation, Femme Mere Enfant University Hospital, Hospices Civils de Lyon, France.,Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, France.,The Lyon Cancer Research Centre, INSERM U1052, UMR 5286, Lyon, France
| | - Xavier Muller
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, France.,The Lyon Cancer Research Centre, INSERM U1052, UMR 5286, Lyon, France
| | - Kayvan Mohkam
- Department of Pediatric Surgery and Liver Transplantation, Femme Mere Enfant University Hospital, Hospices Civils de Lyon, France.,Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, France.,The Lyon Cancer Research Centre, INSERM U1052, UMR 5286, Lyon, France
| | - Remi Dubois
- Department of Pediatric Surgery and Liver Transplantation, Femme Mere Enfant University Hospital, Hospices Civils de Lyon, France
| | - Mickaël Lesurtel
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, France.,The Lyon Cancer Research Centre, INSERM U1052, UMR 5286, Lyon, France
| | - Jean-Yves Mabrut
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, France.,The Lyon Cancer Research Centre, INSERM U1052, UMR 5286, Lyon, France
| |
Collapse
|
28
|
Abstract
OBJECTIVE This study investigates whether liver grafts donated after circulatory death (DCD) that are declined by the entire Euro-transplant region can be salvaged with abdominal normothermic regional perfusion (aNRP). SUMMARY BACKGROUND DATA aNRP is increasingly used for DCD liver grafts because it prevents typical complications. However, it is unclear whether aNRP is capable to rescue pre-transplant declined liver grafts, by providing the opportunity to test function during donation. METHODS Donor livers from DCD donors, declined by all centers in the Euro-transplant region, were included for this study. The comparator cohort included standard DCD livers and livers donated after brain death, transplanted in the same time period. RESULTS After withdrawal of life-sustaining treatment, 28 from the 43 donors had a circulatory death within 2 hours, in which case aNRP was initiated. Out of these 28 cases, in 3 cases perfusion problems occurred, 5 grafts were declined based on liver assessment, and 20 liver grafts were transplanted. The main differences during aNRP between the transplanted grafts and the assessed non-transplanted grafts were ALT levels of 53 (34-68) versus 367 (318-488; P=0.001) U/l and bile production in 100% versus 50% of the grafts (P=0.024). The 12-month graft and patient survival were both 95%, similar to the comparator cohort. The incidence of ischemic cholangiopathy was 11%, which was lower than in the standard DCD cohort (18%). CONCLUSIONS aNRP can safely select and thus is able to rescue DCD liver grafts that were deemed unsuitable for transplantation, while preventing primary non-function and minimizing ischemic cholangiopathy.
Collapse
|
29
|
Melandro F, Basta G, Torri F, Biancofiore G, Del Turco S, Orlando F, Guarracino F, Maremmani P, Lazzeri C, Peris A, De Simone P, Ghinolfi D. Normothermic regional perfusion in liver transplantation from donation after cardiocirculatory death: Technical, biochemical, and regulatory aspects and review of literature. Artif Organs 2022; 46:1727-1740. [PMID: 35733227 DOI: 10.1111/aor.14330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/07/2022] [Revised: 03/21/2022] [Accepted: 05/25/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Organs from donation after circulatory death (DCD) are increasingly used for liver transplantation, due to the persisting organ shortage and waiting list mortality. However, the use of DCD grafts is still limited by the inferior graft survival rate and the increased risk of primary non-function and biliary complications when compared to brain death donors' grafts. METHODS Abdominal normothermic regional perfusion with extracorporeal membrane oxygenation (ECMO) is an in situ preservation strategy. which may mitigate ischemia-reperfusion injuries. and has been proposed to restore blood perfusion after the determination of death thus optimizing liver function before implantation. RESULTS In this systematic review, we highlighted the clinical evidence supporting the use of normothermic regional perfusion in DCD liver underlying the pathophysiological mechanisms, and technical, logistic, and regulatory aspects. CONCLUSIONS Despite the lack of properly designed, prospective, randomized trials, the current available data suggest beneficial effects of normothermic regional perfusion on clinical outcomes after liver transplantation.
Collapse
Affiliation(s)
- Fabio Melandro
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Giuseppina Basta
- Institute of Clinical Physiology, CNR San Cataldo Research Area, Pisa, Italy
| | - Francesco Torri
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Giandomenico Biancofiore
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy.,Department of Surgical, Medical, Biochemical Pathology and Intensive Care, University of Pisa, Pisa, Italy
| | - Serena Del Turco
- Institute of Clinical Physiology, CNR San Cataldo Research Area, Pisa, Italy
| | - Francesco Orlando
- Hepatobiliary Surgery and Liver Transplant Center Hospital A. Cardarelli, Naples, Italy
| | - Fabio Guarracino
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Paolo Maremmani
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Chiara Lazzeri
- Tuscany Regional Transplant Authority, Centro Regionale Allocazione Organi e Tessuti (CRAOT), Florence, Italy
| | - Adriano Peris
- Tuscany Regional Transplant Authority, Centro Regionale Allocazione Organi e Tessuti (CRAOT), Florence, Italy
| | - Paolo De Simone
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy.,Department of Surgical, Medical, Biochemical Pathology and Intensive Care, University of Pisa, Pisa, Italy
| | - Davide Ghinolfi
- Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| |
Collapse
|
30
|
Bardallo RG, da Silva RT, Carbonell T, Palmeira C, Folch-Puy E, Roselló-Catafau J, Adam R, Panisello-Rosello A. Liver Graft Hypothermic Static and Oxygenated Perfusion (HOPE) Strategies: A Mitochondrial Crossroads. Int J Mol Sci 2022; 23:5742. [PMID: 35628554 PMCID: PMC9143961 DOI: 10.3390/ijms23105742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/01/2022] [Revised: 05/06/2022] [Accepted: 05/18/2022] [Indexed: 12/14/2022] Open
Abstract
Marginal liver grafts, such as steatotic livers and those from cardiac death donors, are highly vulnerable to ischemia-reperfusion injury that occurs in the complex route of the graft from "harvest to revascularization". Recently, several preservation methods have been developed to preserve liver grafts based on hypothermic static preservation and hypothermic oxygenated perfusion (HOPE) strategies, either combined or alone. However, their effects on mitochondrial functions and their relevance have not yet been fully investigated, especially if different preservation solutions/effluents are used. Ischemic liver graft damage is caused by oxygen deprivation conditions during cold storage that provoke alterations in mitochondrial integrity and function and energy metabolism breakdown. This review deals with the relevance of mitochondrial machinery in cold static preservation and how the mitochondrial respiration function through the accumulation of succinate at the end of cold ischemia is modulated by different preservation solutions such as IGL-2, HTK, and UW (gold-standard reference). IGL-2 increases mitochondrial integrity and function (ALDH2) when compared to UW and HTK. This mitochondrial protection by IGL-2 also extends to protective HOPE strategies when used as an effluent instead of Belzer MP. The transient oxygenation in HOPE sustains the mitochondrial machinery at basal levels and prevents, in part, the accumulation of energy metabolites such as succinate in contrast to those that occur in cold static preservation conditions. Additionally, several additives for combating oxygen deprivation and graft energy metabolism breakdown during hypothermic static preservation such as oxygen carriers, ozone, AMPK inducers, and mitochondrial UCP2 inhibitors, and whether they are or not to be combined with HOPE, are presented and discussed. Finally, we affirm that IGL-2 solution is suitable for protecting graft mitochondrial machinery and simplifying the complex logistics in clinical transplantation where traditional (static preservation) and innovative (HOPE) strategies may be combined. New mitochondrial markers are presented and discussed. The final goal is to take advantage of marginal livers to increase the pool of suitable organs and thereby shorten patient waiting lists at transplantation clinics.
Collapse
Affiliation(s)
- Raquel G. Bardallo
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain; (R.G.B.); (T.C.)
| | - Rui T. da Silva
- Center for Neuroscience and Cell Biology, Universidade Coimbra, 3000-370 Coimbra, Portugal; (R.T.d.S.); (C.P.)
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (E.F.-P.); (J.R.-C.)
| | - Teresa Carbonell
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain; (R.G.B.); (T.C.)
| | - Carlos Palmeira
- Center for Neuroscience and Cell Biology, Universidade Coimbra, 3000-370 Coimbra, Portugal; (R.T.d.S.); (C.P.)
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (E.F.-P.); (J.R.-C.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (E.F.-P.); (J.R.-C.)
| | - René Adam
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, 94800 Villejuif, France;
| | - Arnau Panisello-Rosello
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC)-IDIBAPS, CIBEREHD, 08036 Barcelona, Catalonia, Spain; (E.F.-P.); (J.R.-C.)
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, 94800 Villejuif, France;
| |
Collapse
|
31
|
Lepoittevin M, Giraud S, Kerforne T, Barrou B, Badet L, Bucur P, Salamé E, Goumard C, Savier E, Branchereau J, Battistella P, Mercier O, Mussot S, Hauet T, Thuillier R. Preservation of Organs to Be Transplanted: An Essential Step in the Transplant Process. Int J Mol Sci 2022; 23:ijms23094989. [PMID: 35563381 PMCID: PMC9104613 DOI: 10.3390/ijms23094989] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/28/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/23/2022] Open
Abstract
Organ transplantation remains the treatment of last resort in case of failure of a vital organ (lung, liver, heart, intestine) or non-vital organ (essentially the kidney and pancreas) for which supplementary treatments exist. It remains the best alternative both in terms of quality-of-life and life expectancy for patients and of public health expenditure. Unfortunately, organ shortage remains a widespread issue, as on average only about 25% of patients waiting for an organ are transplanted each year. This situation has led to the consideration of recent donor populations (deceased by brain death with extended criteria or deceased after circulatory arrest). These organs are sensitive to the conditions of conservation during the ischemia phase, which have an impact on the graft’s short- and long-term fate. This evolution necessitates a more adapted management of organ donation and the optimization of preservation conditions. In this general review, the different aspects of preservation will be considered. Initially done by hypothermia with the help of specific solutions, preservation is evolving with oxygenated perfusion, in hypothermia or normothermia, aiming at maintaining tissue metabolism. Preservation time is also becoming a unique evaluation window to predict organ quality, allowing repair and/or optimization of recipient choice.
Collapse
Affiliation(s)
- Maryne Lepoittevin
- Biochemistry Department, CHU Poitiers, 86021 Poitiers, France; (M.L.); (S.G.); (R.T.)
- Faculty of Medicine and Pharmacy, University of Poitiers, 86073 Poitiers, France;
- INSERM U1313, IRMETIST, 86021 Poitiers, France; (B.B.); (L.B.)
| | - Sébastien Giraud
- Biochemistry Department, CHU Poitiers, 86021 Poitiers, France; (M.L.); (S.G.); (R.T.)
- Faculty of Medicine and Pharmacy, University of Poitiers, 86073 Poitiers, France;
- INSERM U1313, IRMETIST, 86021 Poitiers, France; (B.B.); (L.B.)
| | - Thomas Kerforne
- Faculty of Medicine and Pharmacy, University of Poitiers, 86073 Poitiers, France;
- INSERM U1313, IRMETIST, 86021 Poitiers, France; (B.B.); (L.B.)
- Cardio-Thoracic and Vascular Surgery Intensive Care Unit, Coordination of P.M.O., CHU Poitiers, 86021 Poitiers, France
| | - Benoit Barrou
- INSERM U1313, IRMETIST, 86021 Poitiers, France; (B.B.); (L.B.)
- Sorbonne Université Campus Pierre et Marie Curie, Faculté de Médecine, 75005 Paris, France
- Service Médico-Chirurgical de Transplantation Rénale, APHP, Hôpital Pitié-Salpêtrière, 75013 Paris, France
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
| | - Lionel Badet
- INSERM U1313, IRMETIST, 86021 Poitiers, France; (B.B.); (L.B.)
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Faculté de Médecine, Campus Lyon Santé Est, Université Claude Bernard, 69622 Lyon, France
- Service d’Urologie et Transplantation, Hospices Civils de Lyon, Hôpital Edouard-Herriot, 69003 Lyon, France
| | - Petru Bucur
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service de Chirurgie Digestive et Endocrinienne, Transplantation Hépatique, CHU de Tours, 37170 Chambray les Tours, France
- Groupement d’Imagerie Médicale, CHU de Tours, 37000 Tours, France
- University Hospital Federation SUPORT Tours Poitiers Limoges, 86021 Poitiers, France
| | - Ephrem Salamé
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service de Chirurgie Digestive et Endocrinienne, Transplantation Hépatique, CHU de Tours, 37170 Chambray les Tours, France
- Groupement d’Imagerie Médicale, CHU de Tours, 37000 Tours, France
- University Hospital Federation SUPORT Tours Poitiers Limoges, 86021 Poitiers, France
| | - Claire Goumard
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service de Chirurgie Digestive, Hépato-Bilio-Pancréatique et Transplantation Hépatique, APHP, Hôpital Pitié-Salpêtrière, 75013 Paris, France
| | - Eric Savier
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service de Chirurgie Digestive, Hépato-Bilio-Pancréatique et Transplantation Hépatique, APHP, Hôpital Pitié-Salpêtrière, 75013 Paris, France
| | - Julien Branchereau
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service d’Urologie et de Transplantation, CHU de Nantes, 44000 Nantes, France
| | - Pascal Battistella
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service de Cardiologie et Maladies Vasculaires, CHU de Montpellier, CEDEX 5, 34295 Montpellier, France
| | - Olaf Mercier
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service de Chirurgie Thoracique et Cardio-Vasculaire, Centre Chirurgical Marie LANNELONGUE, 92350 Le Plessis Robinson, France
| | - Sacha Mussot
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- Service de Chirurgie Thoracique et Cardio-Vasculaire, Centre Chirurgical Marie LANNELONGUE, 92350 Le Plessis Robinson, France
| | - Thierry Hauet
- Biochemistry Department, CHU Poitiers, 86021 Poitiers, France; (M.L.); (S.G.); (R.T.)
- Faculty of Medicine and Pharmacy, University of Poitiers, 86073 Poitiers, France;
- INSERM U1313, IRMETIST, 86021 Poitiers, France; (B.B.); (L.B.)
- Société Francophone de Transplantation et de l’Ecole Francophone pour le Prélèvement Multi-Organes, 75013 Paris, France; (P.B.); (E.S.); (C.G.); (E.S.); (J.B.); (P.B.); (O.M.); (S.M.)
- University Hospital Federation SUPORT Tours Poitiers Limoges, 86021 Poitiers, France
- Correspondence:
| | - Raphael Thuillier
- Biochemistry Department, CHU Poitiers, 86021 Poitiers, France; (M.L.); (S.G.); (R.T.)
- Faculty of Medicine and Pharmacy, University of Poitiers, 86073 Poitiers, France;
- INSERM U1313, IRMETIST, 86021 Poitiers, France; (B.B.); (L.B.)
| |
Collapse
|
32
|
Hessheimer AJ, de la Rosa G, Gastaca M, Ruíz P, Otero A, Gómez M, Alconchel F, Ramírez P, Bosca A, López-Andújar R, Atutxa L, Royo-Villanova M, Sánchez B, Santoyo J, Marín LM, Gómez-Bravo MÁ, Mosteiro F, Villegas Herrera MT, Villar Del Moral J, González-Abos C, Vidal B, López-Domínguez J, Lladó L, Roldán J, Justo I, Jiménez C, López-Monclús J, Sánchez-Turrión V, Rodríguez-Laíz G, Velasco Sánchez E, López-Baena JÁ, Caralt M, Charco R, Tomé S, Varo E, Martí-Cruchaga P, Rotellar F, Varona MA, Barrera M, Rodríguez-Sanjuan JC, Briceño J, López D, Blanco G, Nuño J, Pacheco D, Coll E, Domínguez-Gil B, Fondevila C. Abdominal normothermic regional perfusion in controlled donation after circulatory determination of death liver transplantation: Outcomes and risk factors for graft loss. Am J Transplant 2022; 22:1169-1181. [PMID: 34856070 DOI: 10.1111/ajt.16899] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/29/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 01/25/2023]
Abstract
Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p < .001), ischemic type biliary lesions (OR 0.112, 95% CI 0.042-0.299, p < .001), graft loss (HR 0.371, 95% CI 0.267-0.516, p < .001), and patient death (HR 0.540, 95% CI 0.373-0.781, p = .001). Cold ischemia time (HR 1.004, 95% CI 1.001-1.007, p = .021) and re-transplantation indication (HR 9.552, 95% CI 3.519-25.930, p < .001) were significant independent predictors for graft loss among cDCD livers with A-NRP. While use of A-NRP helps overcome traditional limitations in cDCD liver transplantation, opportunity for improvement remains for cases with prolonged cold ischemia and/or technically complex recipients, indicating a potential role for complimentary ex situ perfusion preservation techniques.
Collapse
Affiliation(s)
- Amelia J Hessheimer
- General & Digestive Surgery, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain.,General & Digestive Surgery Service, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Spain.,IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | | | | | | | - Alejandra Otero
- Complejo Hospitalario Universitario La Coruña, A Coruna, Spain
| | - Manuel Gómez
- Complejo Hospitalario Universitario La Coruña, A Coruna, Spain
| | - Felipe Alconchel
- Hospital Clínico Universitario Virgen de la Arrixaca, IMIB, El Palmar, Spain
| | - Pablo Ramírez
- Hospital Clínico Universitario Virgen de la Arrixaca, IMIB, El Palmar, Spain
| | - Andrea Bosca
- Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Rafael López-Andújar
- Hospital Universitario y Politécnico La Fe, Valencia, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Lánder Atutxa
- Hospital Universitario Donostia, San Sebastián, Spain
| | | | | | | | - Luís M Marín
- Hospital Universitario Virgen del Rocío, Seville, Spain
| | | | | | | | | | - Carolina González-Abos
- General & Digestive Surgery Service, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Spain
| | - Bárbara Vidal
- Hospital General Universitario de Castellón, Castellón, Spain
| | | | - Laura Lladó
- Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Spain
| | - José Roldán
- Hospital Universitario de Navarra, Pamplona, Spain
| | - Iago Justo
- Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | | | | | - Gonzalo Rodríguez-Laíz
- Department of General & Digestive Surgery, ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | | | | | - Mireia Caralt
- Hospital Universitario Vall d'Hebrón, Barcelona, Spain
| | - Ramón Charco
- Hospital Universitario Vall d'Hebrón, Barcelona, Spain
| | - Santiago Tomé
- Complejo Hospitalario Universitario Santiago, Santiago de Compostela, Spain
| | - Evaristo Varo
- Complejo Hospitalario Universitario Santiago, Santiago de Compostela, Spain
| | - Pablo Martí-Cruchaga
- HPB and Liver Transplant Unit, General & Digestive Surgery, Clínica Universitaria de Navarra, Pamplona, Spain
| | - Fernando Rotellar
- HPB and Liver Transplant Unit, General & Digestive Surgery, Clínica Universitaria de Navarra, Pamplona, Spain
| | - María A Varona
- Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | - Manuel Barrera
- Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
| | | | | | - Diego López
- Hospital Universitario Infanta Cristina, Badajoz, Spain
| | | | - Javier Nuño
- Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - David Pacheco
- Hospital Universitario Río Hortega, Valladolid, Spain
| | | | | | - Constantino Fondevila
- General & Digestive Surgery, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain.,General & Digestive Surgery Service, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Spain.,IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| |
Collapse
|
33
|
Parente A, Tirotta F, Ronca V, Schlegel A, Muiesan P. Donation after Circulatory Death Liver Transplantation in Paediatric Recipients. TRANSPLANTOLOGY 2022; 3:91-102. [DOI: 10.3390/transplantology3010009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 07/13/2024] Open
Abstract
Waiting list mortality together, with limited availability of organs, are one of the major challenges in liver transplantation (LT). Especially in the paediatric population, another limiting factor is the scarcity of transplantable liver grafts due to additional concerns regarding graft size matching. In adults, donation after circulatory death (DCD) liver grafts have been used to expand the donor pool with satisfactory results. Although several studies suggest that DCD livers could also be used in paediatric recipients with good outcomes, their utilisation in children is still limited to a small number of reports. Novel organ perfusion strategies could be used to improve organ quality and help to increase the number of DCD grafts utilised for children. With the current manuscript, we present the available literature of LT using DCD grafts in paediatric recipients, discussing current challenges with the use of these livers in children and how machine perfusion technologies could be of impact in the future.
Collapse
|
34
|
Panisello-Roselló A, da Silva RT, Folch-Puy E, Carbonell T, Palmeira CM, Fondevila C, Roselló-Catafau J, Adam R. The Use of a Single, Novel Preservation Solution in Split Liver Transplantation and Hypothermic Oxygenated Machine Perfusion. Transplantation 2022; 106:e187-e188. [PMID: 35192583 DOI: 10.1097/tp.0000000000003984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/16/2022]
Affiliation(s)
- Arnau Panisello-Roselló
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain
- AP-HP Hôpital Paul Brousse, UR, Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, Villejuif, Paris, France
- Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - Rui T da Silva
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain
| | - Emma Folch-Puy
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain
- Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - Teresa Carbonell
- Department of Physiology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
| | - Carlos M Palmeira
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal and Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | | | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal and Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - René Adam
- AP-HP Hôpital Paul Brousse, UR, Chronothérapie, Cancers et Transplantation, Université Paris-Saclay, Villejuif, Paris, France
| |
Collapse
|
35
|
Schlegel A, van Reeven M, Croome K, Parente A, Dolcet A, Widmer J, Meurisse N, De Carlis R, Hessheimer A, Jochmans I, Mueller M, van Leeuwen OB, Nair A, Tomiyama K, Sherif A, Elsharif M, Kron P, van der Helm D, Borja-Cacho D, Bohorquez H, Germanova D, Dondossola D, Olivieri T, Camagni S, Gorgen A, Patrono D, Cescon M, Croome S, Panconesi R, Carvalho MF, Ravaioli M, Caicedo JC, Loss G, Lucidi V, Sapisochin G, Romagnoli R, Jassem W, Colledan M, De Carlis L, Rossi G, Di Benedetto F, Miller CM, van Hoek B, Attia M, Lodge P, Hernandez-Alejandro R, Detry O, Quintini C, Oniscu GC, Fondevila C, Malagó M, Pirenne J, IJzermans JNM, Porte RJ, Dutkowski P, Taner CB, Heaton N, Clavien PA, Polak WG, Muiesan P. A multicentre outcome analysis to define global benchmarks for donation after circulatory death liver transplantation. J Hepatol 2022; 76:371-382. [PMID: 34655663 DOI: 10.1016/j.jhep.2021.10.004] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/18/2021] [Revised: 09/17/2021] [Accepted: 10/04/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The concept of benchmarking is established in the field of transplant surgery; however, benchmark values for donation after circulatory death (DCD) liver transplantation are not available. Thus, we aimed to identify the best possible outcomes in DCD liver transplantation and to propose outcome reference values. METHODS Based on 2,219 controlled DCD liver transplantations, collected from 17 centres in North America and Europe, we identified 1,012 low-risk, primary, adult liver transplantations with a laboratory MELD score of ≤20 points, receiving a DCD liver with a total donor warm ischemia time of ≤30 minutes and asystolic donor warm ischemia time of ≤15 minutes. Clinically relevant outcomes were selected and complications were reported according to the Clavien-Dindo-Grading and the comprehensive complication index (CCI). Corresponding benchmark cut-offs were based on median values of each centre, where the 75th-percentile was considered. RESULTS Benchmark cases represented between 19.7% and 75% of DCD transplantations in participating centres. The 1-year retransplant and mortality rates were 4.5% and 8.4% in the benchmark group, respectively. Within the first year of follow-up, 51.1% of recipients developed at least 1 major complication (≥Clavien-Dindo-Grade III). Benchmark cut-offs were ≤3 days and ≤16 days for ICU and hospital stay, ≤66% for severe recipient complications (≥Grade III), ≤16.8% for ischemic cholangiopathy, and ≤38.9 CCI points 1 year after transplant. Comparisons with higher risk groups showed more complications and impaired graft survival outside the benchmark cut-offs. Organ perfusion techniques reduced the complications to values below benchmark cut-offs, despite higher graft risk. CONCLUSIONS Despite excellent 1-year survival, morbidity in benchmark cases remains high. Benchmark cut-offs targeting morbidity parameters offer a valid tool to assess the protective value of new preservation technologies in higher risk groups and to provide a valid comparator cohort for future clinical trials. LAY SUMMARY The best possible outcomes after liver transplantation of grafts donated after circulatory death (DCD) were defined using the concept of benchmarking. These were based on 2,219 liver transplantations following controlled DCD donation in 17 centres worldwide. Donor and recipient combinations with higher risk had significantly worse outcomes. However, the use of novel organ perfusion technology helped high-risk patients achieve similar outcomes as the benchmark cohort.
Collapse
Affiliation(s)
- Andrea Schlegel
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, United Kingdom; Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland; Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
| | - Marjolein van Reeven
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Division of Hepato-Pancreato-Biliary and Transplant Surgery, Rotterdam, the Netherlands
| | - Kristopher Croome
- Department of Transplant, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224 United States
| | - Alessandro Parente
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, United Kingdom
| | - Annalisa Dolcet
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Jeannette Widmer
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland; HPB Surgery and Liver Transplantation, Royal Free Hospital London, United Kingdom
| | - Nicolas Meurisse
- Department of Abdominal Surgery and Transplantation, CHU Liege, University of Liege, Liege, Belgium
| | - Riccardo De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Amelia Hessheimer
- General & Digestive Surgery, Hospital Clínic Barcelona, Barcelona, Spain; CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Ina Jochmans
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium; Abdominal Transplant Surgery, Department of Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Matteo Mueller
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
| | - Otto B van Leeuwen
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Amit Nair
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA; Division of Transplantation/Hepatobiliary Surgery, Department of Surgery, University of Rochester, NY, USA
| | - Koji Tomiyama
- Division of Transplantation/Hepatobiliary Surgery, Department of Surgery, University of Rochester, NY, USA
| | - Ahmed Sherif
- Department of Transplant Surgery, Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, United Kingdom
| | - Mohamed Elsharif
- HPB and Transplant Unit, St James's University Hospital, Leeds LS9 7TF, United Kingdom
| | - Philipp Kron
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland; HPB and Transplant Unit, St James's University Hospital, Leeds LS9 7TF, United Kingdom
| | - Danny van der Helm
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Daniel Borja-Cacho
- Division of Transplantation, Department of Surgery, Northwestern Medicine, Chicago, Illinois, USA
| | - Humberto Bohorquez
- Multi-Organ Transplant Institute, University of Queensland School and the Ochsner Clinical School, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Desislava Germanova
- Department of abdominal surgery, Unit of hepato-biliary surgery and abdominal transplantation, CUB Erasme Hospital, Free University of Brussels (ULB), Brussels, Belgium
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan 20122, Italy
| | - Tiziana Olivieri
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefania Camagni
- Department of Organ Failure and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Andre Gorgen
- Multi-Organ Transplant Program, Division of General Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | - Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Matteo Cescon
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Sarah Croome
- Department of Transplant, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224 United States
| | - Rebecca Panconesi
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | | | - Matteo Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Juan Carlos Caicedo
- Division of Transplantation, Department of Surgery, Northwestern Medicine, Chicago, Illinois, USA
| | - George Loss
- Multi-Organ Transplant Institute, University of Queensland School and the Ochsner Clinical School, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Valerio Lucidi
- Department of abdominal surgery, Unit of hepato-biliary surgery and abdominal transplantation, CUB Erasme Hospital, Free University of Brussels (ULB), Brussels, Belgium
| | | | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Wayel Jassem
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Michele Colledan
- Department of Organ Failure and Transplantation, Papa Giovanni XXIII Hospital, Bergamo, Italy; Università di Milano-Bicocca, Milano, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Giorgio Rossi
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan 20122, Italy
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Charles M Miller
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Magdy Attia
- HPB and Transplant Unit, St James's University Hospital, Leeds LS9 7TF, United Kingdom
| | - Peter Lodge
- HPB and Transplant Unit, St James's University Hospital, Leeds LS9 7TF, United Kingdom
| | | | - Olivier Detry
- Department of Abdominal Surgery and Transplantation, CHU Liege, University of Liege, Liege, Belgium
| | - Cristiano Quintini
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gabriel C Oniscu
- Department of Transplant Surgery, Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, United Kingdom
| | - Constantino Fondevila
- General & Digestive Surgery, Hospital Clínic Barcelona, Barcelona, Spain; CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Massimo Malagó
- HPB Surgery and Liver Transplantation, Royal Free Hospital London, United Kingdom
| | - Jacques Pirenne
- Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium; Abdominal Transplant Surgery, Department of Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Jan N M IJzermans
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Division of Hepato-Pancreato-Biliary and Transplant Surgery, Rotterdam, the Netherlands
| | - Robert J Porte
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
| | - C Burcin Taner
- Department of Transplant, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224 United States
| | - Nigel Heaton
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Pierre-Alain Clavien
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Switzerland
| | - Wojciech G Polak
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Division of Hepato-Pancreato-Biliary and Transplant Surgery, Rotterdam, the Netherlands
| | - Paolo Muiesan
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, United Kingdom; Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy; General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan 20122, Italy.
| | | |
Collapse
|
36
|
Ruiz P, Valdivieso A, Palomares I, Prieto M, Ventoso A, Salvador P, Senosiain M, Fernandez JR, Testillano M, Bustamante FJ, Gastaca M. Similar Results in Liver Transplantation From Controlled Donation After Circulatory Death Donors With Normothermic Regional Perfusion and Donation After Brain Death Donors: A Case-Matched Single-Center Study. Liver Transpl 2021; 27:1747-1757. [PMID: 34455694 DOI: 10.1002/lt.26281] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/21/2021] [Revised: 08/01/2021] [Accepted: 08/21/2021] [Indexed: 12/13/2022]
Abstract
Although good results have been reported with the use of normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation (LT), there is a lack of evidence to demonstrate similar results to donation after brain death (DBD). We present a single-center retrospective case-matched (1:2) study including 100 NRP cDCD LTs and 200 DBD LTs and a median follow-up of 36 months. Matching was done according to donor age, recipient Model for End-Stage Liver Disease score, and cold ischemia time. The following perioperative results were similar in both groups: alanine transaminase peaks of 909 U/L in the DBD group and 836 U/L in the cDCD group and early allograft disfunction percentages of 21% and 19.2%, respectively. The 1-year and 3-year overall graft survival for cDCD was 99% and 93%, respectively, versus 92% and 87%, respectively, for DBD (P = 0.04). Of note, no cases of primary nonfunction or ischemic-type biliary lesion were observed among the cDCD grafts. Our results confirm that NRP cDCD LT meets the same outcomes as those obtained with DBD LT and provides evidence to support the idea that cDCD donors per se should no longer be considered as "marginal donors" when recovered with NRP.
Collapse
Affiliation(s)
- Patricia Ruiz
- Hepatobiliary Surgery and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Bask Country, Barakaldo, Spain
| | - Andres Valdivieso
- Hepatobiliary Surgery and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Bask Country, Barakaldo, Spain
| | - Ibone Palomares
- Hepatobiliary Surgery and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Bask Country, Barakaldo, Spain
| | - Mikel Prieto
- Hepatobiliary Surgery and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Bask Country, Barakaldo, Spain
| | - Alberto Ventoso
- Hepatobiliary Surgery and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Bask Country, Barakaldo, Spain
| | - Patricia Salvador
- Hepatology and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Basque Country, Barakaldo, Spain
| | - Maria Senosiain
- Hepatology and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Basque Country, Barakaldo, Spain
| | - Jose Ramon Fernandez
- Hepatology and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Basque Country, Barakaldo, Spain
| | - Milagros Testillano
- Hepatology and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Basque Country, Barakaldo, Spain
| | - Francisco Javier Bustamante
- Hepatology and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Basque Country, Barakaldo, Spain
| | - Mikel Gastaca
- Hepatobiliary Surgery and Liver Transplant Unit, Cruces University Hospital, BioCruces Health Research Institute, University of the Bask Country, Barakaldo, Spain
| |
Collapse
|
37
|
Liew B, Nasralla D, Iype S, Pollok JM, Davidson B, Raptis DA. Liver transplant outcomes after ex vivo machine perfusion: a meta-analysis. Br J Surg 2021; 108:1409-1416. [PMID: 34791070 DOI: 10.1093/bjs/znab364] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/23/2021] [Accepted: 09/15/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND The pressure on liver-transplant programmes has expanded the usage of extended-criteria allografts. Machine perfusion may be better than conventional static cold storage (SCS) in alleviating ischaemia-reperfusion injury in this setting. Recipient outcomes with hypothermic or normothermic machine perfusion were assessed against SCS here. METHODS A search in MEDLINE, EMBASE and Scopus was conducted in February 2021. Primary studies investigating ex vivo machine perfusion were assessed for the following outcomes: morbidity, ICU and hospital stay, graft and patient survival rates and relative costs. Meta-analysis was performed to obtain pooled summary measures. RESULTS Thirty-four articles involving 1742 patients were included, of which 20 were used for quantitative synthesis. Odds ratios favoured hypothermic machine perfusion (over SCS) with less early allograft dysfunction, ischaemic cholangiopathy, non-anastomotic strictures and graft loss. Hypothermic machine perfusion was associated with a shorter hospital stay and normothermic machine perfusion with reduced graft injury. Two randomized clinical trials found normothermic machine perfusion reduced major complication risks. CONCLUSION Machine perfusion assists some outcomes with potential cost savings.
Collapse
Affiliation(s)
- Belle Liew
- Division of Surgery & Interventional Science, University College London, London, UK
| | - David Nasralla
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Satheesh Iype
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Joerg-Matthias Pollok
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Brian Davidson
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| | - Dimitri A Raptis
- Division of Surgery & Interventional Science, University College London, London, UK.,Department of HPB Surgery and Liver Transplant, Royal Free NHS Foundation Trust, London, UK
| |
Collapse
|
38
|
Go C, Elsisy M, Frenz B, Moses JB, Tevar AD, Demetris AJ, Chun Y, Tillman BW. A retrievable, dual-chamber stent protects against warm ischemia of donor organs in a model of donation after circulatory death. Surgery 2021; 171:1100-1107. [PMID: 34839934 DOI: 10.1016/j.surg.2021.10.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/22/2021] [Revised: 09/27/2021] [Accepted: 10/03/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ischemic injury during the agonal period of donation after circulatory death donors remains a significant barrier to increasing abdominal transplants. A major obstacle has been the inability to improve visceral perfusion, while at the same time respecting the ethics of the organ donor. A retrievable dual-chamber stentgraft could potentially isolate the organ perfusion from systemic hypotension and hypoxia, without increasing cardiac work or committing the donor. METHODS Retrievable dumbbell-shaped stents were laser welded from nitinol wire and covered with polytetrafluoroethylene. Yorkshire pigs were assigned to either agonal control or dumbbell-shaped dual-chamber stentgraft. A central lumen maintained aortic flow, while an outer visceral chamber was perfused with oxygenated blood. A 1-hour agonal phase of hypoxia and hypotension was simulated. Stents were removed by simple sheath advancement. Cardiac monitoring, labs, and visceral flow were recorded followed by recovery of the animal to a goal of 48 hours. RESULTS Cardiac stress did not increase during stent deployment. Visceral pO2 and flow were dramatically improved in stented animal relative to control animals. Five of 7 control animals were killed after renal failure complications, whereas all stent animals survived. Histology confirmed increased ischemic changes among control kidneys compared to stented animals. CONCLUSION A dual-chamber stent improved outcomes after a simulated agonal phase. The stent did not increase cardiac work, thus respecting a key ethical consideration. The ability of a dual-chamber stent to prevent ischemia during organ recovery may become a powerful tool to address the critical donor organ shortage.
Collapse
Affiliation(s)
- Catherine Go
- Division of Vascular Surgery, University of Pittsburgh Medical Center, PA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA
| | - Moataz Elsisy
- Industrial Engineering, Swanson School of Engineering, University of Pittsburgh, PA
| | - Brian Frenz
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA
| | - J B Moses
- Department of Surgery, University of Pittsburgh Medical Center, PA
| | - Amit D Tevar
- Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA
| | - Anthony J Demetris
- Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA
| | - Youngjae Chun
- Industrial Engineering, Swanson School of Engineering, University of Pittsburgh, PA
| | - Bryan W Tillman
- Division of Vascular Surgery, University of Pittsburgh Medical Center, PA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA; Department of Surgery, University of Pittsburgh Medical Center, PA; Division of Vascular Surgery, Ohio State University Wexner Medical Center, Columbus, OH.
| |
Collapse
|
39
|
Cao H, Wu L, Tian X, Zheng W, Yuan M, Li X, Tian X, Wang Y, Song H, Shen Z. HO-1/BMMSC perfusion using a normothermic machine perfusion system reduces the acute rejection of DCD liver transplantation by regulating NKT cell co-inhibitory receptors in rats. Stem Cell Res Ther 2021; 12:587. [PMID: 34819139 PMCID: PMC8611848 DOI: 10.1186/s13287-021-02647-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/22/2021] [Accepted: 10/31/2021] [Indexed: 01/14/2023] Open
Abstract
Background Liver transplantation (LT) is required in many end-stage liver diseases. Donation after cardiac death (DCD) livers are often used, and treatment of acute rejection (ACR) requires the use of immunosuppressive drugs that are associated with complications. Bone marrow mesenchymal stem cells (BMMSCs) are used in treatment following LT; however, they have limitations, including low colonization in the liver. An optimized BMMSC application method is required to suppress ACR. Methods BMMSCs were isolated and modified with the heme oxygenase 1 (HO-1) gene. HO-1/BMMSCs were perfused into donor liver in vitro using a normothermic machine perfusion (NMP) system, followed by LT into rats. The severity of ACR was evaluated based on liver histopathology. Gene chip technology was used to detect differential gene expression, and flow cytometry to analyze changes in natural killer (NK) T cells. Results NMP induced BMMSCs to colonize the donor liver during in vitro preservation. The survival of HO-1/BMMSCs in liver grafts was significantly longer than that of unmodified BMMSCs. When the donor liver contained HO-1/BMMSCs, the local immunosuppressive effect was improved and prolonged, ACR was controlled, and survival time was significantly prolonged. The application of HO-1/BMMSCs reduced the number of NKT cells in liver grafts, increased the expression of NKT cell co-inhibitory receptors, and reduced NKT cell expression of interferon-γ. Conclusions NK cell and CD8+ T cell activation was inhibited by application of HO-1/BMMSCs, which reduced ACR of transplanted liver. This approach could be developed to enhance the success rate of LT. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02647-5.
Collapse
Affiliation(s)
- Huan Cao
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Longlong Wu
- School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Xuan Tian
- School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Weiping Zheng
- Department of Organ Transplantation, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China.,NHC Key Laboratory of Critical Care Medicine, Tianjin, 300192, People's Republic of China
| | - Mengshu Yuan
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Xiang Li
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Xiaorong Tian
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Yuxin Wang
- Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin, 300070, People's Republic of China
| | - Hongli Song
- Department of Organ Transplantation, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China. .,Tianjin Key Laboratory of Organ Transplantation, Tianjin, People's Republic of China.
| | - Zhongyang Shen
- Department of Organ Transplantation, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China. .,Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China.
| |
Collapse
|
40
|
De Beule J, Vandendriessche K, Pengel LHM, Bellini MI, Dark JH, Hessheimer AJ, Kimenai HJAN, Knight SR, Neyrinck AP, Paredes D, Watson CJE, Rega F, Jochmans I. A systematic review and meta-analyses of regional perfusion in donation after circulatory death solid organ transplantation. Transpl Int 2021; 34:2046-2060. [PMID: 34570380 DOI: 10.1111/tri.14121] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/02/2021] [Revised: 09/16/2021] [Accepted: 09/20/2021] [Indexed: 12/29/2022]
Abstract
In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We systematically reviewed outcomes of solid organ transplantation after RP by searching PubMed, Embase, and Cochrane libraries. Eighty-eight articles reporting on outcomes of liver, kidney, pancreas, heart, and lung transplants or donor/organ utilization were identified. Meta-analyses were conducted when possible. Methodological quality was assessed using National Institutes of Health (NIH)-scoring tools. Case reports (13/88), case series (44/88), retrospective cohort studies (35/88), retrospective matched cohort studies (5/88), and case-control studies (2/88) were identified, with overall fair quality. As blood viscosity and rheology change below 20 °C, studies were grouped as hypothermic (HRP, ≤20 °C) or normothermic (NRP, >20 °C) regional perfusion. Data demonstrate that RP is a safe alternative to in situ cold preservation (ISP) in uncontrolled and controlled DCDs. The scarce HRP data are from before 2005. NRP appears to reduce post-transplant complications, especially biliary complications in controlled DCD livers, compared with ISP. Comparisons for kidney and pancreas with ISP are needed but there is no evidence that NRP is detrimental. Additional data on NRP in thoracic organs are needed. Whether RP increases donor or organ utilization needs further research.
Collapse
Affiliation(s)
- Julie De Beule
- Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
| | | | - Liset H M Pengel
- Nuffield Department of Surgical Sciences, Centre for Evidence in Transplantation, University of Oxford, Oxford, UK
| | - Maria Irene Bellini
- Department of Emergency Medicine and Surgery, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - John H Dark
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle, UK
| | - Amelia J Hessheimer
- Department of General & Digestive Surgery, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Hendrikus J A N Kimenai
- Division of Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Simon R Knight
- Nuffield Department of Surgical Sciences, Centre for Evidence in Transplantation, University of Oxford, Oxford, UK.,Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Arne P Neyrinck
- Department of Cardiovascular Sciences, Anesthesiology and Algology, KU Leuven, Leuven, Belgium.,Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium
| | - David Paredes
- Donation and Transplant Coordination Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Christopher J E Watson
- Department of Surgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.,The NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Filip Rega
- Department of Cardiovascular Sciences, Cardiac Surgery, KU Leuven, Leuven, Belgium.,Department of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Ina Jochmans
- Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium.,Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
41
|
Muller X, Rossignol G, Damotte S, Gregoire A, Matillon X, Morelon E, Badet L, Mohkam K, Lesurtel M, Mabrut JY. Graft utilization after normothermic regional perfusion in controlled donation after circulatory death-a single-center perspective from France. Transpl Int 2021; 34:1656-1666. [PMID: 34448267 DOI: 10.1111/tri.13987] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/25/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/15/2022]
Abstract
Normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) is a promising procurement strategy. However, a detailed analysis of graft utilization rates is lacking. This retrospective study included all cDCD donors proposed to a single center for NRP procurement of at least one abdominal organ from 2015 to 2020. Utilization rates were defined as the proportion of transplanted grafts from proposed donors in which withdrawal of life sustaining therapies (WLST) was initiated. In total, 125 cDCD donors underwent WLST with transplantation of at least one graft from 109 (87%) donors. In a total of 14 (11%) procedures NRP failure led to graft discard. Utilization rates for kidney and liver grafts were 83% and 59%, respectively. In 44% of the discarded livers, the reason was poor graft quality based on functional donor warm ischemia >45 min, macroscopic aspect, high-transaminases release, or pathological biopsy. In this study, abdominal NRP in cDCD lead to transplantation of at least one graft in the majority of cases. While the utilization rate for kidneys was high, nearly half of the liver grafts were discarded. Cannulation training, novel graft viability markers, and ex-vivo liver graft perfusion may allow to increase graft utilization.
Collapse
Affiliation(s)
- Xavier Muller
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.,Cancer Research Center of Lyon, INSERM U1052, Lyon, France
| | - Guillaume Rossignol
- Cancer Research Center of Lyon, INSERM U1052, Lyon, France.,Department of Pediatric Surgery and Liver Transplantation, Femme Mère Enfant University Hospital, Hospices Civils de Lyon, University of Lyon I, Bron, France
| | - Sophie Damotte
- Department of Anesthesiology and Critical Care, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
| | - Arnaud Gregoire
- Department of Anesthesiology and Critical Care, Edouard Herriot University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
| | - Xavier Matillon
- Department of Transplantation, Edouard Herriot University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
| | - Emmanuel Morelon
- Department of Urology and Transplantation, Edouard Herriot University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
| | - Lionel Badet
- Department of Transplantation, Edouard Herriot University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France
| | - Kayvan Mohkam
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.,Cancer Research Center of Lyon, INSERM U1052, Lyon, France
| | - Mickaël Lesurtel
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.,Cancer Research Center of Lyon, INSERM U1052, Lyon, France
| | - Jean-Yves Mabrut
- Department of General Surgery and Liver Transplantation, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.,Cancer Research Center of Lyon, INSERM U1052, Lyon, France
| |
Collapse
|
42
|
Ex Vivo Liver Splitting and Hypothermic Oxygenated Machine Perfusion: Technical Refinements of a Promising Preservation Strategy in Split Liver Transplantation. Transplantation 2021; 105:e89-e90. [PMID: 34291769 DOI: 10.1097/tp.0000000000003775] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/26/2022]
|
43
|
Robin F, Jeddou H. Comment on " Hypothermic machine perfusion in liver transplantation-a randomized trial". Hepatobiliary Surg Nutr 2021; 10:364-366. [PMID: 34159163 DOI: 10.21037/hbsn-21-144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/06/2022]
Affiliation(s)
- Fabien Robin
- Department of Hepatobiliary and Digestive Surgery, University Hospital, Rennes 1 University, Rennes, France.,INSERM U1242, Chemistry Oncogenesis Stress Signaling, Rennes 1 University, Rennes, France
| | - Heithem Jeddou
- Department of Hepatobiliary and Digestive Surgery, University Hospital, Rennes 1 University, Rennes, France
| |
Collapse
|