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Elzawahry MA, Reichman T, Sutherland A. New methods for improving pancreas preservation. Curr Opin Organ Transplant 2025:00075200-990000000-00181. [PMID: 40314368 DOI: 10.1097/mot.0000000000001224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
PURPOSE OF REVIEW Pancreas and islet transplantation face critical organ shortage challenges, with many potential grafts discarded due to concerns about consequences of ischemia-reperfusion injury, particularly from donation after circulatory death (DCD) donors. Static cold storage remains standard practice but has significant limitations. Novel preservation technologies may improve transplant outcomes, donor selection and even expand the donor pool. RECENT FINDINGS Normothermic regional perfusion in DCD donors has increased pancreas utilization with promising one-year graft survival comparable to donation after brain-death (DBD) donors. Hypothermic machine perfusion maintains tissue integrity and shows promising preclinical results. Oxygenated hypothermic machine perfusion successfully restores tissue adenosine triphosphate (ATP) levels without notable tissue injury. Normothermic machine perfusion, despite challenges, offers potential for viability assessment and resuscitation. SUMMARY Advanced preservation technologies provide platforms for assessment, reconditioning, and therapeutic interventions for pancreas grafts. Clinical translation requires consensus on perfusion parameters and perfusate composition optimized for pancreatic preservation. Future developments should focus on implementing sensitive and specific assessment methods, including beta-cell specific biomarkers, to confidently select and utilize marginal pancreas grafts for transplantation.
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Affiliation(s)
- Mohamed A Elzawahry
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Oxford Transplant Centre, Headington, Oxford, UK
| | - Trevor Reichman
- Ajmera Transplant Centre, Toronto General Hospital, University Health Network; Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Andrew Sutherland
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, UK; Department of Clinical Surgery, University of Edinburgh, Edinburgh, UK
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2
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Mesnard B, Ogbemudia E, Bruneau S, Le Bas-Bernardet S, Minault D, Hervouet J, Kervella D, Masset C, Cantarovich D, Rigaud J, Badet L, Friend P, Ploeg R, Blancho G, Hunter J, Prudhomme T, Branchereau J. Pancreas Preservation: Hypothermic Oxygenated Perfusion to Improve Graft Reperfusion. Transplantation 2025; 109:e1-e10. [PMID: 39656523 DOI: 10.1097/tp.0000000000005111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/14/2024]
Abstract
BACKGROUND The clinical standard for pancreas preservation for transplantation is static cold storage (SCS). Oxygenation during preservation has been shown to be advantageous in clinical studies. This study evaluates the efficiency of different oxygenation modalities during hypothermic pancreas preservation. METHODS Thirty-two porcine pancreases were procured in a controlled donation after circulatory death model and were divided to be preserved in 8 groups: (1) SCS, (2) hypothermic machine perfusion (HMP), (3) hypothermic oxygenated machine perfusion (HOPE) with 21% oxygen, (4) HOPE and 100%, (5) SCS and oxygen carrier, M101, (6) HMP and M101, (7) HOPE 21% and M101, and (8) HOPE 100% and M101. All the groups underwent 24 h of hypothermic preservation, followed by 2 h of normothermic reperfusion. Oxygen partial pressures were assessed using parenchymal probes. Perfusion parameters, perfusate samples, and tissue biopsies were analyzed. RESULTS This study showed that HMP was linked to higher tissue oxygen partial pressures, lower succinate levels, and better reperfusion parameters. Furthermore, the addition of M101 to either SCS or HMP was associated with lower succinate and creatinine phosphokinase accumulation, suggesting a protective effect against ischemia. CONCLUSIONS Our research has demonstrated the efficacy of machine perfusion in hypothermic conditions in providing oxygen to the pancreas during preservation and conditioning the pancreatic microvasculature for reperfusion during transplantation. Furthermore, the addition of M101 suggests a protective effect on the graft from ischemia.
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Affiliation(s)
- Benoit Mesnard
- Department of Urology and Transplantation Surgery, Nantes University Hospital, Nantes, France
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | | | - Sarah Bruneau
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - David Minault
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Jeremy Hervouet
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Delphine Kervella
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Christophe Masset
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Diego Cantarovich
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Jérôme Rigaud
- Department of Urology and Transplantation Surgery, Nantes University Hospital, Nantes, France
| | - Lionel Badet
- Department of Urology Surgery and Transplantation, Edouard Herriot Hospital, Lyon, France
| | - Peter Friend
- Nuffield Department of Surgical Science, Oxford, United Kingdom
| | - Rutger Ploeg
- Nuffield Department of Surgical Science, Oxford, United Kingdom
| | - Gilles Blancho
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - James Hunter
- Nuffield Department of Surgical Science, Oxford, United Kingdom
| | - Thomas Prudhomme
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
| | - Julien Branchereau
- Department of Urology and Transplantation Surgery, Nantes University Hospital, Nantes, France
- Nantes Université, CHU Nantes1, INSERM, Centre for Research in Transplantation and Translational Immunology, Nantes, France
- Nuffield Department of Surgical Science, Oxford, United Kingdom
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3
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Niroomand A, Nita GE, Lindstedt S. Machine Perfusion and Bioengineering Strategies in Transplantation-Beyond the Emerging Concepts. Transpl Int 2024; 37:13215. [PMID: 39267617 PMCID: PMC11390383 DOI: 10.3389/ti.2024.13215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/19/2024] [Indexed: 09/15/2024]
Abstract
Solid organ transplantation has progressed rapidly over the decades from the first experimental procedures to its role in the modern era as an established treatment for end-stage organ disease. Solid organ transplantation including liver, kidney, pancreas, heart, and lung transplantation, is the definitive option for many patients, but despite the advances that have been made, there are still significant challenges in meeting the demand for viable donor grafts. Furthermore, post-operatively, the recipient faces several hurdles, including poor early outcomes like primary graft dysfunction and acute and chronic forms of graft rejection. In an effort to address these issues, innovations in organ engineering and treatment have been developed. This review covers efforts made to expand the donor pool including bioengineering techniques and the use of ex vivo graft perfusion. It also covers modifications and treatments that have been trialed, in addition to research efforts in both abdominal organs and thoracic organs. Overall, this article discusses recent innovations in machine perfusion and organ bioengineering with the aim of improving and increasing the quality of donor organs.
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Affiliation(s)
- Anna Niroomand
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden
| | - George Emilian Nita
- Department of Transplantation Surgery, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Division of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Sandra Lindstedt
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Lund Stem Cell Center, Lund University, Lund, Sweden
- Department of Cardiothoracic Surgery and Transplantation, Skåne University Hospital, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
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4
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Kneifel F, Vondran F, Vogel T. [Machine perfusion in transplantation surgery]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:610-617. [PMID: 39052038 DOI: 10.1007/s00104-024-02122-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/04/2024] [Indexed: 07/27/2024]
Abstract
The use of machine perfusion in solid organ transplantation has developed tremendously worldwide in recent years. Although the number of randomized controlled trials in the field of organ preservation is still limited, machine perfusion has been shown to be superior to static cold storage of donor organs. Various devices for clinical use with hypothermia or normothermia are already available for most organs. Whether and which perfusion strategy is superior to the others is the subject of current clinical research. This also applies to the further evaluation of possible synergistic effects in the sequential use of the various protocols. The common goal of all dynamic perfusion technologies is to optimize organ preservation between removal and transplantation. By testing the quality of marginal donor organs prior to transplantation, it should also be possible to use these organs without exposing the patient to increased risk. This can lead to a significant expansion of the donor pool. This is particularly important in Germany, where there is an ongoing shortage of organs and restrictive legislation regarding the expansion of the donor pool. Furthermore, the perfusion technology offers the possibility to serve as a platform for other ex situ and in situ therapies on isolated organs. In addition to the conditioning of pre-damaged organs for transplantation, this could lead to further applications in the context of targeted organ therapies and also to improved transplant logistics in the future.
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Affiliation(s)
- Felicia Kneifel
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Florian Vondran
- Klinik für Allgemein‑, Viszeral‑, Kinder- und Transplantationschirurgie, RWTH Universitätsklinikum Aachen, Pauwelsstr. 30, 52074, Aachen, Deutschland
| | - Thomas Vogel
- Klinik für Allgemein‑, Viszeral‑, Kinder- und Transplantationschirurgie, RWTH Universitätsklinikum Aachen, Pauwelsstr. 30, 52074, Aachen, Deutschland.
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5
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Buemi A, Mourad NI, Bouzin C, Devresse A, Hoton D, Daumerie A, Zech F, Darius T, Kanaan N, Gianello P, Mourad M. Exploring Preservation Modalities in a Split Human Pancreas Model to Investigate the Effect on the Islet Isolation Outcomes. Transplant Direct 2024; 10:e1654. [PMID: 38881744 PMCID: PMC11177812 DOI: 10.1097/txd.0000000000001654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/13/2024] [Accepted: 03/15/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND In islet transplantation, the use of dynamic hypothermic preservation techniques is a current challenge. This study compares the efficacy of 3 pancreas preservation methods: static cold storage, hypothermic machine perfusion (HMP), and oxygenated HMP. METHODS A standardized human pancreas split model was employed using discarded organs from both donation after brain death (n = 15) and donation after circulatory death (DCD) (n = 9) donors. The pancreas head was preserved using static cold storage (control group), whereas the tail was preserved using the 3 different methods (study group). Data on donor characteristics, pancreas histology, isolation outcomes, and functional tests of isolated islets were collected. RESULTS Insulin secretory function evaluated by calculating stimulation indices and total amount of secreted insulin during high glucose stimulation (area under the curve) through dynamic perifusion experiments was similar across all paired groups from both DCD and donation after brain death donors. In our hands, islet yield (IEQ/g) from the pancreas tails used as study groups was higher than that of the pancreas heads as expected although this difference did not always reach statistical significance because of great variability probably due to suboptimal quality of organs released for research purposes. Moreover, islets from DCD organs had greater purity than controls (P ≤ 0.01) in the HMP study group. Furthermore, our investigation revealed no significant differences in pancreas histology, oxidative stress markers, and apoptosis indicators. CONCLUSIONS For the first time, a comparative analysis was conducted, using a split model, to assess the effects of various preservation methods on islets derived from pancreas donors. Nevertheless, no discernible variances were observed in terms of islet functionality, histological attributes, or isolation efficacy. Further investigations are needed to validate these findings for clinical application.
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Affiliation(s)
- Antoine Buemi
- Surgery and Abdominal Transplantation Division, Department of Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Nizar I. Mourad
- Pôle de Chirurgie Expérimentale et Transplantation, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Caroline Bouzin
- IREC Imaging Platform (2IP, RRID:SCR_023378), Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Arnaud Devresse
- Nephrology Division, Department of Internal Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Delphine Hoton
- Department of Anatomical Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Aurelie Daumerie
- IREC Imaging Platform (2IP, RRID:SCR_023378), Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Francis Zech
- Pôle de Chirurgie Expérimentale et Transplantation, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Tom Darius
- Surgery and Abdominal Transplantation Division, Department of Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Nada Kanaan
- Nephrology Division, Department of Internal Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Pierre Gianello
- Pôle de Chirurgie Expérimentale et Transplantation, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Michel Mourad
- Surgery and Abdominal Transplantation Division, Department of Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
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6
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Mazilescu LI, Parmentier C, Kalimuthu SN, Ganesh S, Kawamura M, Goto T, Noguchi Y, Selzner M, Reichman TW. Normothermic ex situ pancreas perfusion for the preservation of porcine pancreas grafts. Am J Transplant 2022; 22:1339-1349. [PMID: 35258859 PMCID: PMC9314088 DOI: 10.1111/ajt.17019] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/28/2022] [Accepted: 02/23/2022] [Indexed: 01/25/2023]
Abstract
Pancreas transplantation improves and extends the life of patients with insulin-dependent diabetes. Pancreata from extended criteria donors have been increasingly used due to the scarcity of available grafts. Normothermic ex situ pancreas perfusion (NESPP) can keep grafts metabolically active, potentially allowing for assessment and organ repair, and could improve outcomes of marginal grafts. A novel NESPP technique was developed and tested. Porcine pancreata were removed after a short period of warm ischemia and subjected to 6 h of NESPP. Perfusion parameters, potential graft assessment markers and graft injury were measured. Next, pancreata subjected to 3 h of NESPP were transplanted and animals were followed for up to 3 days. Graft function and injury post-transplantation were evaluated. Using this novel system of perfusion, pancreata were perfused for an extended period of time with minimal edema. Histology at the end of perfusion showed intact islet cells with only mild signs of tissue injury. NESPP transplanted grafts showed immediate function after transplantation, with glucose levels in normal range. NESPP maintains a physiologic environment and excellent graft function without causing significant graft injury. Porcine pancreas transplantation is feasible and allows for in vivo graft assessment of pancreas function and injury after NESPP.
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Affiliation(s)
- Laura I. Mazilescu
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada,Division of NephrologyThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of General, Visceral, and Transplantation SurgeryUniversity Hospital EssenEssenGermany,Division of General SurgeryToronto General HospitalUniversity Health NetworkTorontoOntarioCanada
| | | | - Sangeetha N. Kalimuthu
- Department of PathologyUniversity Health Network and University of TorontoTorontoOntarioCanada
| | - Sujani Ganesh
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Masataka Kawamura
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Toru Goto
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Yuki Noguchi
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Markus Selzner
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada,Division of General SurgeryToronto General HospitalUniversity Health NetworkTorontoOntarioCanada
| | - Trevor W. Reichman
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada,Division of General SurgeryToronto General HospitalUniversity Health NetworkTorontoOntarioCanada
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7
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Branchereau J, Ogbemudia AE, Bas-Bernardet SL, Prudhomme T, Rigaud J, Karam G, Blancho G, Mesnard B. Novel Organ Perfusion and Preservation Strategies in Controlled Donation After Circulatory Death in Pancreas and Kidney Transplantation. Transplant Proc 2021; 54:77-79. [PMID: 34879976 DOI: 10.1016/j.transproceed.2021.09.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/13/2021] [Accepted: 09/28/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Kidney and pancreatic transplants from controlled donation after circulatory death donors are vulnerable to ischemia-reperfusion injuries. In this context of transplant shortage, there is a need to optimize the function of these transplants and to develop novel perfusion and preservation strategies in controlled donation after circulatory death in kidney and pancreatic transplants. IN SITU PERFUSION AND PRESERVATION STRATEGIES In situ regional normothermic perfusion improves the outcome of kidney transplants from controlled donation after circulatory death and provides equivalent results for the kidney from brain-dead donors. In situ regional normothermic perfusion is under investigation for pancreatic transplants. EX SITU PERFUSION AND PRESERVATION STRATEGIES Perfusion on hypothermic machine perfusion is highly recommended for the kidney from controlled donation after cardiac death. Hypothermic oxygenated perfusion machine decreases the rate of graft rejection and graft failure in kidney transplantation. Ex situ normothermic perfusion is an easy way to assess renal function. In the future, kidney transplants could benefit from drug therapy during ex situ normothermic perfusion. In pancreas transplantation, hypothermic machine perfusion and ex situ normothermic perfusion present encouraging results in preclinical studies.
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Affiliation(s)
- J Branchereau
- Department of Urology and Transplantation Surgery, Nantes, France; Nuffield Department of Surgical Science, Oxford, United Kingdom; Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Nantes University, Nantes, France.
| | - A E Ogbemudia
- Nuffield Department of Surgical Science, Oxford, United Kingdom
| | - S Le Bas-Bernardet
- Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Nantes University, Nantes, France
| | - T Prudhomme
- Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Nantes University, Nantes, France
| | - J Rigaud
- Department of Urology and Transplantation Surgery, Nantes, France
| | - G Karam
- Department of Urology and Transplantation Surgery, Nantes, France; Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Nantes University, Nantes, France
| | - G Blancho
- Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Nantes University, Nantes, France
| | - B Mesnard
- Department of Urology and Transplantation Surgery, Nantes, France; Centre de Recherche en Transplantation et Immunologie (ou CRTI), Inserm, Nantes University, Nantes, France
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8
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Ogbemudia AE, Hakim G, Dengu F, El-Gilani F, Dumbill R, Mulvey J, Sayal K, Prudhomme T, Mesnard B, Rozenberg K, Lo Faro L, James T, Oliver J, Sharples E, Mittal S, Johnson P, Friend PJ, Ploeg R, Hunter J, Branchereau J. Development of ex situ normothermic reperfusion as an innovative method to assess pancreases after preservation. Transpl Int 2021; 34:1630-1642. [PMID: 34448276 DOI: 10.1111/tri.13990] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/07/2021] [Indexed: 12/26/2022]
Abstract
Static cold storage (SCS) is the standard method for pancreas preservation prior to transplantation; however, it does not permit organ assessment. Normothermic reperfusion (NR) is utilized clinically for other organs to assess viability. Our aim was to develop NR using normothermic machine perfusion technique to simulate reperfusion at the time of transplantation, enabling evaluation of oxygenated hypothermic machine perfusion (HMPO2) as a newer strategy to optimize pancreas preservation. 13 porcine pancreases procured after circulatory death were divided into 3 groups: 4 pancreases preserved using SCS, and 2 groups preserved by HMPO2 (n = 4 and n = 5, differing by type of preservation solution). Duration of perfusion or cold storage was 6 hours before the 1-hour assessment using NR. Outcome measures were perfusion characteristics, biochemistry and change in tissue water mass as oedema assessment. During NR, the HMPO2 groups demonstrated better perfusion characteristics, normal macroscopic appearances, decreased water mass and one HMPO2 group demonstrated a response to glucose stimulation. Conversely, the SCS group showed an increased water mass and developed early macroscopic appearances of oedema, interstitial haemorrhage and minimal portal outflow. This study suggests that ex situ assessment of pancreases by NR is promising, and that HMPO2 may be better than SCS.
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Affiliation(s)
- Ann Etohan Ogbemudia
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Gabriella Hakim
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK
| | - Fungai Dengu
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Faysal El-Gilani
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Richard Dumbill
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - John Mulvey
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK
| | - Karen Sayal
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK.,CRUK, Oxford Cancer Centre, University of Oxford, Oxford, UK
| | - Thomas Prudhomme
- Department Urology, Kidney Transplantation and Andrology, Toulouse Rangueil University, Toulouse, France
| | - Benoit Mesnard
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Kaithlyn Rozenberg
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK
| | - Letizia Lo Faro
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK
| | - Timothy James
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Joshua Oliver
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Edward Sharples
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Shruti Mittal
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Paul Johnson
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,DRWF Human Islet Isolation Facility, Oxford, UK
| | - Peter J Friend
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Rutger Ploeg
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - James Hunter
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Oxford University Hospitals NHS Foundation Trust, Oxford, UK.,University Hospitals Coventry and Warwickshire NHS Trust, Oxford, UK
| | - Julien Branchereau
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, University of Oxford, Oxford, UK.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation Et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France
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9
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Prudhomme T, Kervella D, Ogbemudia AE, Gauttier V, Le Bas-Bernardet S, Minault D, Hervouet J, Cantarovich D, Karam G, Renaudin K, Blancho G, Branchereau J. Successful pancreas allotransplantations after hypothermic machine perfusion in a novel diabetic porcine model: a controlled study. Transpl Int 2021; 34:353-364. [PMID: 33275807 DOI: 10.1111/tri.13797] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/21/2020] [Accepted: 11/30/2020] [Indexed: 11/28/2022]
Abstract
The standard technique for pancreas preservation for transplantation is static cold storage (SCS). In this experimental study, we compare SCS to hypothermic machine perfusion (HMP) of the pancreas to assess if the latter could safely prolong the ischaemia period prior to transplantation. We worked in two phases, first with organ preservation for 24 h and second, preservation for either 2 or 6 h before allotransplantation. In phase 1, exocrine injury markers were found to be nonsignificantly lower, in the HMP group (n = 3) vs. SCS (n = 3) after 24 h of preservation; amylase (P = 0.2), lipase (P = 0.3) and lactate dehydrogenase (P = 0.1). In phase 2, 14 recipient diabetic pigs (after total pancreatectomy) received allotransplantations with n = 4 and n = 4 pancreases after HMP for 2 and 6 h vs. n = 3 and n = 3 pancreases after SCS for 2 and 6 h, respectively. There were no differences in recipient survival (P = 0.7), and mean survival was 14 days (0-53 days). All recipients had allograft function defined as detectable C-peptide and independent normoglycemia. We have not highlighted vascular thrombosis in all allotransplantations. This study reports the first successful pancreas allotransplantation after HMP preservation for up to 6 h with no evidence of graft thrombosis.
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Affiliation(s)
- Thomas Prudhomme
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Delphine Kervella
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | | | - Vanessa Gauttier
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - David Minault
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Jérémy Hervouet
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Diego Cantarovich
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Georges Karam
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Karine Renaudin
- Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France.,Département d'Anatomie et de Cytologie Pathologique, CHU Nantes, Nantes, France
| | - Gilles Blancho
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Julien Branchereau
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie, UMR1064, INSERM, Université de Nantes, Nantes, France.,Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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10
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Ischemia-Reperfusion Injuries Assessment during Pancreas Preservation. Int J Mol Sci 2021; 22:ijms22105172. [PMID: 34068301 PMCID: PMC8153272 DOI: 10.3390/ijms22105172] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/25/2021] [Accepted: 05/10/2021] [Indexed: 12/20/2022] Open
Abstract
Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of the pancreas were performed at the beginning of the 20th century. These perfusions led to organ oedema, hemorrhage, and venous congestion after revascularization. Despite these early hurdles, a number of factors now favor the use of perfusion during preservation: the encouraging results of HMP in kidney transplantation, the development of new perfusion solutions, and the development of organ perfusion machines for the lung, heart, kidneys and liver. This has led to a resurgence of research in machine perfusion for whole organ pancreas preservation. This review highlights the ischemia-reperfusion injuries assessment during ex vivo pancreas perfusion, both for assessment in pre-clinical experimental models as well for future use in the clinic. We evaluated perfusion dynamics, oedema assessment, especially by impedance analysis and MRI, whole organ oxygen consumption, tissue oxygen tension, metabolite concentrations in tissue and perfusate, mitochondrial respiration, cell death, especially by histology, total cell free DNA, caspase activation, and exocrine and endocrine assessment.
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11
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Abstract
PURPOSE OF REVIEW To summarize recently published studies of preservation strategies including machine perfusion in pancreas transplantation. RECENT FINDINGS The shortage of conventional donors is leading units to use extended criteria donors (ECDs) and donors after cardiac death (DCD). Static cold storage (SCS) is still the standard method of preservation for pancreases and University of Wisconsin remains the gold standard preservation solution. In experimental studies, oxygen delivered during preservation reduced tissue injury and improved islet cell yield and function. Hypothermic machine perfusion of discarded human pancreases has been shown to improve adenosine triphosphate levels without adversely effect histology and oedema compared with SCS. Normothermic machine perfusion of discarded human organs has so far been challenging and led to increasing injury, rather than preservation. There are currently no clinical studies in pancreas transplant with the exception of a small number of pancreases being transplanted following normothermic regional perfusion. SUMMARY The storm of new organ preservation methods is now being more widely studied in the pancreas, with some promising results. These new strategies have the potential to allow expansion of the donor pool and greater utilization of ECD and DCD organs.
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12
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Prudhomme T, Renaudin K, Lo Faro ML, Cantarovich D, Kervella D, Minault D, Hervouet J, Le Bas-Bernardet S, Karam G, Blancho G, Branchereau J. Ex situ hypothermic perfusion of nonhuman primate pancreas: A feasibility study. Artif Organs 2020; 44:736-743. [PMID: 31995645 DOI: 10.1111/aor.13655] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 01/16/2020] [Accepted: 01/23/2020] [Indexed: 12/15/2022]
Abstract
Pancreatic static cold storage (SCS) is the gold-standard method for pancreas preservation. Our main objective was to evaluate feasibility of hypothermic perfusion (HP) of nonhuman primates' pancreases for potential organ transplantation. Seven baboon pancreases were tested. Animals were included in a study approved by the French Research Ministry of Health. Two groups were compared: the control group (n = 2) was preserved using conventional SCS for 24-h and the perfusion group (n = 5) used HP for 24-h, with three different perfusion pressures (PP): 15 (n = 3), 20 (n = 1), and 25 mm Hg (n = 1). In the control group, focal congestion of islets was observed after 6-h. At 24-h, ischemic necrosis and multifocal congestion also occurred. In the HP group, at 15 mm Hg PP, multifocal congestion of islets was present at 24-h. At 20 mm Hg PP, no ischemic necrosis was found after 6-h. At 12-h and 24-h, focal congestion of islets was seen. At 25 mm Hg PP, focal congestion of islets appeared after 12-h. Immunostaining for insulin, glucagon, and somatostatin was normal and similar in controls and perfused pancreas transplants even after 24-h. Apoptosis index represented by cleaved caspase 3 activity, was less than 1% in perfusion and control groups, even after 24-h. HP of nonhuman primate pancreas is feasible and not deleterious as far as 24-h compared to SCS. SCS for more than 12-h was harmful for the transplants. Systolic perfusion pressure between 15-20 mm Hg did not cause any pathological injury of the tested organs.
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Affiliation(s)
- Thomas Prudhomme
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Karine Renaudin
- Département d'anatomie et cytologie pathologique, CHU Nantes, Nantes, France
| | - Maria Letizia Lo Faro
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, United Kingdom
| | - Diego Cantarovich
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Delphine Kervella
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France
| | - David Minault
- Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Jérémy Hervouet
- Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Georges Karam
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Gilles Blancho
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France
| | - Julien Branchereau
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie (CRTI), UMR1064, INSERM, Université de Nantes, Nantes, France.,Oxford Transplant Centre, Nuffield Department of Surgical Sciences, Churchill Hospital, Oxford, United Kingdom
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13
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Rijkse E, IJzermans JNM, Minnee RC. Machine perfusion in abdominal organ transplantation: Current use in the Netherlands. World J Transplant 2020; 10:15-28. [PMID: 32110511 PMCID: PMC7031624 DOI: 10.5500/wjt.v10.i1.15] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 12/03/2019] [Accepted: 12/19/2019] [Indexed: 02/05/2023] Open
Abstract
Scarcity of donor organs and the increment in patients awaiting a transplant increased the use of organs from expanded criteria donors or donation after circulatory death. Due to the suboptimal outcomes of these donor organs, there is an increased interest in better preservation methods, such as ex vivo machine perfusion or abdominal regional perfusion to improve outcomes. This state-of-the-art review aims to discuss the available types of perfusion techniques, its potential benefits and the available evidence in kidney, liver and pancreas transplantation. Additionally, translational steps from animal models towards clinical studies will be described, as well as its application to clinical practice, with the focus on the Netherlands. Despite the lack of evidence from randomized controlled trials, currently available data suggest especially beneficial effects of normothermic regional perfusion on biliary complications and ischemic cholangiopathy after liver transplantation. For ex vivo machine perfusion in kidney transplantation, hypothermic machine perfusion has proven to be beneficial over static cold storage in a randomized controlled trial, while normothermic machine perfusion is currently under investigation. For ex vivo machine perfusion in liver transplantation, normothermic machine perfusion has proven to reduce discard rates and early allograft dysfunction. In response to clinical studies, hypothermic machine perfusion for deceased donor kidneys has already been implemented as standard of care in the Netherlands.
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Affiliation(s)
- Elsaline Rijkse
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam 3015 GD, Netherlands
| | - Jan NM IJzermans
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam 3015 GD, Netherlands
| | - Robert C Minnee
- Division of HPB and Transplant Surgery, Department of Surgery, Erasmus MC University Medical Center, Rotterdam 3015 GD, Netherlands
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14
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Prudhomme T, Kervella D, Le Bas-Bernardet S, Cantarovich D, Karam G, Blancho G, Branchereau J. Ex situ Perfusion of Pancreas for Whole-Organ Transplantation: Is it Safe and Feasible? A Systematic Review. J Diabetes Sci Technol 2020; 14:120-134. [PMID: 31409133 PMCID: PMC7189158 DOI: 10.1177/1932296819869312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Pancreas transplantation is currently one of the best treatments proposed in highly selected patients with unstable and brittle type 1 diabetes. The objective of pancreas transplantation is to restore normoglycemia and avoid the occurrence of complications associated with diabetes. Graft pancreatitis and thrombosis, arising from ischemia reperfusion injuries, are major causes of graft loss in the postoperative period. Ex situ perfusion, in hypothermic or normothermic settings, allowed to improve ischemic reperfusion injury in other organ transplantations (kidney, liver, or lung). The development of pancreatic graft perfusion techniques would limit these ischemic reperfusion injuries. OBJECTIVE Evaluation of the safety and feasibility of ex situ perfusion of pancreas for whole-organ transplantation. METHODS English literature about pancreas perfusion was analyzed using electronic database Medline via PubMed (1950-2018). Exclusion criteria were studies that did not specify the technical aspects of machine perfusion and studies focused only on pancreas perfusion for islet isolation. RESULTS Hypothermic machine perfusion for pancreas preservation has been evaluated in nine studies and normothermic machine perfusion in ten studies. We evaluated machine perfusion model, types of experimental model, anatomy, perfusion parameters, flushing and perfusion solution, length of perfusion, and comparison between static cold storage and perfusion. CONCLUSIONS This review compared ex vivo machine perfusion of experimental pancreas for whole-organ transplantation. Pancreas perfusion is feasible and could be a helpful tool to evaluate pancreas prior to transplantation. Pancreas perfusion (in hypothermic or normothermic settings) could reduce ischemic reperfusion injuries, and maybe could avoid pancreas thrombosis and reduce morbidity of pancreas transplantation.
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Affiliation(s)
- Thomas Prudhomme
- Centre de Recherche en Transplantation
et Immunologie UMR 1064, INSERM, Université de Nantes, France
- Institut de Transplantation Urologie
Néphrologie (ITUN), CHU Nantes, France
| | - Delphine Kervella
- Centre de Recherche en Transplantation
et Immunologie UMR 1064, INSERM, Université de Nantes, France
- Institut de Transplantation Urologie
Néphrologie (ITUN), CHU Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Centre de Recherche en Transplantation
et Immunologie UMR 1064, INSERM, Université de Nantes, France
- Institut de Transplantation Urologie
Néphrologie (ITUN), CHU Nantes, France
| | - Diego Cantarovich
- Institut de Transplantation Urologie
Néphrologie (ITUN), CHU Nantes, France
| | - Georges Karam
- Institut de Transplantation Urologie
Néphrologie (ITUN), CHU Nantes, France
| | - Gilles Blancho
- Centre de Recherche en Transplantation
et Immunologie UMR 1064, INSERM, Université de Nantes, France
- Institut de Transplantation Urologie
Néphrologie (ITUN), CHU Nantes, France
| | - Julien Branchereau
- Centre de Recherche en Transplantation
et Immunologie UMR 1064, INSERM, Université de Nantes, France
- Institut de Transplantation Urologie
Néphrologie (ITUN), CHU Nantes, France
- Julien Branchereau, Centre de Recherche en
Transplantation et Immunologie UMR 1064, INSERM, 30 Bd Jean Monnet, Nantes
44035, France.
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15
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Branchereau J, Renaudin K, Kervella D, Bernadet S, Karam G, Blancho G, Cantarovich D. Hypothermic pulsatile perfusion of human pancreas: Preliminary technical feasibility study based on histology. Cryobiology 2018; 85:56-62. [PMID: 30292812 DOI: 10.1016/j.cryobiol.2018.10.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 09/21/2018] [Accepted: 10/01/2018] [Indexed: 01/21/2023]
Abstract
BACKGROUND There are currently two approaches to hypothermic preservation for most solid organs: static or dynamic. Cold storage is the main method used for static storage (SS), while hypothermic pulsatile perfusion (HPP) and other machine perfusion-based methods, such as normothermic machine perfusion and oxygen persufflation, are the methods used for dynamic preservation. HPP is currently approved for kidney transplantation. METHODS We evaluated, for the first time, the feasibility of HPP on 11 human pancreases contraindicated for clinical transplantation because of advanced age and/or history of severe alcoholism and/or abnormal laboratory tests. Two pancreases were used as SS controls, pancreas splitting was performed on 2 other pancreases for SS and HPP and 7 pancreases were tested for HPP. HPP preservation lasted 24 h at 25 mmHg. Resistance index was continuously monitored and pancreas and duodenum histology was evaluated every 6 h. RESULTS The main finding was the complete absence of edema of the pancreas and duodenum at all time-points during HPP. Insulin, glucagon and somatostatin staining was normal. Resistance index decreased during the first 12 h and remained stable thereafter. CONCLUSION 24 h hypothermic pulsatile perfusion of marginal human pancreas-duodenum organs was feasible with no deleterious parenchymal effect. These observations encourage us to further develop this technique and evaluate the safety of HPP after clinical transplantation.
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Affiliation(s)
- J Branchereau
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
| | - K Renaudin
- Department of Pathology, CHU Nantes, Nantes, France
| | - Delphine Kervella
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France
| | - S Bernadet
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France
| | - Georges Karam
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Gilles Blancho
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - D Cantarovich
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
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16
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Hypothermic Oxygenated Machine Perfusion of the Human Donor Pancreas. Transplant Direct 2018; 4:e388. [PMID: 30498765 PMCID: PMC6233671 DOI: 10.1097/txd.0000000000000829] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/18/2018] [Indexed: 12/11/2022] Open
Abstract
Supplemental digital content is available in the text. Background Transplantation of beta cells by pancreas or islet transplantation is the treatment of choice for a selected group of patients suffering from type 1 diabetes mellitus. Pancreata are frequently not accepted for transplantation, because of the relatively high vulnerability of these organs to ischemic injury. In this study, we evaluated the effects of hypothermic machine perfusion (HMP) on the quality of human pancreas grafts. Methods Five pancreata derived from donation after circulatory death (DCD) and 5 from donation after brain death (DBD) donors were preserved by oxygenated HMP. Hypothermic machine perfusion was performed for 6 hours at 25 mm Hg by separate perfusion of the mesenteric superior artery and the splenic artery. Results were compared with those of 10 pancreata preserved by static cold storage. Results During HMP, homogeneous perfusion of the pancreas could be achieved. Adenosine 5′-triphosphate concentration increased 6,8-fold in DCD and 2,6-fold in DBD pancreata. No signs of cellular injury, edema or formation of reactive oxygen species were observed. Islets of Langerhans with good viability and in vitro function could be isolated after HMP. Conclusions Oxygenated HMP is a feasible and safe preservation method for the human pancreas that increases tissue viability.
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17
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Dholakia S, Royston E, Sharples EJ, Sankaran V, Ploeg RJ, Friend PJ. Preserving and perfusing the allograft pancreas: Past, present, and future. Transplant Rev (Orlando) 2018; 32:127-131. [DOI: 10.1016/j.trre.2018.02.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 02/09/2018] [Accepted: 02/19/2018] [Indexed: 01/12/2023]
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18
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Hamaoui K, Gowers S, Sandhu B, Vallant N, Cook T, Boutelle M, Casanova D, Papalois V. Development of pancreatic machine perfusion: translational steps from porcine to human models. J Surg Res 2018; 223:263-274. [PMID: 29325720 DOI: 10.1016/j.jss.2017.11.052] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 10/31/2017] [Accepted: 11/21/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hypothermic machine perfusion (HMP) is increasingly being used for extended criteria kidney grafts. Pancreatic HMP is challenging because physiologically the pancreas is a low-flow organ susceptible to edema. We report the successful development of preclinical HMP models using porcine pancreases, as well as human pancreases unsuitable for clinical transplantation. METHODS Ten porcine pancreases were used in the development of these perfusion models. Pancreases underwent 24 h of static cold storage (SCS, n = 3) and then viability assessment on an isolated oxygenated normothermic reperfusion (NRP) circuit or 24-h SCS, 5 h of HMP, and then NRP (SCS-HMP, n = 3). Human pancreases (n = 3) were used in the development of a preclinical model. RESULTS Porcine HMP demonstrated stable perfusion indices at low pressures, with a weight gain of between 15.3% and 27.6%. During NRP, SCS-HMP pancreases demonstrated stable perfusion flow indices (PFIs) throughout reperfusion (area under the curve was in the range of 0.49-2.04 mL/min/100 g/mm Hg), whereas SCS-only pancreases had deteriorating PFI with a decline of between 19% and 46%. Human pancreas models demonstrated stable PFI between 0.18 and 0.69 mL/min/100 g/mm Hg during HMP with weight gain of between 3.9% and 14.7%. NRP perfusion in porcine and human models was stable, and functional assessment via insulin secretion demonstrated beta cell viability. Exocrine function was intact with production of pancreatic secretions only in human grafts. CONCLUSIONS Application of machine perfusion in preclinical porcine and human pancreas models is feasible and successful; the development of these translational models could be beneficial in improving pancreas preservation before transplantation and allowing organ viability assessment and optimization.
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Affiliation(s)
- Karim Hamaoui
- Department of Surgery, Imperial College London, London, UK.
| | - Sally Gowers
- Department of Bioengineering, Imperial College London, London, UK
| | - Bynvant Sandhu
- Department of Surgery, Imperial College London, London, UK
| | | | - Terry Cook
- Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Martyn Boutelle
- Department of Bioengineering, Imperial College London, London, UK
| | - Daniel Casanova
- Department of Surgery, Imperial College London, London, UK; Department of Surgery, University of Cantabria, Santander, Spain
| | - Vassilios Papalois
- Department of Surgery, Imperial College London, London, UK; Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
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19
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Krezdorn N, Tasigiorgos S, Wo L, Turk M, Lopdrup R, Kiwanuka H, Win TS, Bueno E, Pomahac B. Tissue conservation for transplantation. Innov Surg Sci 2017; 2:171-187. [PMID: 31579751 PMCID: PMC6754021 DOI: 10.1515/iss-2017-0010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023] Open
Abstract
Pathophysiological changes that occur during ischemia and subsequent reperfusion cause damage to tissues procured for transplantation and also affect long-term allograft function and survival. The proper preservation of organs before transplantation is a must to limit these injuries as much as possible. For decades, static cold storage has been the gold standard for organ preservation, with mechanical perfusion developing as a promising alternative only recently. The current literature points to the need of developing dedicated preservation protocols for every organ, which in combination with other interventions such as ischemic preconditioning and therapeutic additives offer the possibility of improving organ preservation and extending it to multiple times its current duration. This review strives to present an overview of the current body of knowledge with regard to the preservation of organs and tissues destined for transplantation.
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Affiliation(s)
- Nicco Krezdorn
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Hannover Medical School, Hannover, Germany
| | - Sotirios Tasigiorgos
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Luccie Wo
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Marvee Turk
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Rachel Lopdrup
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Harriet Kiwanuka
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Thet-Su Win
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Ericka Bueno
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Bohdan Pomahac
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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20
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Kuan KG, Wee MN, Chung WY, Kumar R, Mees ST, Dennison A, Maddern G, Trochsler M. Extracorporeal machine perfusion of the pancreas: technical aspects and its clinical implications – a systematic review of experimental models. Transplant Rev (Orlando) 2016; 30:31-47. [DOI: 10.1016/j.trre.2015.06.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 06/11/2015] [Accepted: 06/14/2015] [Indexed: 12/25/2022]
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21
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Bruns H, Schemmer P. Machine perfusion in solid organ transplantation: where is the benefit? Langenbecks Arch Surg 2014; 399:421-427. [PMID: 24429900 DOI: 10.1007/s00423-014-1161-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 01/01/2014] [Indexed: 12/26/2022]
Abstract
BACKGROUND Machine perfusion (MP) in solid organ transplantation has been a topic of variable importance for decades. At the dawn of organ transplantation, MP was one of the standard techniques for preservation; today's gold standard for organ preservation for transplantation is cold storage (CS). The outcome after transplantation of solid organs has tremendously improved over the last five decades. MP has been continuously under investigation and may be an option for organ preservation in selected cases; however, there is only little evidence from clinical trials that can be used to advocate for MP as a routine organ preservation method. METHODS This article reviews the current knowledge on MP in the field of solid organ transplantation with special focus on findings from clinical trials. CONCLUSION Especially in heart and lung transplantation, MP seems to be a promising tool to improve postoperative outcome, but a general evidence-based recommendation for or against an application of MP cannot be given due to the lack of the highest level of clinical evidence. Gold standards such as CS should not be left behind without good reason. Randomized clinical trials are desperately needed to further improve outcome and for better understanding of the underlying pathophysiological mechanisms.
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Affiliation(s)
- Helge Bruns
- Department of General and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
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22
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Current state of pancreas preservation and implications for DCD pancreas transplantation. Transplantation 2013; 95:1419-24. [PMID: 23579769 DOI: 10.1097/tp.0b013e318285558f] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
One of the main factors limiting potential uptake of pancreas transplantation, particularly in the United Kingdom, is the shortage of grafts. There has therefore been a recent expansion, particularly in the United Kingdom, in the utilization of grafts from donation after cardiac death (DCD) donors. These grafts are subjected to a greater ischemic insult and are arguably at higher risk of poor functional outcome. Although conventional preservation techniques may be adequate for donation after brain death (DBD) and low-risk DCD pancreases, as the number of DCD pancreas transplants increase and the threshold for rejecting organs decreases, the importance of optimal preservation techniques is going to increase. Over recent years, there have been significant advances in preservation techniques for DCD kidneys, improving the outcome of these marginal grafts. However, the use of such techniques for pancreas preservation is extremely limited and mainly historical. This overview describes the background and results of the established method of pancreas preservation for DBD, namely, cold static storage, and describes the use of the two-layer method. It also reviews pulsatile machine perfusion and normothermic perfusion for pancreas preservation techniques, which have shown promise in the preservation of DCD kidney grafts. The use of these techniques in pancreas preservation is predominantly historical but warrants reevaluation as to the feasibility of applying these techniques to DCD pancreas grafts not only for preservation but also for viability assessment. Further areas for development of pancreas preservation are discussed.
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23
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Squifflet JP, LeDinh H, de Roover A, Meurisse M. Pancreas Preservation for Pancreas and Islet Transplantation: A Minireview. Transplant Proc 2011; 43:3398-401. [DOI: 10.1016/j.transproceed.2011.09.052] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Islet transplantation: factors in short-term islet survival. Arch Immunol Ther Exp (Warsz) 2011; 59:421-9. [PMID: 21984594 DOI: 10.1007/s00005-011-0143-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 05/25/2011] [Indexed: 12/20/2022]
Abstract
Islet transplantation has the potential to cure type 1 diabetes. In recent years, the proportion of patients achieving initial insulin independence has improved, but longer term outcomes remain poor compared to those for whole pancreas transplants. This review article will discuss factors affecting islet yield and viability leading up to transplantation and in the immediate post-transplant period.
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Guibert EE, Petrenko AY, Balaban CL, Somov AY, Rodriguez JV, Fuller BJ. Organ Preservation: Current Concepts and New Strategies for the Next Decade. Transfus Med Hemother 2011; 38:125-142. [PMID: 21566713 PMCID: PMC3088735 DOI: 10.1159/000327033] [Citation(s) in RCA: 206] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2011] [Accepted: 01/26/2011] [Indexed: 12/12/2022] Open
Abstract
SUMMARY: Organ transplantation has developed over the past 50 years to reach the sophisticated and integrated clinical service of today through several advances in science. One of the most important of these has been the ability to apply organ preservation protocols to deliver donor organs of high quality, via a network of organ exchange to match the most suitable recipient patient to the best available organ, capable of rapid resumption of life-sustaining function in the recipient patient. This has only been possible by amassing a good understanding of the potential effects of hypoxic injury on donated organs, and how to prevent these by applying organ preservation. This review sets out the history of organ preservation, how applications of hypothermia have become central to the process, and what the current status is for the range of solid organs commonly transplanted. The science of organ preservation is constantly being updated with new knowledge and ideas, and the review also discusses what innovations are coming close to clinical reality to meet the growing demands for high quality organs in transplantation over the next few years.
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Affiliation(s)
- Edgardo E. Guibert
- Centro Binacional (Argentina-Italia) de Investigaciones en Criobiología Clínica y Aplicada (CAIC), Universidad Nacional de Rosario, Argentina
| | - Alexander Y. Petrenko
- Department of Cryobiochemistry, Institute for Problems of Cryobiology and Cryomedicine, Ukraine Academy of Sciences, Kharkov, Ukraine
| | - Cecilia L. Balaban
- Centro Binacional (Argentina-Italia) de Investigaciones en Criobiología Clínica y Aplicada (CAIC), Universidad Nacional de Rosario, Argentina
| | - Alexander Y. Somov
- Department of Cryobiochemistry, Institute for Problems of Cryobiology and Cryomedicine, Ukraine Academy of Sciences, Kharkov, Ukraine
| | - Joaquín V. Rodriguez
- Centro Binacional (Argentina-Italia) de Investigaciones en Criobiología Clínica y Aplicada (CAIC), Universidad Nacional de Rosario, Argentina
| | - Barry J. Fuller
- Cell, Tissue and Organ Preservation Unit, Department of Surgery & Liver Transplant Unit, UCL Medical School, Royal Free Hospital Campus, London, UK
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Taylor MJ, Baicu SC. Current state of hypothermic machine perfusion preservation of organs: The clinical perspective. Cryobiology 2010; 60:S20-35. [PMID: 19857479 PMCID: PMC2891866 DOI: 10.1016/j.cryobiol.2009.10.006] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Revised: 10/01/2009] [Accepted: 10/20/2009] [Indexed: 01/16/2023]
Abstract
This review focuses on the application of hypothermic perfusion technology as a topic of current interest with the potential to have a salutary impact on the mounting clinical challenges to improve the quantity and quality of donor organs and the outcome of transplantation. The ex vivo perfusion of donor organs on a machine prior to transplant, as opposed to static cold storage on ice, is not a new idea but is being re-visited because of the prospects of making available more and better organs for transplantation. The rationale for pursuing perfusion technology will be discussed in relation to emerging data on clinical outcomes and economic benefits for kidney transplantation. Reference will also be made to on-going research using other organs with special emphasis on the pancreas for both segmental pancreas and isolated islet transplantation. Anticipated and emerging benefits of hypothermic machine perfusion of organs are: (i) maintaining the patency of the vascular bed, (ii) providing nutrients and low demand oxygen to support reduced energy demands, (iii) removal of metabolic by-products and toxins, (iv) provision of access for administration of cytoprotective agents and/or immunomodulatory drugs, (v) increase of available assays for organ viability assessment and tissue matching, (vi) facilitation of a change from emergency to elective scheduled surgery with reduced costs and improved outcomes, (vii) improved clinical outcomes as demonstrated by reduced PNF and DGF parameters, (viii) improved stabilization or rescue of ECD kidneys or organs from NHBD that increase the size of the donor pool, (ix) significant economic benefit for the transplant centers and reduced health care costs, and (x) provision of a technology for ex vivo use of non-transplanted human organs for pharmaceutical development research.
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Taylor MJ, Baicu S, Greene E, Vazquez A, Brassil J. Islet isolation from juvenile porcine pancreas after 24-h hypothermic machine perfusion preservation. Cell Transplant 2010; 19:613-28. [PMID: 20149300 DOI: 10.3727/096368910x486316] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Pancreas procurement for islet isolation and transplantation is limited by concerns for the detrimental effects of postmortem ischemia. Hypothermic machine perfusion (HMP) preservation technology has had a major impact in circumventing ischemic injury in clinical kidney transplantation and is applied here to the preservation and procurement of viable islets after hypothermic perfusion preservation of porcine pancreata because pigs are now considered the donor species of choice for xenogeneic islet transplantation. Pancreases were surgically removed from young (<6 months) domestic Yorkshire pigs (25-32 kg), either before or after 30 min of warm ischemia time (WIT), and cannulated for perfusion. Each pancreas was assigned to one of six preservation treatment groups: fresh controls-processed immediately (cold ischemia <1 h) (G1, n = 7); static cold storage-flushed with cold UW-Viaspan and stored in UW-Viaspan at 2-4 degrees C for 24 h with no prior WIT (G2, n = 9); HMP perfused on a LifePort(R) machine at 4-6 degrees C and low pressure (10 mmHg) for 24 h with either KPS1 solution (G3, n = 7) or Unisol-UHK (G4, n = 7). Additional treatment groups to evaluate the effects of prior warm ischemia examined islet isolation after 30 min WIT in situ without (G5, n = 6) or with subsequent 24-h HMP with KPS1 (G6, n = 7). The pancreas was intraductally distended with Liberase PI enzyme and normothermically digested. The isolated islets were purified by a continuous density-gradient centrifugation. Perfusion-induced glandular edema was G3 = 138 +/- 19%, G4 = 160 +/- 16%, and G6 = 127 +/- 22%. Islet yield (IEQ/g of pancreas) varied between the groups: G1 = 1,425 +/- 610, G2 = 1,002 +/- 262, G3 = 2,242 +/- 449 (p < 0.05 vs. G2), G4 = 1,901 +/- 420 (p < 0.05 vs. G2), G5 = 1,756 +/- 329, and G6 = 1,396 +/- 243. Islet stimulation indices were equivalent between the groups and similar to controls (G1). Insulin content (ng/IE) was different between the treatment groups with the highest insulin content in islets harvested from HMP pancreata. Dithizone staining for islets consistently showed more uniform digestion of the perfused organs, with greater separation of the tissue, less entrapped islets, and higher islet yield and purity. The salutary effects of HMP for 24 h were also manifest after 30-min prior warm ischemia. We conclude that 24 h of HMP is well tolerated, leading to moderate edema but no loss of function of the harvested islets. The edema appears to aid in enzymatic digestion, producing a greater yield and purity of islets compared with pancreas subjected to 24 h of static cold storage.
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Ridgway D, Manas D, Shaw J, White S. Preservation of the donor pancreas for whole pancreas and islet transplantation. Clin Transplant 2010; 24:1-19. [DOI: 10.1111/j.1399-0012.2009.01151.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Ductal Injection of University of Wisconsin Solution Prior to Pancreas Preservation Prevents Oxidative Cell Damage. Transplant Proc 2009; 41:3628-31. [DOI: 10.1016/j.transproceed.2009.06.230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2008] [Revised: 06/02/2009] [Accepted: 06/24/2009] [Indexed: 01/11/2023]
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Abstract
PURPOSE OF REVIEW Organ preservation aims at reducing ischemia-reperfusion injury and maintains or even improves its function, and, therefore, increases transplant safety and efficiency. With the chronic lack of organs for transplantation, marginal donors are more and more frequently used in Western countries. New challenges, therefore, have to be met in organ preservation. RECENT FINDINGS We summarize the effects of cold preservation on various organ grafts, with particular emphasis on the pancreas. We review the different preservation solutions currently available in the clinic, and we present the current knowledge and clinical experience in pancreas and islet transplantation. SUMMARY Overall, in whole pancreas and islet transplantation, current cold preservation solutions (University of Wisconsin solution, Celsior, histidine-tryptophan-ketoglutarate) seem to be equivalent, with only few studies showing better results with University of Wisconsin solution. Regarding preservation with the two-layer method, conflicting results have been reported, and proper prospective controlled studies have yet to be performed to gather evidence on its impact on islet yield and function. Some recent developments and future strategies in general organ preservation not yet applied to pancreas preservation are reviewed at the end of the article.
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Abstract
PURPOSE OF REVIEW To summarize advances and limitations in pancreas procurement and preservation for pancreas and islet transplantation, and review advances in islet protection and preservation. RECENT FINDINGS Pancreases procured after cardiac death, with in-situ regional organ cooling, have been successfully used for islet transplantation. Colloid-free Celsior and histidine-tryptophan-ketoglutarate preservation solutions are comparable to University of Wisconsin solution when used for cold storage before pancreas transplantation. Colloid-free preservation solutions are inferior to University of Wisconsin solution for pancreas preservation prior to islet isolation and transplantation. Clinical reports on pancreas transplants suggest that the two-layer method may not offer significant benefits over cold storage with the University of Wisconsin solution: improved oxygenation may depend on the graft size; benefits in experimental models may not translate to human organs. Improvements in islet yield and quality occurred from pancreases treated with inhibitors of stress-induced apoptosis during procurement, storage, isolation or culture desirable before islet isolation and transplantation and may improve islet yield and quality. Methods for real-time, noninvasive assessment of pancreas quality during preservation have been implemented and objective islet-potency assays have been developed and validated. These innovations should contribute to objective evaluation and establishment of improved pancreas-preservation and islet-isolation strategies. SUMMARY Cold storage may be adequate for preservation before pancreas transplants, but insufficient when pancreases are processed for islets or when expanded donors are used. Supplementation of cold-storage solutions with cytoprotective agents and perfusion may improve pancreas and islet transplant outcomes.
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Iwanaga Y, Sutherland DE, Harmon JV, Papas KK. Pancreas preservation for pancreas and islet transplantation. Curr Opin Organ Transplant 2008; 13:445-51. [PMID: 18685343 PMCID: PMC2858000 DOI: 10.1097/mot.0b013e328303df04] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW To summarize advances and limitations in pancreas procurement and preservation for pancreas and islet transplantation, and review advances in islet protection and preservation. RECENT FINDINGS Pancreases procured after cardiac death, with in-situ regional organ cooling, have been successfully used for islet transplantation. Colloid-free Celsior and histidine-tryptophan-ketoglutarate preservation solutions are comparable to University of Wisconsin solution when used for cold storage before pancreas transplantation. Colloid-free preservation solutions are inferior to University of Wisconsin solution for pancreas preservation prior to islet isolation and transplantation. Clinical reports on pancreas and islet transplants suggest that the two-layer method may not offer significant benefits over cold storage with the University of Wisconsin solution: improved oxygenation may depend on the graft size; benefits in experimental models may not translate to human organs. Improvements in islet yield and quality occurred from pancreases treated with inhibitors of stress-induced apoptosis during procurement, storage, isolation or culture. Pancreas perfusion may be desirable before islet isolation and transplantation and may improve islet yields and quality. Methods for real-time, noninvasive assessment of pancreas quality during preservation have been implemented and objective islet potency assays have been developed and validated. These innovations should contribute to objective evaluation and establishment of improved pancreas preservation and islet isolation strategies. SUMMARY Cold storage may be adequate for preservation before pancreas transplants, but insufficient when pancreases are processed for islets or when expanded donors are used. Supplementation of cold storage solutions with cytoprotective agents and perfusion may improve pancreas and islet transplant outcomes.
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Affiliation(s)
- Yasuhiro Iwanaga
- Transplantation Unit, Kyoto University Hospital, Kyoto, Japan
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
| | - David E.R. Sutherland
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
| | - James V. Harmon
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
| | - Klearchos K. Papas
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
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Hosoe M, Furusawa T, Noguchi J, Tokunaga T. Growth of follicles of various animals following ovarian grafting under the kidney capsules of immunodeficient mice. Reprod Med Biol 2008; 7:45-54. [PMID: 29699286 DOI: 10.1111/j.1447-0578.2007.00200.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Aim: Various researchers have studied xenografting ovarian tissues into immunodeficient mice to accelerate the follicular growth of several mammalian species. In this study, the authors focused on the following three points in growing follicles in transplanted ovarian tissues under kidney capsules: the effects of the storage conditions of the donor ovarian tissues, the effects of donor age on the survival rates of grafted mouse ovaries, and the methods used to grow the follicles of xenografted bovine ovaries. Methods and Results: When ovaries stored for 0, 6, 12 or 24 h at 4°C and at room temperature were transplanted under the kidney capsules of immunodeficient mice, fewer mouse and rabbit grafts survived following 24 h storage. The survival rates of bovine grafts were relatively low for all storage times. When mouse ovaries were held for 24 h at 4°C or at room temperature, low-temperature storage effectively improved the survival rates of the grafts. Although the survival rates of grafted genital ridges containing premeiotic germ cells from fetuses and grafted ovaries from mice 0, 10, 20, 40 and 80 days after birth were similar among donors of different ages, the cleavage rate of oocytes following insemination was significantly lower in the grafts from the ovaries of 80-day-old mice. Antral follicles formed in surviving bovine ovarian grafts. Cumulus-oocyte complexes were collected from the grafted ovaries of fetuses and calves, and the oocytes reached the metaphase II stage following culture, but they did not develop to the pronuclear stage after in vitro fertilization. Conclusion: Our findings provide basic data on xenografting ovarian tissues into immunodeficient mice to accelerate the growth of follicles. (Reprod Med Biol 2008; 7: 45-54).
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Affiliation(s)
- Misa Hosoe
- Reproductive Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, Ibaraki, Japan
| | - Tadashi Furusawa
- Reproductive Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, Ibaraki, Japan
| | - Junko Noguchi
- Reproductive Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, Ibaraki, Japan
| | - Tomoyuki Tokunaga
- Reproductive Biology Research Unit, Division of Animal Sciences, National Institute of Agrobiological Sciences, Ibaraki, Japan
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Fuller BJ, Lee CY. Hypothermic perfusion preservation: the future of organ preservation revisited? Cryobiology 2007; 54:129-45. [PMID: 17362905 DOI: 10.1016/j.cryobiol.2007.01.003] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2006] [Revised: 01/11/2007] [Accepted: 01/11/2007] [Indexed: 12/24/2022]
Abstract
Hypothermic perfusion preservation (HPP) was an integral step in the development of early clinical transplantation programmes, and considerable progress was made in understanding the basic principles underlying the technique. In subsequent years, the development of better preservation solutions for cold hypoxic storage, along with pragmatic choices made on grounds of costs and logistics, saw a fall in the application of HPP. More recently, the acute shortage of suitable organ donors and the inevitable pressure to use organs from sub-optimal (or expanded criteria) donors, has forced a re-evaluation of HPP, and the development of a new generation of HPP machines and associated perfusion solutions. This review sets out the historical development of HPP across the range of organs in which the method was originally investigated, describes the biological benefits and drawbacks associated with HPP, and sets out the most recent literature on the topic (including comments on the interest in use of higher temperatures in organ perfusion).
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Affiliation(s)
- Barry J Fuller
- University Department of Surgery and Liver Transplant Unit, Royal Free and University College Medical School, Hampstead, London NW3 2QG, UK.
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35
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Richings NM, Shaw G, Temple-Smith PD, Renfree MB. Growth and histology of ovarian follicles after cold storage in the tammar wallaby. Reprod Fertil Dev 2006; 18:677-88. [PMID: 16930514 DOI: 10.1071/rd06007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2006] [Accepted: 05/02/2006] [Indexed: 11/23/2022] Open
Abstract
Cold storage is a simple method for storing and transporting tissues and organs. The reliability of this method for maintaining structure and function of marsupial ovarian tissue was assessed using histological techniques and follicle culture. Tammar wallaby ovaries were placed in cold storage (phosphate-buffered saline at 4°C) for 24 or 48 h. Although necrotic changes were evident in the germinal epithelium, cortex and interstitial tissue after cold storage, there was little evidence of necrotic changes in ovarian follicles and oocytes appeared normal. Secondary follicles isolated from ovarian tissue after cold storage grew by a similar amount to non-stored follicles when cultured for 4 days in vitro, but no follicles from any group developed to tertiary follicles. Cold storage for up to 24 h had little obvious effect on the structure of ovarian tissue and follicles isolated from this tissue maintained their structure during culture. However, degeneration in culture increased with storage time and was significantly higher after cold storage for 48 h. As demonstrated in the tammar wallaby, cold storage has potential as a method for storage and transport of marsupial ovaries up to 24 h.
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Affiliation(s)
- Nadine M Richings
- Department of Zoology, The University of Melbourne, Vic. 3010, Australia.
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36
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Tytko A, Exner B, Schrock E, Barthel M, Siegel EG, Köhler H, Nebendahl K, Leonhardt U. Hydroxyethyl starch does not improve pancreas preservation with HTK. LANGENBECKS ARCHIV FUR CHIRURGIE 1993; 378:82-5. [PMID: 7682642 DOI: 10.1007/bf00202114] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The effect of hydroxyethyl starch on pancreas preservation with cardioplegic histidine-tryptophan-ketoglutarate solution (HTK) was investigated. The study was performed using an in vitro reperfusion system of the porcine pancreas. During organ preservation pancreatic weight, arterial pressure, volume flow, and washout of amylase and lactate were quantified. Addition of hydroxyethyl starch did not affect arteriovenous volume flow or washout of amylase and lactate during protective perfusion after pancreas preparation. However, hydroxyethyl starch in HTK prevented an increase in pancreatic weight at the end of the protective perfusion (102.2 +/- 4.55% vs 127.8 +/- 4.62% in controls; p < 0.005) and after 24 h cold ischemia (72.9 +/- 3.91% vs. 83.5 +/- 3.49% in controls; p < 0.05). Hydroxyethyl starch did not affect postischemic organ quality assessed during reperfusion in a perfusion chamber by pancreatic vascular resistance, amylase and lactate release, insulin secretion, and oxygen consumption. We conclude that hydroxyethyl starch does not bring about any further improvement in immediate postischemic organ quality assessed in an in vitro reperfusion system.
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Affiliation(s)
- A Tytko
- Department of Medicine, University of Göttingen, Germany
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38
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Heise JW, Casanova D, Field MJ, Munn SR, Najarian JS, Sutherland DE. Cold storage preservation of pancreatic tissue prior to and after islet preparation in a dog autotransplantation model. J Surg Res 1989; 47:30-38. [PMID: 2472512 DOI: 10.1016/0022-4804(89)90044-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Utilizing an intrasplenic canine islet autotransplant model, the effects of cold storage preservation on pancreatic tissue prior to and after collagenase dispersion were examined. A control series, in which freshly retrieved and prepared tissue was transplanted, yielded a 75% success rate (6/8). In contrast, when the pancreas was stored in modified silica gel filtered plasma (SGF I) for 24 hr, no autotransplant was successful (0/6). However, when the islet tissue was prepared following pancreatectomy and then stored in a mannitol-containing modification of SGF (SGF III), autotransplantation was successful in 83% (5/6) after 24 hr of preservation and in 60% (3/5) after 48 hr of preservation. Similarly, the islet tissue was stored in a hyperkalemic hydroxyethyl starch solution (HES) and this was successful in 20% (1/5) after 24 hr of preservation and in 50% (1/2) after 48 hr of preservation. Cold storage preservation techniques for the pancreas prior to islet isolation need to be refined, but dispersed islet-enriched pancreatic tissue can be successfully maintained at 4 degrees C for up to 48 hr prior to transplantation in dogs using established pancreas preservation solutions.
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Affiliation(s)
- J W Heise
- Department of Surgery, University of Minnesota, Minneapolis 55455
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Southard J, Pienaar H, McAnulty J, D’Alessandro A, Hoffmann R, Pirsch J, Kalayoglu M, Sollinger H, Belzer F. The University of Wisconsin solution for organ preservation. Transplant Rev (Orlando) 1989. [DOI: 10.1016/s0955-470x(89)80008-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Sutherland DE, Goetz FC, Moudry KC, Najarian JS. Pancreas transplantation: the Minnesota experience. THE JOURNAL OF DIABETIC COMPLICATIONS 1988; 2:125-9. [PMID: 2975661 DOI: 10.1016/s0891-6632(88)80022-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Between July 1978 and April 1987, a total of 182 pancreas transplants were performed at the University of Minnesota. For the first 100 cases (through October 1984), a variety of surgical techniques and immunosuppressive regimens were used, and 1 year patient and graft functional (insulin-independent) survival rates were 88% and 27%, respectively. From November 1984 to April 1987, a triple therapeutic drug regimen of cyclosporine, azathioprine, and prednisone was used for maintenance immunosuppression, and bladder drainage (BD) (n = 39; 38 cadaver (CAD) and 1 related (REL) donor grafts) and enteric drainage (ED) (n = 40; 21 CAD and 19 REL donor grafts) techniques were compared in 59 nonuremic, nonkidney (NUNK) transplant recipients, 21 recipients of previous kidney (PK) transplants and 8 uremic recipients of simultaneous pancreas and kidney (SPK) transplants. The survival rates were higher in recipients of BD CAD and ED REL than of ED CAD grafts (58% and 59% versus 29% at one year for all, and 84%, 84% and 40% for technically successful cases), but patient survival rates were similar (90%, 93% and 90% at one year). BD allows for early diagnosis of rejection based on urine amylase monitoring, and REL grafts are less prone to incite rejection; thus, we are currently performing only BD for grafts from CAD donors, while both techniques are used for REL donor grafts.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- D E Sutherland
- Department of Surgery, University of Minnesota, Minneapolis
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41
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Squifflet JP, Moudry K, Sutherland DE. Is HLA matching relevant in pancreas transplantation? A registry analysis. Transpl Int 1988; 1:26-9. [PMID: 3075915 DOI: 10.1007/bf00337845] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The International Pancreas Transplant Registry data base was analyzed for the effect of HLA and mismatching on pancreas survival rate. Typing data was available for both donor and recipient at the A, B and DR loci in 524 of 855 cadaver cases reported since 1982 and in 37 related cases. For cadaver cases, the 1-year functional survival rates for grafts mismatched at less than or equal to 3 (N = 163) versus greater than or equal to 4 (N = 361) A, B and DR antigens were 49% versus 39% (P = 0.121); for technically successful (TS) cases the rates were 66% (N = 123) versus 54% (N = 257) (P = 0.038). An effect was seen at A, B and DR loci, but the differences were not significant when considered separately. THe analysis of TS related donor transplants showed a 1-year graft survival rate of 89% for HLA mismatched donors (N = 11) and of 80% for HLA identical donors (N = 11). The survival rate of the latter is significantly higher (P = 0.046) than that of the TS cadaver donor transplants (59% at 1 year, N = 361). The data suggest that the results of pancreas transplantation will be improved by minimizing HLA mismatches. However, a reanalysis with a more complete data base is needed before firm conclusions can be drawn.
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Affiliation(s)
- J P Squifflet
- Department of Transplantation, Clinique U.C.L. Saint Luc, Brussels, Belgium
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42
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Squifflet J, Moudry K, Sutherland DER. Is HLA matching relevant in pancreas transplantation?: A registry analysis. Transpl Int 1988. [DOI: 10.1111/j.1432-2277.1988.tb01775.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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43
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Abstract
The number of pancreas transplants being performed and the success rate have continued to increase. Most pancreas transplants have been placed in diabetic recipients of kidney transplants, but application to nonuremic, non-kidney transplant recipients without end-stage disease is increasing. Drainage of pancreatic graft duct into the bladder allows exocrine function to be assessed directly and has led to earlier diagnosis and treatment of rejection episodes. The improvement in graft survival rates has been associated with the use of cyclosporine in combination with other immunosuppressants. The effect that establishment of a euglycemic state by successful pancreas transplantation has on the specific complications of diabetes is just beginning to be discerned but appears to be favorable if the transplant is performed sufficiently early in the course of the disease.
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Affiliation(s)
- D E Sutherland
- Department of Surgery, University of Minnesota Hospitals, Minneapolis 55455
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44
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Abstract
Canine pancreas tissue slices were incubated at 5 degrees C for 24 hr in solutions containing different saccharides (raffinose, sucrose, mannitol, or glucose). At the end of incubation tissue water (TW expressed as kg H2O/kg dry wt) was determined as a measure of tissue edema. Tissue edema was greatest in slices stored in Eurocollins (EC) solution (TW = 4.96 +/- 0.14) which contains glucose for osmotic pressure. The degree of edema was decreased by saccharides in proportion to their molecular mass: mannitol (MW = 180, TW = 3.84 +/- 0.08), sucrose (MW = 348, TW = 3.54 +/- 0.08), and raffinose (MW = 594, TW = 3.30 +/- 0.07). Tissue edema was also greatest in slices incubated in solutions containing the smallest molecular mass anions: Cl- (TW = 4.02 +/- 0.16), gluconate (TW = 3.69 +/- 0.10), and lactobionate (TW = 3.28 +/- 0.13). Cold storage of the intact pancreas in EC solution for 24 hr did not induce as much edema as in slices (TW = 2.88 +/- 0.10). However, on isolated reperfusion at normothermia (37 degrees C) the pancreas became edematous (TW = 3.33 +/- 0.12). Storage of the pancreas in a lactobionate-raffinose solution did not induce edema after 90 min of normothermic reperfusion. The suppression of tissue edema in the pancreas may be essential to obtaining long-term preservation (24-72 hr) of this organ which is currently limited to about 6-8 hr in EC solution. The newly developed lactobionate-raffinose solution appears to control tissue edema in both tissue slices and the intact-flushed out organ.
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Kneteman NM, Rajotte RV, Warnock GL. Long-term normoglycemia in pancreatectomized dogs transplanted with frozen/thawed pancreatic islets. Cryobiology 1986; 23:214-21. [PMID: 3089686 DOI: 10.1016/0011-2240(86)90047-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Storage of pancreatic islets by cryopreservation would greatly facilitate a large scale program of clinical islet transplantation. We report success on long-term follow-up with autotransplantation of frozen/thawed canine pancreatic fragments. Total pancreatectomy and islet isolation by collagenase ductal perfusion and mechanical disruption preceded either acute autotransplantation or cryogenic preservation prior to autotransplantation. Cryopreservation was by dimethylsulfoxide equilibration, cooling at 0.25 degrees C/min to -75 degrees C, storage in liquid N2 and thawing at 3.5 degrees C/min. Four of five acutely autotransplanted dogs remained normoglycemic for 20 months, with three of four maintaining normal K values on intravenous glucose tolerance test (IVGTT) and nondiabetic values on oral GTT. Four of four dogs transplanted with frozen/thawed islets remained normoglycemic for 15 months with three of four maintaining nondiabetic IV GTT K values and normal oral GTTs for 15 months. Both acutely transplanted and frozen/thawed islets are capable of maintaining long-term metabolic control. Cryopreservation preserved viability of sufficient canine pancreatic islets to reverse diabetes with autotransplantation. Function of the frozen-thawed islets showed minimal deterioration during a follow-up of 15 to 18 months.
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Schulak JA, Kisthard J. The effect of warm ischemia and cold-storage preservation on rat pancreas transplantation. J Surg Res 1984; 36:134-9. [PMID: 6363821 DOI: 10.1016/0022-4804(84)90078-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Pancreatic isografts subjected to preharvest warm ischemia as well as cold-storage preservation in Collins' solution were studied after transplantation into diabetic rats to determine whether warm ischemia will limit the ability to preserve pancreas grafts for transplantation. Warm ischemic periods of up to 2 hr did not alter islet function as measured by daily glucose levels and response to intravenous glucose challenge. Likewise, hypothermic preservation of nonischemic pancreata was also well tolerated for up to 24 hr. However, the combination of preharvest warm ischemia and cold storage was deleterious. Whereas 60 min of warm injury coupled with 12 hr of cold storage resulted in successful transplantation in 86% of recipients, lengthening the duration of either warm or cold ischemia uniformly resulted in nonfunctioning grafts. Thus while islet function in the transplanted pancreas is very tolerant of warm ischemia alone, these studies suggest that it should be kept to a minimum if cold storage preservation is to be used.
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Florack G, Sutherland DE, Cavallini M, Najarian JS. Technical aspects of segmental pancreatic autotransplantation in dogs. Am J Surg 1983; 146:565-74. [PMID: 6356947 DOI: 10.1016/0002-9610(83)90289-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Heterotopic segmental pancreatic autotransplantation in dogs is more appropriate than allograft models for the investigation of several problems associated with transplantation. We have defined the anatomic variations of blood supply in the pancreatic tail and designed various modifications of vascular anastomosis to the iliac vessels in order to eliminate technical failures, such as thrombosis, as much as possible. In 187 of 240 dogs (77.9 percent), the pancreatic artery originated from the splenic artery and the pancreatic vein entered the splenic vein (normal anatomy). The main venous variation was direct confluence of the pancreatic and portal veins (12.1 percent), and the main arterial variation was origin of the pancreatic artery from the superior mesenteric artery (10 percent). Ninety-seven animals with normal anatomy qualified for a comparative study of seven methods of segmental pancreatic autotransplantation. Venous anastomoses were always performed in an end-to-side fashion between the splenic and external iliac veins. Arterial anastomosis techniques follow. Group I: interposition of the splenic artery into the external iliac artery; (14 days, failure rate 50 percent), Group II: end-to-end arterial anastomosis of the splenic artery to a long external iliac artery segment with the graft directed caudad, resulting in an acute curve to the vessel loop (8 dogs, failure rate 38 percent); Group III: end-to-end arterial anastomosis to a long external iliac artery with the graft directed cephalad, resulting in a gentle curve to the vessel loop (11 dogs, failure rate 36 percent); Group IV: end-to-end arterial anastomosis to a short external iliac artery stump (20 dogs, failure rate 20 percent); Group V: same as in Group IV with the addition of a distal splenic arteriovenous fistula (12 dogs, failure rate 17 percent); Group VI: end-to-side anastomosis of the splenic artery to the external iliac artery (31 dogs, failure rate 6 percent); Group VII: same as in Group VI but with the addition of an arteriovenous fistula of the distal splenic vessels (1 dog, failure rate 0). The end-to-side technique proved to be straight-forward and reliable. The low failure rate with this method allows metabolic preservation and other aspects of pancreatic transplantation to be studied and the results to be interpreted without the influence of a high complication rate from the operation itself.
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