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1
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O'Brien Laramy M, Robinson J, Venkatramani CJ, Horn S, Steiner C, Son YJ. Drug Development Considerations for Additives to Organ Preservation Solutions. Transplantation 2025; 109:764-773. [PMID: 39375888 DOI: 10.1097/tp.0000000000005221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified. We have supplemented this strategy with a comparison to available regulatory guidance from the US Food and Drug Administration to highlight potential areas for further clarification. The strategy articulated here is based on Genentech's internal experience for a program intended for use in kidney transplantation.
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Affiliation(s)
| | - Jamie Robinson
- Pharma Technical Regulatory, Genentech, Inc., South San Francisco, CA
| | - C J Venkatramani
- Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA
| | - Stephanie Horn
- Pharma Technical Regulatory-Device and Combination Products, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Carine Steiner
- Analytical Research & Development, Pharma Technical Development, F. Hoffmann-La Roche, Basel, Switzerland
| | - Yoen-Ju Son
- Pharma Technical Development Project and Portfolio Development, South San Francisco, CA
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2
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Leber B, Stimmeder S, Briendl K, Weber J, Rohrhofer L, Aigelsreiter A, Niedrist T, Sucher R, Stiegler P. Equal performance of HTK-based and UW-based perfusion solutions in sub-normothermic liver machine perfusion. Sci Rep 2025; 15:7601. [PMID: 40038333 PMCID: PMC11880568 DOI: 10.1038/s41598-025-90799-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 02/17/2025] [Indexed: 03/06/2025] Open
Abstract
Machine perfusion (MP) is gaining importance in liver transplantation, the only cure for many end-stage liver diseases. Varieties of different MP protocols are available. Currently, various MP protocols are available, differing not only in perfusion temperature but also in the specific perfusion solution required. We aimed to investigate the performance of an HTK-based perfusate during sub-normothermic MP (SNMP) of discarded human liver grafts compared to that of a UW-based solution. Twenty discarded livers (rejected for transplantation by all centers) were subjected to ex-vivo SNMP at 21°C with either HTK- or UW-based solution for 12 h. Perfusate and tissue samples collected before the start, after 6 h, and at the end of SNMP were analyzed for liver enzymes, along with mRNA expression of perfusate and tissue markers associated with organ damage. Hepatocellular viability was assessed by measuring bile production, monitoring pH stability, and analyzing histological changes in HE stained tissue sections. After propensity score matching 16 livers were analyzed. Overall, no differences between HTK- and UW-based solution were detected, except for an increased MLKL mRNA expression and impaired pH stability during SNMP with HTK-based perfusate. No other investigated parameters of cell injury, inflammation or hepatocellular viability supported this finding. Bile production was higher in the 6 HTK-perfused livers compared to the three UW-perfused livers that produced bile. Overall, these findings suggest that HTK performs comparably to a UW-based solution during 12 h of liver SNMP.
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Affiliation(s)
- Bettina Leber
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria.
| | - Sabrina Stimmeder
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Kathrin Briendl
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Jennifer Weber
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Lisa Rohrhofer
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Ariane Aigelsreiter
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Tobias Niedrist
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Robert Sucher
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Philipp Stiegler
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
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Coskun A, Yegen C, Arbak S, Attaallah W, Gunal O, Elmas MA, Ucal Y, Can O, Baş B, Yildirim Z, Seckin I, Demirci S, Serteser M, Ozpinar A, Belce A, Basdemir G, Moldur DE, Derelioglu EI, Yozgatli TK, Erdemgil Y, Unsal I. Melatonin in preservation solutions prevents ischemic injury in rat kidneys. PLoS One 2022; 17:e0273921. [PMID: 36044512 PMCID: PMC9432748 DOI: 10.1371/journal.pone.0273921] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022] Open
Abstract
Transplantation is lifesaving and the most effective treatment for end-stage organ failure. The transplantation success depends on the functional preservation of organs prior to transplantation. Currently, the University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) are the most commonly used preservation solutions. Despite intensive efforts, the functional preservation of solid organs prior to transplantation is limited to hours. In this study, we modified the UW solution containing components from both the UW and HTK solutions and analyzed their tissue-protective effect against ischemic injury. The composition of the UW solution was changed by reducing hydroxyethyl starch concentration and adding Histidine/Histidine-HCl which is the main component of HTK solution. Additionally, the preservation solutions were supplemented with melatonin and glucosamine. The protective effects of the preservation solutions were assessed by biochemical and microscopical analysis at 2, 10, 24, and 72 h after preserving the rat kidneys with static cold storage. Lactate dehydrogenase (LDH) activity in preservation solutions was measured at 2, 10, 24, and 72. It was not detectable at 2 h of preservation in all groups and 10 h of preservation in modified UW+melatonin (mUW-m) and modified UW+glucosamine (mUW-g) groups. At the 72nd hour, the lowest LDH activity (0.91 IU/g (0.63–1.17)) was measured in the mUW-m group. In comparison to the UW group, histopathological damage score was low in modified UW (mUW), mUW-m, and mUW-g groups at 10, 24, and 72 hours. The mUW-m solution at low temperature was an effective and suitable solution to protect renal tissue for up to 72 h.
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Affiliation(s)
- Abdurrahman Coskun
- Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
- Acibadem Labmed Clinical Laboratories, Istanbul, Turkey
- * E-mail:
| | - Cumhur Yegen
- Department of General Surgery, Marmara University, School of Medicine, Istanbul, Turkey
| | - Serap Arbak
- Department of Histology and Embryology, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | - Wafi Attaallah
- Department of General Surgery, Marmara University, School of Medicine, Istanbul, Turkey
| | - Omer Gunal
- Department of General Surgery, Marmara University, School of Medicine, Istanbul, Turkey
| | - Merve Acikel Elmas
- Department of Histology and Embryology, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | - Yasemin Ucal
- Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | - Ozge Can
- Faculty of Engineering, Department of Medical Engineering, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Banu Baş
- Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | - Zeynep Yildirim
- Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | - Ismail Seckin
- Department of Histology and Embryology, Istanbul University Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Sibel Demirci
- Department of Histology and Embryology, Biruni University, School of Medicine, Istanbul, Turkey
| | - Mustafa Serteser
- Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
- Acibadem Labmed Clinical Laboratories, Istanbul, Turkey
| | - Aysel Ozpinar
- Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | - Ahmet Belce
- Department of Medical Biochemistry, Biruni University, School of Medicine, Istanbul, Turkey
| | - Gulcin Basdemir
- Department of Pathology, Memorial Hospital, Istanbul, Turkey
| | - Derya Emel Moldur
- Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | | | | | - Yigit Erdemgil
- Department of Medical Biochemistry, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
| | - Ibrahim Unsal
- Acibadem Labmed Clinical Laboratories, Istanbul, Turkey
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Gluconate-Lactobionate-Dextran Perfusion Solutions Attenuate Ischemic Injury and Improve Function in a Murine Cardiac Transplant Model. Cells 2022; 11:cells11101653. [PMID: 35626690 PMCID: PMC9139252 DOI: 10.3390/cells11101653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/03/2022] [Accepted: 05/10/2022] [Indexed: 12/10/2022] Open
Abstract
Static cold storage is the cheapest and easiest method and current gold standard to store and preserve donor organs. This study aimed to compare the preservative capacity of gluconate-lactobionate-dextran (Unisol) solutions to histidine-tryptophan-ketoglutarate (HTK) solution. Murine syngeneic heterotopic heart transplantations (Balb/c-Balb/c) were carried out after 18 h of static cold storage. Cardiac grafts were either flushed and stored with Unisol-based solutions with high-(UHK) and low-potassium (ULK) ± glutathione, or HTK. Cardiac grafts were assessed for rebeating and functionality, histomorphologic alterations, and cytokine expression. Unisol-based solutions demonstrated a faster rebeating time (UHK 56 s, UHK + Glut 44 s, ULK 45 s, ULK + Glut 47 s) compared to HTK (119.5 s) along with a better contractility early after reperfusion and at the endpoint on POD 3. Ischemic injury led to a significantly increased leukocyte recruitment, with similar degrees of tissue damage and inflammatory infiltrate in all groups, yet the number of apoptotic cells tended to be lower in ULK compared to HTK. In UHK- and ULK-treated animals, a trend toward decreased expression of proinflammatory markers was seen when compared to HTK. Unisol-based solutions showed an improved preservative capacity compared with the gold standard HTK early after cardiac transplantation. Supplemented glutathione did not further improve tissue-protective properties.
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5
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Sakai T, Ko JS, Crouch CE, Kumar S, Little MB, Chae MS, Ganoza A, Gómez-Salinas L, Humar A, Kim SH, Koo BN, Rodriguez G, Sirianni J, Smith NK, Song JG, Ullah A, Hendrickse A. Perioperative management of adult living donor liver transplantation: Part 1 - recipients. Clin Transplant 2022; 36:e14667. [PMID: 35435293 DOI: 10.1111/ctr.14667] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/06/2022] [Accepted: 03/31/2022] [Indexed: 11/29/2022]
Abstract
Living donor liver transplantation was first developed to mitigate the limited access to deceased donor organs in Asia in the 1990s. This alternative liver transplantation option has become an established and widely practiced transplantation method for adult patients suffering from end-stage liver disease. It has successfully addressed the shortage of deceased donors. The Society for the Advancement of Transplant Anesthesia and the Korean Society of Transplant Anesthesia jointly reviewed published studies on the perioperative management of live donor liver transplant recipients. The review aims to offer transplant anesthesiologists and critical care physicians a comprehensive overview of the perioperative management of adult live liver transplantation recipients. We feature the status, outcomes, surgical procedure, portal venous decompression, anesthetic management, prevention of acute kidney injury, avoidance of blood transfusion, monitoring and therapeutic strategies of hemodynamic derangements, and Enhanced Recovery After Surgery protocols for liver transplant recipients. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Tetsuro Sakai
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.,Clinical and Translational Science Institute, University of Pittsburgh, PA, USA.,McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA, USA
| | - Justin Sangwook Ko
- Department of Anesthesiology & Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Cara E Crouch
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sathish Kumar
- Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA
| | - Michael B Little
- Department of Anesthesiology, UT Health San Antonio, San Antonio, TX, USA
| | - Min Suk Chae
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Armando Ganoza
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Luis Gómez-Salinas
- Department of Anesthesiology and Pain Medicine, Hospital General Universitario de Alicante, Alicante, Spain
| | - Abhi Humar
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Sang Hyun Kim
- Department of Anesthesiology and Pain Medicine, Soonchunhyang University Bucheon Hospital, Gyeonggi-do, Republic of Korea
| | - Bon-Nyeo Koo
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Gonzalo Rodriguez
- Department of Surgery, Hospital General Universitario de Alicante, Alicante, Spain
| | - Joel Sirianni
- Department of Anesthesia & Perioperative Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Natalie K Smith
- Department of Anesthesiology, Perioperative & Pain Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Jun-Gol Song
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Aisha Ullah
- Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Adrian Hendrickse
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Sharma A, Rao JS, Han Z, Gangwar L, Namsrai B, Gao Z, Ring HL, Magnuson E, Etheridge M, Wowk B, Fahy GM, Garwood M, Finger EB, Bischof JC. Vitrification and Nanowarming of Kidneys. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2101691. [PMID: 34382371 PMCID: PMC8498880 DOI: 10.1002/advs.202101691] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/18/2021] [Indexed: 05/16/2023]
Abstract
Vitrification can dramatically increase the storage of viable biomaterials in the cryogenic state for years. Unfortunately, vitrified systems ≥3 mL like large tissues and organs, cannot currently be rewarmed sufficiently rapidly or uniformly by convective approaches to avoid ice crystallization or cracking failures. A new volumetric rewarming technology entitled "nanowarming" addresses this problem by using radiofrequency excited iron oxide nanoparticles to rewarm vitrified systems rapidly and uniformly. Here, for the first time, successful recovery of a rat kidney from the vitrified state using nanowarming, is shown. First, kidneys are perfused via the renal artery with a cryoprotective cocktail (CPA) and silica-coated iron oxide nanoparticles (sIONPs). After cooling at -40 °C min-1 in a controlled rate freezer, microcomputed tomography (µCT) imaging is used to verify the distribution of the sIONPs and the vitrified state of the kidneys. By applying a radiofrequency field to excite the distributed sIONPs, the vitrified kidneys are nanowarmed at a mean rate of 63.7 °C min-1 . Experiments and modeling show the avoidance of both ice crystallization and cracking during these processes. Histology and confocal imaging show that nanowarmed kidneys are dramatically better than convective rewarming controls. This work suggests that kidney nanowarming holds tremendous promise for transplantation.
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Affiliation(s)
- Anirudh Sharma
- Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
| | | | - Zonghu Han
- Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
| | - Lakshya Gangwar
- Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
| | | | - Zhe Gao
- Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
| | - Hattie L. Ring
- Center for Magnetic Resonance ResearchDepartment of RadiologyUniversity of MinnesotaMinneapolisMN55455USA
| | - Elliott Magnuson
- Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
| | - Michael Etheridge
- Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
| | - Brian Wowk
- 21st Century Medicine IncFontanaCA92336USA
| | | | - Michael Garwood
- Center for Magnetic Resonance ResearchDepartment of RadiologyUniversity of MinnesotaMinneapolisMN55455USA
| | - Erik B. Finger
- Department of SurgeryUniversity of MinnesotaMinneapolisMN55455USA
| | - John C. Bischof
- Department of Mechanical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
- Department of Biomedical EngineeringUniversity of MinnesotaMinneapolisMN55455USA
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7
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Histidine buffered media maintains pH stabile during cooled transportation of human ovarian tissue. J Ovarian Res 2021; 14:116. [PMID: 34474666 PMCID: PMC8414771 DOI: 10.1186/s13048-021-00861-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 08/18/2021] [Indexed: 12/26/2022] Open
Abstract
The aim of this study was to investigate whether pH is stable when transporting ovarian tissue in media buffered with either HEPES or histidine. Furthermore, if the choice of transport media impacts the in vitro maturation rate of oocytes collected in connection with ovarian tissue cryopreservation. Human ovaries (n = 34) collected for ovarian tissue cryopreservation were transported immersed in either 30 ml of HEPES buffered (follicle flushing media (Origio; Denmark)) or histidine buffered media (Custodiol®-HTK, Koehler-Chemie, Germany). Tissue was transported on ice for 4–5 h. At arrival, the ovary was weighed, and the pH of the media was measured at 0 °C. From 15 patients, immature oocytes were collected for in vitro maturation, oocytes that matured to metaphase II were evaluated. The pH measured in the HEPES buffered media (pH = 7.5 ± 0.13, n = 18) was significantly higher (p < 0.001) than the pH measured in the histidine buffered media (pH = 7.2 ± 0.05, n = 16). The standard deviation of pH measurements for the histidine buffered media was significantly lower than for the HEPES buffered media measurements (p < 0.0001). A total of 170 and 247 immature oocytes were collected and in vitro matured from ovaries transported in HEPES and histidine buffered media, respectively. The maturation rate of immature oocytes after IVM was similar in the two groups. The results show that pH in the histidine buffered media is closer to the physiological level and more stable than in HEPES buffered medium and support the use of histidine buffered media for cooled transportation of human ovaries.
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Guerreiro BM, Silva JC, Torres CAV, Alves VD, Lima JC, Reis MAM, Freitas F. Development of a Cryoprotective Formula Based on the Fucose-Containing Polysaccharide FucoPol. ACS APPLIED BIO MATERIALS 2021; 4:4800-4808. [PMID: 35007029 DOI: 10.1021/acsabm.1c00007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study reports the performance of the polysaccharide FucoPol as an enhancer of cryoprotective formulations. FucoPol at a concentration of 0.25% (w/v) was added to several normothermic Dulbecco-derived solutions and hypothermic Euro-Collins, Custodiol-HTK, and Unisol-CV media, substituting some constituents in the latter class to develop FucoPol-based formulations that were tested for their ability to cryopreserve Vero cells. Supplementation yielded post-thaw cell recovery enhancements of at least 70% and averaged at 82%. The FucoPol-supplemented formulations Dulbecco(+)+FP and Unisol-CVS3 achieved cell viabilities capable of competing with the commercial cryogenic formula CryoStor CS5. Particularly in Unisol-CVS3, mannitol, glucose, gluconate, and dextran were all substituted by 0.25% FucoPol, and still, a similar viability was achieved. Multiparametric correlation clustering showed that FucoPol cryoprotection synergizes best with K+, Ca2+, and Cl- in its microenvironment. Component substitution analysis demonstrated that FucoPol acts consistently as a cryoprotectant, an impermeant, and a colloidal stabilizer, providing a combined alternative to glucose, mannitol, gluconate, and dextran, thus highlighting its potential in the development of high-performing cryoprotective formulas.
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Affiliation(s)
- Bruno M Guerreiro
- UCIBIO-REQUIMTE, Chemistry Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal.,CENIMAT/I3N, Physics Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal.,LAQV-REQUIMTE, Chemistry Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal
| | - Jorge C Silva
- CENIMAT/I3N, Physics Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal
| | - Cristiana A V Torres
- UCIBIO-REQUIMTE, Chemistry Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal
| | - Vítor D Alves
- LEAF - Linking Landscape, Environment, Agriculture and Food, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, Lisboa 1349-017, Portugal
| | - João C Lima
- LAQV-REQUIMTE, Chemistry Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal
| | - Maria A M Reis
- UCIBIO-REQUIMTE, Chemistry Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal
| | - Filomena Freitas
- UCIBIO-REQUIMTE, Chemistry Department, NOVA School of Sciences and Technology, Caparica 2829-516, Portugal
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Kruszyna T, Richter P. Hypothermic Machine Perfusion of Kidneys Compensates for Extended Storage Time: A Single Intervention With a Significant Impact. Transplant Proc 2021; 53:1085-1090. [PMID: 33579549 DOI: 10.1016/j.transproceed.2021.01.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/17/2020] [Accepted: 01/08/2021] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Delayed graft function (DGF) adversely affects graft survival and function. Machine perfusion (MP) improves DGF rate and may compensate for extended storage time. MATERIAL AND METHODS In this single-center cohort study, we included 193 consecutive kidney transplantations. MP was used in 78 kidneys (36%) and static cold storage (CS) in 115 kidneys (64%). CS kidneys were transplanted first followed by MP kidneys if stored differently. Pairs of kidneys from the same donor were subjected for subgroup analysis and included 58 pairs. The primary endpoints were the rate of DGF and 1- and 5-year graft survival. The secondary endpoints were the rate of the primary nonfunction, mortality, acute rejection, duration of DGF, and 5-year estimated glomerular filtration rate. RESULTS Median cold ischemia time (CIT) was significantly different between the MP and CS groups (24 vs 20 hours, P < .05). MP significantly reduced the rate of DGF (MP vs CS: 21.8% vs 42.6%, P < .05, odds ratio 0.34, 95% confidence interval 0.17-0.67) with no impact on overall 1- and 5-year survival rates. Storage method did not affect the duration of DGF, mortality rate, acute rejection, or the 5-year estimated glomerular filtration rate. CONCLUSIONS Hypothermic pulsatile MP significantly reduced the rate of DGF in kidneys transplanted with CIT equal to or longer than 12 hours. It is safe and may compensate for longer storage time.
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Affiliation(s)
- Tomasz Kruszyna
- Department of General, Oncological, Gastroenterological Surgery and Transplantation, University Hospital in Krakow, Poland.
| | - Piotr Richter
- Department of General, Oncological, Gastroenterological Surgery and Transplantation, University Hospital in Krakow, Poland
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10
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Van den Eynde J, Achtergaele J, Fieuws S, Jochmans I, Sainz-Barriga M, Monbaliu D, Pirenne J, Gilbo N. The effect of organ preservation solutions on short-term outcomes after liver transplantation: a single-center retrospective study. Transpl Int 2021; 34:327-338. [PMID: 33280170 DOI: 10.1111/tri.13799] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/22/2020] [Accepted: 12/02/2020] [Indexed: 12/30/2022]
Abstract
The effect of preservation solutions on outcomes has been subject of many debates but the relative benefits of the various solutions remain unclear. We retrospectively compared short-term outcomes of 885 liver transplantations performed between 1/2000 and 12/2017 and preserved with either Histidine-Tryptophan-Ketoglutarate (HTK, n = 190), University of Wisconsin (UW, n = 557), or Institute George Lopez 1 preservation solution (IGL-1, n = 139). Inverse probability of treatment weighting (IPTW) was performed to account for baseline differences between groups and analyses were adjusted for confounders. In the IPTW analyses, peak AST within 7 days was 44% higher (95% CI 15-81%, P < 0.001) in HTK than in UW. Mean model of early allograft function (MEAF) score was 0.61 points (95% CI 0.12-1.10, P = 0.01) higher in HTK than in UW. Early allograft dysfunction (EAD) was more likely to occur with HTK compared to IGL-1 (IPTW OR = 2.87, 95% CI = 1.00-8.19, P = 0.049) and UW (IPTW OR = 1.75, 95% CI = 1.06-2.88, P = 0.023). The type of preservation solution had no impact on hospital stay, ICU stay, incidence of biliary strictures, or graft and recipient survival. HTK was the least effective on reducing graft injury and increased the probability of graft dysfunction after transplantation. UW and IGL-1 were equally effective in reducing graft injury and dysfunction.
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Affiliation(s)
- Jef Van den Eynde
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Jannick Achtergaele
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Steffen Fieuws
- Leuven Biostatistics and Statistical Bioinformatics Centre (L-BioStat), KU Leuven, Leuven, Belgium
| | - Ina Jochmans
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Mauricio Sainz-Barriga
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Jacques Pirenne
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Nicholas Gilbo
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Abdominal Transplant Surgery, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
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11
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Casanova D, Gutierrez G, Noriega MG, Castillo F. Complications during multiorgan retrieval and pancreas preservation. World J Transplant 2020; 10:381-391. [PMID: 33437671 PMCID: PMC7769728 DOI: 10.5500/wjt.v10.i12.381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 08/04/2020] [Accepted: 10/05/2020] [Indexed: 02/05/2023] Open
Abstract
In pancreas transplantation, complications can arise at each step of the process, from the initial selection of donors and recipients through the surgical technique itself and the post-operative period, when lifelong immunosuppression is required. In the early steps, careful retrieval and preservation of the pancreas are crucial for the viability of the organ and ultimate success of the transplant. The pancreas is a low-flow gland, making it highly sensitive to transplantation conditions and presenting risk of pancreatitis due to periods of ischemia. The two groups of donors - after brain death (DBD) or after cardiac arrest (DCD) - require different strategies of retrieval and preservation to avoid or reduce the risk of complications developing during and after the transplantation. For DBD donor transplantation, multiorgan retrieval and cold preservation is the conventional technique. Asystole donor (DCD) transplantation, in contrast, can benefit from the newest technologies, such as hypothermic and especially normothermic preservation machines (referred to as NECMO), to optimize organ preservation. The latter has led to an increase in the pool of donors by facilitating recuperation of organs for transplantation that would have been discarded otherwise.
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Affiliation(s)
- Daniel Casanova
- Department of Surgery, University Hospital Marques de Valdecilla, University Cantabria, Santander 39008, Cantabria, Spain
| | - Gonzalo Gutierrez
- Department of Surgery, University Hospital Marques de Valdecilla, Santander 39008, Cantabria, Spain
| | - Monica Gonzalez Noriega
- Department of Surgery, University Hospital Marques de Valdecilla, Santander 39008, Cantabria, Spain
| | - Federico Castillo
- Department of Surgery, University Hospital Marques de Valdecilla, Santander 39008, Cantabria, Spain
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12
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Rodrigues MG, Castro PMV, Almeida TCD, Danziere FR, Sergi Filho FA, Zeballos Sempertegui BE, Branez JR, Mota LT, Perosa de Miranda M, Gomes Dos Santos R, Genzini T. Impact of Cold Ischemia Time on the Function of Liver Grafts Preserved With Custodiol. Transplant Proc 2020; 53:661-664. [PMID: 33139037 DOI: 10.1016/j.transproceed.2020.03.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 02/21/2020] [Accepted: 03/12/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE This study aimed to evaluate how cold ischemia time (CIT) interferes with liver graft function in the first 7 days after surgery for Custodiol (HTK) preserved organs. METHODS This retrospective observational study analyzed the medical records of 38 transplantation patients at Hospital Leforte Liberdade, São Paulo, in 2018. The study population was divided into 2 groups (group A, CIT < 8 hours; group B, CIT > 8 hours). Postoperative parameters-such as international normalized ratio, total bilirubin, aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GGT), lactate dehydrogenase, lactate, creatinine, red blood cell transfusion, need for hemodialysis, use of vasoactive drugs, endotracheal intubation time, length of stay in the intensive care unit (ICU), and length of hospital stay-were compared. RESULTS Group A (CIT < 8 hours) presented less need for red blood cell transfusions (odds ratio 0.29; confidence interval 0.06-0.98; P = .04), had a shorter hospital stay (P = .024), and had lower levels of total bilirubin (P = .05) and GGT (P = .05) in the first 7 postoperative days. The other variables showed no statistically significant difference. CONCLUSION In livers preserved with Custodiol, CIT > 8 hours generated higher levels of total bilirubin and GGT in the postoperative period, in addition to higher hospital costs; greater need for red blood cell transfusions; and longer hospitalization, including longer stays in the ICU.
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Affiliation(s)
| | | | | | | | | | | | - Juan Rafel Branez
- Grupo HEPATO-Hepatology, Transplants, and Gastroenterology, São Paulo, Brazil
| | | | - Marcelo Perosa de Miranda
- Grupo HEPATO-Hepatology, Transplants, and Gastroenterology, São Paulo, Brazil; Liver and Pancreas Transplant Program in Hospital Leforte, São Paulo, Brazil
| | | | - Tércio Genzini
- Grupo HEPATO-Hepatology, Transplants, and Gastroenterology, São Paulo, Brazil; Liver and Pancreas Transplant Program in Hospital Leforte, São Paulo, Brazil
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13
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Li S, Huang Z, Li X, Zhao Y, Jiang X, Wen Y, Luo H, Wang L, Guan Q, Cafeeva I, Brooks DE, Nguan CYC, Kizhakkedathu JN, Du C. Evaluation of hyperbranched polyglycerol for cold perfusion and storage of donor kidneys in a pig model of kidney autotransplantation. J Biomed Mater Res B Appl Biomater 2020; 109:853-863. [PMID: 33098184 PMCID: PMC8246781 DOI: 10.1002/jbm.b.34750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/17/2020] [Accepted: 10/06/2020] [Indexed: 02/05/2023]
Abstract
Hyperbranched polyglycerol (HPG) is a biocompatible polyether polymer that is a potential colloid component in a preservation solution for suppressing interstitial edema during cold storage of a donor organ. This study evaluated the outcomes of kidney transplants after cold perfusion and storage with a HPG‐based preservation solution (HPGS) in a pig model of kidney autotransplantation. The left kidneys of farm pigs (weighing 35–45 kg) were perfused with and stored in either cold HPGS or standard UW solution (UWS), followed by transplantation to the right side after right nephrectomy. The survival and function of transplants were determined by the urine output, and serum creatinine (SCr) and blood urea nitrogen (BUN) of recipients. Transplant injury was examined by histological analysis. Here, we showed that there was no significant difference between HPGS and UWS in the prevention of tissue edema, but HPGS was more effective than UWS for initial blood washout of kidney perfusion and for the prevention of cold ischemia injury during cold storage. After autotransplantation, the kidneys preserved with HPGS (HPG group) had better functional recovery than those with UWS (UW group), indicated by significantly more urine output and lower levels of SCr and BUN. The survived grafts in HPG group had less tissue damage than those in UW group. In conclusion, as compared to the UWS the HPGS has less negative impact on kidney cold ischemia during cold storage, resulting in improving immediate functional recovery after transplantation, suggesting that HPG is a promising colloid for donor kidney preservation.
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Affiliation(s)
- Shadan Li
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, China.,Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Zhongli Huang
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Urology, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaowei Li
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, China
| | - Youguang Zhao
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, China
| | - Xin Jiang
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, China
| | - Yang Wen
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, China
| | - Hao Luo
- Department of General Surgery, The General Hospital of Western Theater Command, Chengdu, China
| | - Liang Wang
- Department of Urology, The General Hospital of Western Theater Command, Chengdu, China
| | - Qiunong Guan
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Irina Cafeeva
- Centre for Blood Research, and the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Donald E Brooks
- Centre for Blood Research, and the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christopher Y C Nguan
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jayachandran N Kizhakkedathu
- Centre for Blood Research, and the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Caigan Du
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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14
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Structure and Function of Porcine Arteries Are Preserved for up to 6 Days Using the HypoRP Cold-storage Solution. Transplantation 2020; 104:e125-e134. [PMID: 32000259 DOI: 10.1097/tp.0000000000003141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Maintaining functional vessels during preservation of vascularized composite allografts (VCAs) remains a major challenge. The University of Wisconsin (UW) solution has demonstrated significant short-term benefits (4-6 h). Here we determined whether the new hypothermic resuscitation and preservation solution HypoRP improves both structure, survival, and function of pig arteries during storage for up to 6 days. METHODS Using porcine swine mesenteric arteries, the effects of up to 6-day incubation in a saline (PBS), UW, or HypoRP solution on the structure, cell viability, metabolism, and function were determined. RESULTS After incubation at 4°C, for up to 6 days, the structures of the arteries were significantly disrupted, especially the tunica media, following incubation in PBS, in contrast with incubation in the HypoRP solution and to a lesser extent, in UW solution. Those disruptions were associated with increased active caspase 3 indicative of apoptosis. Additionally, while incubation in PBS led to a significant decrease in the metabolic activity, UW and HypoRP solutions allowed a stable to increased metabolic activity following 6 days of cold storage. Functional responsiveness to phenylephrine (PE) and sodium nitroprusside (SNP) decreased over time for artery rings stored in PBS and UW solution but not for those stored in HypoRP solution. Moreover, artery rings cold-stored in HypoRP solution were more sensitive to ATP. CONCLUSIONS The HypoRP solution improved long-term cold storage of porcine arteries by limiting structural alterations, including the collagen matrix, reducing apoptosis, and maintaining artery contraction-relaxation functions for up to 6 days.
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15
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Chen Y, Shi J, Xia TC, Xu R, He X, Xia Y. Preservation Solutions for Kidney Transplantation: History, Advances and Mechanisms. Cell Transplant 2019; 28:1472-1489. [PMID: 31450971 PMCID: PMC6923544 DOI: 10.1177/0963689719872699] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Solid organ transplantation was one of the greatest medical advances during the past few
decades. Organ preservation solutions have been applied to diminish ischemic/hypoxic
injury during cold storage and improve graft survival. In this article, we provide a
general review of the history and advances of preservation solutions for kidney
transplantation. Key components of commonly used solutions are listed, and effective
supplementations for current available preservation solutions are discussed. At cellular
and molecular levels, further insights were provided into the pathophysiological
mechanisms of effective ingredients against ischemic/hypoxic renal injury during cold
storage. We pay special attention to the cellular and molecular events during
transplantation, including ATP depletion, acidosis, mitochondrial dysfunction, oxidative
stress, inflammation, and other intracellular mechanisms.
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Affiliation(s)
- Yimeng Chen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Jian Shi
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Terry C Xia
- The University of Connecticut, Storrs, CT, USA
| | - Renfang Xu
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Xiaozhou He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Ying Xia
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
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16
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Liebenthron J, Montag M, Reinsberg J, Köster M, Isachenko V, van der Ven K, van der Ven H, Krüssel JS, von Wolff M. Overnight ovarian tissue transportation for centralized cryobanking: a feasible option. Reprod Biomed Online 2019; 38:740-749. [PMID: 30733076 DOI: 10.1016/j.rbmo.2019.01.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 12/21/2018] [Accepted: 01/03/2019] [Indexed: 12/11/2022]
Abstract
RESEARCH QUESTION Is overnight transportation of ovarian tissue before cryopreservation in a centralized cryobank from the FertiPROTEKT network feasible? DESIGN Data from 1810 women with cryopreserved ovarian tissue after overnight transportation from December 2000 to December 2017 were analysed with a focus on transportation, tissue activity parameters and pregnancy, and delivery rates after transplantation. RESULTS A total of 92.4% of tissue samples arrived at ideal temperatures of 2-8°C, 0.4% were transported at temperatures lower than ideal and 6.4% were transported at temperatures that were too high, generally due to mishandling of the inlayed cool packs of the transportation boxes. In 62 women, 78 tissue transplantations were carried out. A subgroup of 30 women who underwent a single orthotopic transplantation with fulfilled criteria of a complete follow-up after transplantation until the end of study, a premature ovarian insufficiency after gonadotoxic therapy as well as the absence of pelvic radiation, was further analysed. In this group, transplantations into a peritoneal pocket accounted for 90%. Transplants were still active at 1 year and above after transplantation in 93.3%. Pregnancy and delivery rates were 46.7% and 43.3%, respectively, with one ongoing pregnancy at the end of the study. CONCLUSIONS Overnight transportation for central cryobanking is a feasible concept that results in high reproducible success rates through standardized professional tissue freezing and storage.
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Affiliation(s)
- Jana Liebenthron
- UniCareD, University Cryobank for Assisted Reproductive Medicine and Fertility Protection at UniKiD, University Women's Hospital Düsseldorf, Moorenstr. 5, Düsseldorf 40225, Germany.
| | - Markus Montag
- Ilabcomm GmbH, Eisenachstr. 34, Augustin 53757 St., Germany
| | - Jochen Reinsberg
- Department of Gynecological Endocrinology and Reproductive Medicine, University Clinic Bonn, Sigmund-Freud-Str. 25, Bonn 53125, Germany
| | - Maria Köster
- KWZ Germany GmbH, Joseph-Schumpeter-Allee 1, Bonn 53227, Germany
| | - Vladimir Isachenko
- Department of Gynecological Endocrinology and Reproductive Medicine, University Clinic Cologne, Kerpener Straße 34, Cologne 50931, Germany
| | - Katrin van der Ven
- MVZ für Frauenheilkunde und IvF-Medizin Bonn GbR, Godesberger Allee 64, Bonn 53175, Germany
| | - Hans van der Ven
- MVZ für Frauenheilkunde und IvF-Medizin Bonn GbR, Godesberger Allee 64, Bonn 53175, Germany
| | - Jan-Steffen Krüssel
- UniCareD, University Cryobank for Assisted Reproductive Medicine and Fertility Protection at UniKiD, University Women's Hospital Düsseldorf, Moorenstr. 5, Düsseldorf 40225, Germany
| | - Michael von Wolff
- University Women's Hospital Bern, Division of Gynecological Endocrinology and Reproductive Medicine, Effingerstrasse 102, Bern 3010, Switzerland
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17
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Stammers AH, Tesdahl EA, Mongero LB, Stasko A. Does the type of cardioplegia used during valve surgery influence operative nadir hematocrit and transfusion requirements? Perfusion 2018; 33:638-648. [PMID: 29874956 DOI: 10.1177/0267659118777199] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
INTRODUCTION Myocardial protection is performed using diverse cardioplegic (CP) solutions with various combinations of chemical and blood constituents. Newer CP formulations that extend ischemic intervals may require greater asanguineous volume, contributing to hemodilution. METHODS We evaluated intraoperative hemodilution and red blood cell (RBC) transfusion rates among three common CP solutions during cardiac valve surgery. Data from 5,830 adult cardiac primary valve procedures where either four-to-one blood CP (4:1), del Nido solution (DN) or microplegia (MP) was used at 173 United States surgical centers. The primary outcome was the nadir hematocrit (Hct) during cardiopulmonary bypass (CPB), with a secondary outcome of total units of RBC transfused intraoperatively. Outcomes were assessed using mixed-effects regression, with controls for patient size, age, first Hct in the operating room, ultrafiltration volume, net bypass circuit priming volume, anesthesia and perfusion asanguineous volumes, cross-clamp and total procedure times, procedure type, reoperation, hospital, surgeon and twelve other patient and procedural variables. RESULTS A total of 2,641 patients received 4:1 (45.3%), 1,864 received DN (32.0%) and 1,325 received MP (22.7%). There were only slight differences in the central tendency (mean (SD)) for crude nadir Hct on CPB: 4:1, 25.5 (4.5), DN, 26.0 (4.6) and MP, 26.5 (4.7). After controlling for numerous operative and patient characteristics, the regression-adjusted estimate of the nadir Hct on CPB for MP was 26.2%, compared to 25.7% for 4:1 and 25.7% for DN; differences between MP and the other methods were statistically significant (p<0.01). Unadjusted mean RBC units transfused per patient was very similar across the groups (4:1, 2.2; MP, 2.3; DN, 2.4). Regression-adjusted estimates for the number of units of RBC transfused intraoperatively showed no statistically significant differences between CP methods. CONCLUSIONS In patients undergoing cardiac valve surgery, the type of CP did not have a strong clinical impact on hemodilution or transfusion. Choice of a myocardial preservation solution can be made independently of its effect on intraoperative Hct.
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18
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Jing L, Yao L, Zhao M, Peng LP, Liu M. Organ preservation: from the past to the future. Acta Pharmacol Sin 2018; 39:845-857. [PMID: 29565040 DOI: 10.1038/aps.2017.182] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 12/31/2017] [Indexed: 12/13/2022]
Abstract
Organ transplantation is the most effective therapy for patients with end-stage disease. Preservation solutions and techniques are crucial for donor organ quality, which is directly related to morbidity and survival after transplantation. Currently, static cold storage (SCS) is the standard method for organ preservation. However, preservation time with SCS is limited as prolonged cold storage increases the risk of early graft dysfunction that contributes to chronic complications. Furthermore, the growing demand for the use of marginal donor organs requires methods for organ assessment and repair. Machine perfusion has resurfaced and dominates current research on organ preservation. It is credited to its dynamic nature and physiological-like environment. The development of more sophisticated machine perfusion techniques and better perfusates may lead to organ repair/reconditioning. This review describes the history of organ preservation, summarizes the progresses that has been made to date, and discusses future directions for organ preservation.
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19
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Wiederkehr JC, Igreja MR, Gonçalves N, Nogara M, Godoy M, Drago C, Massutti AM, Wiederkehr HA, Wiederkehr BA. Liver Transplantation Using Prolonged Cold Ischemia Time Grafts Preserved With Institute George-Lopez-1 Solution. Transplant Proc 2018; 50:711-713. [PMID: 29661421 DOI: 10.1016/j.transproceed.2018.02.041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Institute George-Lopez-1 (IGL-1) solution is a preservation solution with lower potassium and lower viscosity than the University of Wisconsin solution that has been recently used in liver transplantation. In the present series, we compare the outcome of liver grafts from brain-dead donors preserved in IGL-1cold storage solution, with cold ischemia times (CITs) longer than 8 hours and those less than 8 hours. Two hundred fifty-two liver transplantations performed from January 2014 to December 2016 at Hospital Santa Isabel, Blumenau, Brazil, were retrospectively analyzed. The patients were divided in two groups according to the CIT. Group I patients (N = 155) had less than 8 hours of CIT with a mean age of 54 ± 11.35 years, whereas group II patients (N = 97) had more than 8 hours of CIT with a mean age of 52 ± 12.5 years. There was no difference between the groups related to indication for liver transplantation and donor characteristics. The only difference statically significant on laboratory data was between the levels of aspartate aminotransferase at day 1 after transplantation. On day 7 post-transplantation there was no difference statistically significant between aspartate aminotransferase, alanine aminotransferase, and bilirubin levels between the two groups. Similar 1-year patient survival rates were found in both groups, with 85.88% for group I and 85.75% in group II. The IGL-1 solution has been shown to be safe, effective, and with good results in liver transplantations. Early graft function and 1-year patient survival rates did not differ when grafts preserved for less than 8 hours were compared to those with CIT greater than 8 hours.
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Affiliation(s)
- J C Wiederkehr
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil.
| | - M R Igreja
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
| | - N Gonçalves
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
| | - M Nogara
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
| | - M Godoy
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
| | - C Drago
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
| | - A M Massutti
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
| | - H A Wiederkehr
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
| | - B A Wiederkehr
- Liver Transplant Division, Santa Isabel Hospital, Blumenau, SC, Brazil
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20
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Hameed AM, Laurence JM, Lam VWT, Pleass HC, Hawthorne WJ. A systematic review and meta-analysis of cold in situ perfusion and preservation of the hepatic allograft: Working toward a unified approach. Liver Transpl 2017; 23:1615-1627. [PMID: 28734125 PMCID: PMC5725662 DOI: 10.1002/lt.24829] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 05/03/2017] [Accepted: 07/16/2017] [Indexed: 01/01/2023]
Abstract
The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route (aortic or dual) or perfusion/preservation solution in donation after brain death (DBD) liver transplantation. The Embase, MEDLINE, and Cochrane databases were used (1980-2017). Random effects modeling was used to estimate effects on transplantation outcomes based on (1) aortic or dual in situ perfusion and (2) the use of University of Wisconsin (UW), histidine tryptophan ketoglutarate (HTK), Celsior, and/or Institut Georges Lopez-1 (IGL-1) solutions for perfusion/preservation. A total of 22 articles were included (2294 liver transplants). The quality of evidence ranged from very low to moderate Grading of Recommendations, Assessment, Development and Evaluations score. Meta-analyses were conducted for 14 eligible studies. Although there was no difference in the primary nonfunction (PNF) rate, a higher peak alanine aminotransferase (ALT) was recorded in dual compared with aortic-only UW-perfused livers (standardized mean difference, 0.24; 95% confidence interval, 0.01-0.47); a back-table portal venous flush was undertaken in the majority of aortic-only perfused livers. There were no relevant differences in peak enzymes, PNF, thrombotic graft loss, biliary complications, or 1-year graft survival in comparisons between dual-perfused livers using UW, HTK, Celsior, or IGL-1. In conclusion, there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes, and it may be favored because of its simplicity. However, there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others. Liver Transplantation 23 1615-1627 2017 AASLD.
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Affiliation(s)
- Ahmer M. Hameed
- Centre for Transplant and Renal Research, Westmead Institute for Medical ResearchWestmeadNew South WalesAustralia,Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia
| | - Jerome M. Laurence
- Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia,Department of Surgery,Institute of Academic Surgery, Royal Prince Alfred HospitalUniversity of SydneyCamperdownNew South WalesAustralia
| | - Vincent W. T. Lam
- Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia
| | - Henry C. Pleass
- Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia,Department of Surgery
| | - Wayne J. Hawthorne
- Centre for Transplant and Renal Research, Westmead Institute for Medical ResearchWestmeadNew South WalesAustralia,Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia
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21
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Saidi SA, Meurisse N, Jochmans I, Heedfeld V, Wylin T, Parkkinen J, Pirenne J, Monbaliu D, El Feki A, van Pelt J. Hepatocellular uptake of cyclodextrin-complexed curcumin during liver preservation: A feasibility study. Biopharm Drug Dispos 2017; 39:18-29. [PMID: 28972677 DOI: 10.1002/bdd.2108] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 08/03/2017] [Accepted: 09/11/2017] [Indexed: 12/18/2022]
Abstract
The increasing demand for donor organs and the decreasing organ quality is prompting research toward new methods to reduce ischemia reperfusion injury (IRI). Several strategies have been proposed to protect preserved organs from this injury. Before curcumin/dextrin complex (CDC), a potent antioxidant and anti-inflammatory agent, can be used clinically we need to better understand the intracellular uptake under hypothermic conditions on a rat model of liver donation after circulatory death (DCD) and brain death (DBD). To be able to use the fluorescence of CDC for quantification the stability of CDC in different preservation solutions at 4°C or 37°C was investigated. Livers from Wistar rats were procured after being flushed-out through the portal vein using CDC-enriched preservation solutions and stored at 4°C for variable periods. The CDC signal was stable in different preservation solutions over a period of 4 h and allowed the rapid and lasting uptake of curcumin into cells. After 4 h of preservation, CDC was no longer visible microscopically, and HPLC analysis showed very low to non-detectable tissue levels of CDC, proving metabolization during preservation. However, the distribution of CDC was not affected by warm ischemia damage (p = 0.278) nor by flushing the livers before or after 4 h of cold storage and without a warm preflush. Finally, curcumin reduced oxidative stress, lowered histological injury and did not change gene expression after WI/cold storage. Therefore, the use of CDC flush solution for the initial organ flush can offer a promising approach to the enhancement of liver preservation and the maintenance of its quality.
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Affiliation(s)
- Saber Abdelkader Saidi
- Liver Research Facility, Laboratory of Hepatology, Faculty of Medicine, University Hospital Gasthuisberg, Leuven, Belgium.,Laboratory of Animal Ecophysiology/Department of Life Sciences, Sfax, Tunisia.,Faculty of Science and Arts-Khulais, Jeddah University, Saudi Arabia
| | - Nicolas Meurisse
- Department of Abdominal Surgery and Transplantation, CHU Liege, B4000, Liege, Belgium
| | - Ina Jochmans
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium.,Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium
| | - Veerle Heedfeld
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Tine Wylin
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Jaakko Parkkinen
- Department of Biomedicine/Biochemistry, University of Helsinki, Helsinki, Finland
| | - Jacques Pirenne
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Department of Abdominal Transplantation Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Abdelfattah El Feki
- Laboratory of Animal Ecophysiology/Department of Life Sciences, Sfax, Tunisia
| | - Jos van Pelt
- Liver Research Facility, Laboratory of Hepatology, Faculty of Medicine, University Hospital Gasthuisberg, Leuven, Belgium
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Ischémie–reperfusion. Liquides de conservation et machines de perfusion en transplantation rénale. Prog Urol 2016; 26:964-976. [DOI: 10.1016/j.purol.2016.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/20/2016] [Accepted: 08/22/2016] [Indexed: 12/12/2022]
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Li S, Constantinescu I, Guan Q, Kalathottukaren MT, Brooks DE, Nguan CYC, Kizhakkedathu JN, Du C. Advantages of replacing hydroxyethyl starch in University of Wisconsin solution with hyperbranched polyglycerol for cold kidney perfusion. J Surg Res 2016; 205:59-69. [PMID: 27621000 DOI: 10.1016/j.jss.2016.06.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 05/01/2016] [Accepted: 06/06/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Efficient and effective perfusion during organ procurement is required for the best prevention of donor organ injury preceding transplantation. However, current organ preservation solutions, including hydroxyethyl starch (HES)-based University of Wisconsin (UW) solution, do not always yield the best outcomes. Our previous study demonstrated that replacing HES with hyperbranched polyglycerol (HPG) reduced donor heart injury during cold storage. The current research was designed to examine the advantages of HPG-based solution for cold kidney perfusion. METHODS Perfusion efficiency of HPG versus UW solution was tested using mouse kidneys at 4°C. The blood washout was evaluated by using a semiquantitative scoring system and tissue damage by histologic analysis. The interaction of HPG or UW solution with human red blood cells (RBCs) was examined by measuring RBC sedimentation and aggregation. RESULTS The lower viscosity of HPG solution was correlated with faster and more efficient perfusion through donor kidneys as compared with UW. HPG solution was also more effective than UW in removing RBCs from the kidney and was associated with less tissue damage to donor kidneys. In vitro UW solution caused significant RBC sedimentation and hyperaggregation, whereas HPG showed minimal impact on RBC sedimentation and prevented RBC aggregation. CONCLUSIONS This experimental study demonstrated that compared with UW, HPG solution was more efficient and effective in the removal of the blood from donor kidneys and offered better protection from donor tissue damage, suggesting that the HPG solution is a promising candidate to supplant standard UW solution for donor kidney perfusion in transplantation.
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Affiliation(s)
- Shadan Li
- Department of Urology, Chengdu Military General Hospital, Chengdu, Sichuan, China; Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Iren Constantinescu
- Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
| | - Qiunong Guan
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Manu T Kalathottukaren
- Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
| | - Donald E Brooks
- Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christopher Y C Nguan
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jayachandran N Kizhakkedathu
- Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Caigan Du
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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Abstract
PURPOSE OF REVIEW To summarize the history of organ preservation and place into this context the current trends in preservation. RECENT FINDINGS Multiple large retrospective studies have analyzed cold preservation solutions in an attempt to determine superiority with largely negative results. Experimental and some clinical studies have examined machine perfusion of procured grafts, in both hypothermic and normothermic contexts with variable, but promising, results. Lastly, there are experimental efforts to evaluate mesenchymal stem cell therapy on rehabilitation of marginal donor organs. SUMMARY New trends in organ preservation may soon translate into more efficient use of the limited donor pool.
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Short term ex vivo storage of kidneys cause progressive nuclear ploidy changes of renal tubular epitheliocytes. Sci Rep 2015; 5:10341. [PMID: 26036971 PMCID: PMC4453160 DOI: 10.1038/srep10341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 04/10/2015] [Indexed: 01/03/2023] Open
Abstract
In renal transplantation, there has been considerable success, mainly in term of post-transplant graft function. However, upon closer scrutiny, it is known that severe dysfunction, including persistence of renal failure is seen after transplantation. The major condition that potentially cause significant lesion may be hypothesized to be related to the hypothermic approach to storage. To systematically examine these issues, we stored mammalian (sheep) kidneys in UWS at 4 °C for four different time points (0, 1, 3 and 6 hours). We obtained renal histological sections and examined tubular architecture as well as nuclear characteristics of tubular epitheliocytes. The results of our preliminary investigations suggest that there are temporal changes of tubular epitheliocytes, as well as genomic changes. These changes were also seen in tissues stored at room temperature. Our observations suggest the need for additional studies for redesigning of improvised storage solutions. Pilot studies using Celsior also revealed similar kind of nuclear changes, suggesting that storage conditions are contributory, including perfusion versus static conditions. The results may explain persistence of tubular injury several days after orthotopic transplantation, and may potentially be contributory to delayed graft function (DGF).
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Quinones QJ, Ma Q, Zhang Z, Barnes BM, Podgoreanu MV. Organ protective mechanisms common to extremes of physiology: a window through hibernation biology. Integr Comp Biol 2014; 54:497-515. [PMID: 24848803 DOI: 10.1093/icb/icu047] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Supply and demand relationships govern survival of animals in the wild and are also key determinants of clinical outcomes in critically ill patients. Most animals' survival strategies focus on the supply side of the equation by pursuing territory and resources, but hibernators are able to anticipate declining availability of nutrients by reducing their energetic needs through the seasonal use of torpor, a reversible state of suppressed metabolic demand and decreased body temperature. Similarly, in clinical medicine the majority of therapeutic interventions to care for critically ill or trauma patients remain focused on elevating physiologic supply above critical thresholds by increasing the main determinants of delivery of oxygen to the tissues (cardiac output, perfusion pressure, hemoglobin concentrations, and oxygen saturation), as well as increasing nutritional support, maintaining euthermia, and other general supportive measures. Techniques, such as induced hypothermia and preconditioning, aimed at diminishing a patient's physiologic requirements as a short-term strategy to match reduced supply and to stabilize their condition, are few and underutilized in clinical settings. Consequently, comparative approaches to understand the mechanistic adaptations that suppress metabolic demand and alter metabolic use of fuel as well as the application of concepts gleaned from studies of hibernation, to the care of critically ill and injured patients could create novel opportunities to improve outcomes in intensive care and perioperative medicine.
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Affiliation(s)
- Quintin J Quinones
- *Department of Anesthesiology, Systems Modeling of Perioperative Organ Injury Laboratory, Duke University, Box 3094, Durham, NC 27710, USA; Institute for Arctic Biology, University of Alaska, Fairbanks, AK, USA
| | - Qing Ma
- *Department of Anesthesiology, Systems Modeling of Perioperative Organ Injury Laboratory, Duke University, Box 3094, Durham, NC 27710, USA; Institute for Arctic Biology, University of Alaska, Fairbanks, AK, USA
| | - Zhiquan Zhang
- *Department of Anesthesiology, Systems Modeling of Perioperative Organ Injury Laboratory, Duke University, Box 3094, Durham, NC 27710, USA; Institute for Arctic Biology, University of Alaska, Fairbanks, AK, USA
| | - Brian M Barnes
- *Department of Anesthesiology, Systems Modeling of Perioperative Organ Injury Laboratory, Duke University, Box 3094, Durham, NC 27710, USA; Institute for Arctic Biology, University of Alaska, Fairbanks, AK, USA
| | - Mihai V Podgoreanu
- *Department of Anesthesiology, Systems Modeling of Perioperative Organ Injury Laboratory, Duke University, Box 3094, Durham, NC 27710, USA; Institute for Arctic Biology, University of Alaska, Fairbanks, AK, USA*Department of Anesthesiology, Systems Modeling of Perioperative Organ Injury Laboratory, Duke University, Box 3094, Durham, NC 27710, USA; Institute for Arctic Biology, University of Alaska, Fairbanks, AK, USA
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Preservation solutions for static cold storage of abdominal allografts: which is best? Curr Opin Organ Transplant 2014; 19:100-7. [PMID: 24553501 DOI: 10.1097/mot.0000000000000063] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW To update the reader on the recent literature in liver, kidney, pancreas, and intestine static cold preservation, and to identify which solutions are most advantageous for each organ. RECENT FINDINGS The comparison of randomized trials of histidine-tryptophan-ketoglutarate (HTK), Celsior, and University of Wisconsin solutions has shown equivalent risk of delayed graft function after kidney transplantation. Similar outcomes have been observed after pancreas preservation with University of Wisconsin, HTK, and Celsior solution. In live-donor liver transplantation, University of Wisconsin and HTK solution have shown equivalent results, whereas in the recent trials of deceased-donor liver transplantation, University of Wisconsin, HTK, and Celsior solutions have shown equivalence. Contrary to the most clinical trials, national registry data in kidney, pancreas, and liver transplantation demonstrate more detrimental effects and earlier graft loss after preservation with HTK versus University of Wisconsin solution. Early outcomes after intestinal transplantation with University of Wisconsin or HTK solution have shown no significant difference and animal studies indicate intraluminal preservation may be beneficial. SUMMARY The University of Wisconsin solution is the standard criterion static cold preservation for the procurement of liver, kidney, pancreas, and intestine. University of Wisconsin, HTK, and Celsior solutions all provide similar allograft outcomes in most clinical trials, but subtle differences have become more apparent in the recent studies and registry reports.
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