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Li T, Chang P, Wang Y, Song Y, Qu P, Wang B, Lyu Y, Hu L. HOPE and AMPK activation reduce reperfusion injury and metabolic dysfunction in primate steatotic liver grafts. Sci Rep 2025; 15:11762. [PMID: 40189683 PMCID: PMC11973157 DOI: 10.1038/s41598-025-96265-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 03/27/2025] [Indexed: 04/09/2025] Open
Abstract
Living liver transplantation has become a significant and evolving aspect of organ transplantation, with a notable proportion of cases involving pediatric patients. Metabolic-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease. The growing number of individuals with MAFLD has led to an annual increase in the proportion of non-alcoholic fatty liver donors for pediatric living liver transplantation. Hypothermic oxygenated perfusion (HOPE) has been demonstrated to improve graft quality through the implementation of a continuous mechanical perfusion cycle. However, there is currently a paucity of evidence regarding its ability to reduce steatosis and improve prognosis within a shorter time window of living-organ transplantation, especially in primate models. This study simulated steatotic liver grafts in living liver transplantation using the MAFLD model of the cynomolgus monkey and explored the effects of HOPE combined with the AMPK activator AICAR on the amelioration of the donor liver. The left outer lobe livers were statically cold preserved for two hours, subjected to HOPE for two hours, or treated with HOPE + AICAR (1 mmol/L) for two hours, respectively. Subsequently, a normothermic ex vivo reperfusion model (IRM) simulating post-transplant reperfusion was established using diluted autologous blood. Following simulated reperfusion in vitro, steatotic liver grafts in the static cold preservation group exhibited notable reperfusion injury. The degree of reperfusion injury induced by the remaining two groups was reduced, with the HOPE + AICAR group showing the most significant reduction (P < 0.05). The adenosine triphosphate (ATP) level of the hepatic tissues in the HOPE + AICAR group was observed to improve at two hours of reperfusion, exhibiting a significantly higher level than that in the cold-preserved group (P < 0.05). Furthermore, the HOPE + AICAR group exhibited a notable decline in MDA levels (P < 0.05), accompanied by a considerable reduction in 8-OHdG and lactate concentrations in both the liver tissue and perfusate. Additionally, there was a marked decrease in the release of TNF-α and IL-6 cytokines, along with a reduction in TLR-4 activation (P < 0.05). In comparison to the cold-preserved and HOPE groups, the HOPE + AICAR group demonstrated the capacity to alter the degree of steatosis following a two-hour treatment period, as evidenced by a notable reduction in liver tissue triglyceride and cholesterol levels (P < 0.05). Additionally, p-AMPK levels in liver tissue were significantly increased in the HOPE + AICAR group (P < 0.05). The combination of HOPE and AMPK activators has been shown to reduce the degree of steatotic liver grafts in a relatively short time, significantly reduce reperfusion injury, and improve liver function. This study contributes to the existing body of knowledge on mechanical perfusion in primate models, addressing a previously identified gap in the literature.
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Affiliation(s)
- Tao Li
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pengkang Chang
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yimeng Wang
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yihong Song
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pengxiang Qu
- Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liangshuo Hu
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Fernandes EDSM, Corrêa RR, Furtado RLL, Brüggenwirth IMA, Yang C, de Mello FPT, de Oliveira Andrade R, Pimentel LMS, Girão CL, César C, Siqueira MAP, Braga EP, Carvalho ACG, Porte RJ, Bouskela E. Oxygenated versus non-oxygenated flush out during deceased donor liver procurement: The first proof-of-concept study in humans. Artif Organs 2024; 48:1297-1307. [PMID: 38949484 DOI: 10.1111/aor.14815] [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: 02/12/2024] [Revised: 05/24/2024] [Accepted: 06/11/2024] [Indexed: 07/02/2024]
Abstract
BACKGROUND Liver transplantation is used for treating end-stage liver disease, fulminant hepatitis, and oncological malignancies and organ shortage is a major limiting factor worldwide. The use of grafts based on extended donor criteria have become internationally accepted. Oxygenated machine perfusion technologies are the most recent advances in organ transplantation; however, it is only applied after a period of cold ischemia. Due to its high cost, we aimed to use a novel device, OxyFlush®, based on oxygenation of the preservation solution, applied during liver procurement targeting the maintenance of ATP during static cold storage (SCS). METHODS Twenty patients were randomly assigned to the OxyFlush or control group based on a 1:1 ratio. In the OxyFlush group, the perfusion solution was oxygenated with OxyFlush® device while the control group received a non-oxygenated solution. Liver and the common bile duct (CBD) biopsies were obtained at three different time points. The first was at the beginning of the procedure, the second during organ preparation, and the third after total liver reperfusion. Biopsies were analyzed, and adenosine triphosphate (ATP) levels and histological scores of the liver parenchyma and CBD were assessed. Postoperative laboratory tests were performed. RESULTS OxyFlush® was able to maintain ATP levels during SCS and improved the damage caused by the lack of oxygen in the CBD. However, OxyFlush® did not affect laboratory test results and histological findings of the parenchyma. CONCLUSION We present a novel low-cost device that is feasible and could represent a valuable tool in organ preservation during SCS.
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Affiliation(s)
- Eduardo de Souza Martins Fernandes
- Laboratory for Clinical and Experimental Research on Vascular Biology (Biovasc), Department of Physiological Sciences, Rio de Janeiro State University, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, Adventista Silvestre Hospital, Rio de Janeiro, Brazil
- Liver Transplant, São Francisco de Assis Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Clementino Fraga Filho University Hospital, UFRJ, Rio de Janeiro, Brazil
| | - Raphael Rodrigues Corrêa
- Department of Surgery, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Isabel M A Brüggenwirth
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Cindy Yang
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Felipe Pedreira Tavares de Mello
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, Adventista Silvestre Hospital, Rio de Janeiro, Brazil
- Liver Transplant, São Francisco de Assis Hospital, Rio de Janeiro, Brazil
| | - Ronaldo de Oliveira Andrade
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, Adventista Silvestre Hospital, Rio de Janeiro, Brazil
- Liver Transplant, São Francisco de Assis Hospital, Rio de Janeiro, Brazil
| | - Leandro Moreira Savattone Pimentel
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, Adventista Silvestre Hospital, Rio de Janeiro, Brazil
- Liver Transplant, São Francisco de Assis Hospital, Rio de Janeiro, Brazil
| | - Camila Liberato Girão
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, Adventista Silvestre Hospital, Rio de Janeiro, Brazil
- Liver Transplant, São Francisco de Assis Hospital, Rio de Janeiro, Brazil
| | - Camilla César
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, Adventista Silvestre Hospital, Rio de Janeiro, Brazil
- Liver Transplant, São Francisco de Assis Hospital, Rio de Janeiro, Brazil
| | - Munique Ana Pimentel Siqueira
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, DASA São Lucas Hospital, Rio de Janeiro, Brazil
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, Adventista Silvestre Hospital, Rio de Janeiro, Brazil
- Liver Transplant, São Francisco de Assis Hospital, Rio de Janeiro, Brazil
| | | | | | - Robert J Porte
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Eliete Bouskela
- Laboratory for Clinical and Experimental Research on Vascular Biology (Biovasc), Department of Physiological Sciences, Rio de Janeiro State University, Rio de Janeiro, Brazil
- Obesity Unit, Centro de Pesquisas Clínicas Multiusuário (CePeM), Hospital Universitário Pedro Ernesto (HUPE), State University of Rio de Janeiro, Rio de Janeiro, Brazil
- Postgraduate Program in Clinical and Experimental Physiopathology (Fisclinex), Faculty of Medical Sciences, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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Hsieh C, Hsu Y, Chen Y, Liang H, Lin K, Chen W, Wu H, Hunang S, Hung Y. Using extracorporeal membrane oxygenation in donations after cardiac death or brain death: A single-center experience and long-term outcome. Ann Gastroenterol Surg 2024; 8:312-320. [PMID: 38455485 PMCID: PMC10914688 DOI: 10.1002/ags3.12749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/17/2023] [Accepted: 09/29/2023] [Indexed: 03/09/2024] Open
Abstract
Aims The use of extended criteria donors is a routine practice that sometimes involves extracorporeal membrane oxygenation (ECMO) in donations after cardiac death or brain death. Methods We performed a retrospective study in a single center from January 2006 to December 2019. The study included 90 deceased donor liver transplants. The patients were divided into three groups: the donation after brain death (DBD) group (n = 58, 64.4%), the DBD with ECMO group (n = 11, 12.2%) and the donation after cardiac death (DCD) with ECMO group (n = 21, 23.3%). Results There were no significant differences between the DBD with ECMO group and the DBD group. When comparing the DCD with ECMO group and the DBD group, there were statistically significant differences for total warm ischemia time (p < 0.001), total cold ischemia time (p = 0.023), and split liver transplantation (p < 0.001), and there was significantly poor recovery in regard to total bilirubin level (p = 0.027) for the DCD with ECMO group by repeated measures ANOVA. The 5-year survival rates of the DBD, DBD with ECMO, and DCD with ECMO groups were 78.1%, 90.9%, and 75.6%, respectively. The survival rate was not significantly different when comparing the DBD group to either the DBD with ECMO group (p = 0.435) or the DCD with ECMO group (p = 0.310). Conclusions Using ECMO in donations after cardiac death or brain death is a good technology, and it contributed to 35.6% of the liver graft pool.
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Affiliation(s)
- Chia‐En Hsieh
- Department of Nursing, Liver Transplantation CenterChung Shan Medical University HospitalTaichungTaiwan
| | - Ya‐Lan Hsu
- Department of Nursing, Liver Transplantation CenterChung Shan Medical University HospitalTaichungTaiwan
| | - Yao‐Li Chen
- Department of Surgery, Liver Transplantation CenterChung Shan Medical University HospitalTaichungTaiwan
- School of MedicineChung Shan Medical UniversityTaichungTaiwan
| | - Hsin‐Rou Liang
- Department of SurgeryKaohsiung Medical University Chung‐Ho Memorial HospitalKaohsiungTaiwan
| | - Kuo‐Hua Lin
- General SurgeryChanghua Christian HospitalChanghuaTaiwan
| | - Wen‐Yuan Chen
- Department of Pharmacy, Liver Transplantation CenterChung Shan Medical University HospitalTaichungTaiwan
| | - Hsiu‐Man Wu
- Department of NursingChanghua Christian HospitalChanghuaTaiwan
| | - Sin‐Bao Hunang
- Department of Family and Community MedicineChung Shan Medical University HospitalTaichungTaiwan
- Department of Medical Humanities, School of MedicineChung Shan Medical UniversityTaichungTaiwan
| | - Yu‐Ju Hung
- Department of Surgery, Liver Transplantation CenterChung Shan Medical University HospitalTaichungTaiwan
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Longchamp A, Nakamura T, Uygun K, Markmann JF. Role of Machine Perfusion in Liver Transplantation. Surg Clin North Am 2024; 104:45-65. [PMID: 37953040 DOI: 10.1016/j.suc.2023.07.001] [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] [Indexed: 11/14/2023]
Abstract
Given the current severe shortage of available livers for transplantation, there is an urgent need to maximize the utilization of donor organs. One of the strategies to increase the number of available livers for transplantation is to improve organ utilization through the use of elderly, overweight, or organs donated after circulatory death. However, the utilization of these "marginal" organs was associated with an increased risk of early allograft dysfunction, primary nonfunction, ischemic biliary complications, or even re-transplantation. Ischemia-reperfusion injury is a key mechanism in the pathogenesis of these complications.
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Affiliation(s)
- Alban Longchamp
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Tsukasa Nakamura
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Korkut Uygun
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - James F Markmann
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Iwata H, Nakajo T, Kaneko H, Okazawa Y, Zin NKM, Bochimoto H, Ohashi M, Kawada Y, Kamikawa S, Kudo T, Okada Y, Ohara M, Obara H, Matsuno N. Combined Use of Subnormothermic Extracorporeal Support and Hypothermic Oxygenated Machine Perfusion for Liver Graft After Cardiac Death in Pigs. Transplant Proc 2023:S0041-1345(23)00133-1. [PMID: 37088618 DOI: 10.1016/j.transproceed.2023.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/13/2023] [Indexed: 04/25/2023]
Abstract
BACKGROUND The use of grafts from donors after cardiac death (DCD) would greatly contribute to the expansion of the donor organ pool. This study aims to determine the benefits of extracorporeal membrane oxygenation (ECMO) and hypothermic oxygenated machine perfusion (HOPE) in a large animal model of DCD liver. METHODS After cardiac arrest, the abdominal aorta and the inferior vena cava were cannulated and connected to an ECMO circuit. Porcine livers were perfused in situ with ECMO at 22°C for 60 minutes after 45 minutes of cardiac death. Then, the livers were perfused for 4 hours by cold storage (CS) or HOPE. In group 1, non-in situ ECMO and grafts were preserved by HOPE. In group 2, in situ ECMO and grafts were preserved by HOPE. In group 3, in situ ECMO and grafts were preserved by CS. After preservation, all grafts were evaluated using an isolated reperfusion model (IRM) with autologous blood for 2 hours. RESULTS During HOPE, aspartate aminotransferase (AST) levels and hepatic arterial pressure in group 2 tended to be lower than in group 1. Hematoxylin-eosin staining findings after HOPE showed more massive sinusoidal congestion and hepatocyte cytoplasmic vacuolization in group 1 than in group 2. The AST and LDH levels in group 2 at the start-up of IRM tended to be lower than in group 1. CONCLUSIONS The combined use of in situ subnormothermic ECMO and HOPE is essential for the functional recovery of DCD liver grafts.
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Affiliation(s)
- Hiroyoshi Iwata
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Tetsuya Nakajo
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Hiroki Kaneko
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Yuga Okazawa
- Department of Mechanical System Engineering, Tokyo Metropolitan University, Hachioji, Tokyo, Japan
| | - Nur Khatijah Mohd Zin
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Hiroki Bochimoto
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Makito Ohashi
- Department of Clinical Engineering, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Yoko Kawada
- Department of Clinical Engineering, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan
| | - Shota Kamikawa
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Takahiro Kudo
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Yoko Okada
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Mizuho Ohara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Hiromichi Obara
- Department of Mechanical System Engineering, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
| | - Naoto Matsuno
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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Calcification of the visceral aorta and celiac trunk is associated with renal and allograft outcomes after deceased donor liver transplantation. Abdom Radiol (NY) 2023; 48:608-620. [PMID: 36441198 PMCID: PMC9902327 DOI: 10.1007/s00261-022-03629-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/16/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE Atherosclerosis affects clinical outcomes in the setting of major surgery. Here we aimed to investigate the prognostic role of visceral aortic (VAC), extended visceral aortic (VAC+), and celiac artery calcification (CAC) in the assessment of short- and long-term outcomes following deceased donor orthotopic liver transplantation (OLT) in a western European cohort. METHODS We retrospectively analyzed the data of 281 consecutive recipients who underwent OLT at a German university medical center (05/2010-03/2020). The parameters VAC, VAC+, or CAC were evaluated by preoperative computed tomography-based calcium quantification according to the Agatston score. RESULTS Significant VAC or CAC were associated with impaired postoperative renal function (p = 0.0016; p = 0.0211). Patients with VAC suffered more frequently from early allograft dysfunction (EAD) (38 vs 26%, p = 0.031), while CAC was associated with higher estimated procedural costs (p = 0.049). In the multivariate logistic regression analysis, VAC was identified as an independent predictor of EAD (2.387 OR, 1.290-4.418 CI, p = 0.006). Concerning long-term graft and patient survival, no significant difference was found, even though patients with calcification showed a tendency towards lower 5-year survival compared to those without (VAC: 65 vs 73%, p = 0.217; CAC: 52 vs 72%, p = 0.105). VAC+ failed to provide an additional prognostic value compared to VAC. CONCLUSION This is the first clinical report to show the prognostic role of VAC/CAC in the setting of deceased donor OLT with a particular value in the perioperative phase. Further studies are warranted to validate these findings. CT computed tomography, OLT orthotopic liver transplantation.
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Bochimoto H, Ishihara Y, Mohd Zin NK, Iwata H, Kondoh D, Obara H, Matsuno N. Ultrastructural changes in porcine liver sinusoidal endothelial cells of machine perfused liver donated after cardiac death. World J Gastroenterol 2022; 28:2100-2111. [PMID: 35664031 PMCID: PMC9134135 DOI: 10.3748/wjg.v28.i19.2100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/17/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The machine perfusion (MP) preservation including hypothermic MP (HMP) and midthermic MP (MMP) has been considered as a promising strategy to preserve the functions of liver donated after cardiac death. The importance of understanding liver sinusoidal endothelial cells (LSEC) damage in regulating liver injury during MP has been emphasized. However, the ultrastructural changes in the LSEC and sinusoids around them after MP are unclear.
AIM To investigate the ultrastructural changes in the LSEC and sinusoids around them after MP.
METHODS Porcine liver grafts undergo a warm ischemia time of 60 minutes perfused for 4 h with modified University of Wisconsin gluconate solution. Group A grafts were preserved with HMP at 8 °C constantly for 4 h. Group B grafts were preserved with a rewarming solution at 22 °C by MMP for 4 h. Then the ultrastructural changes in the LSEC and sinusoids in Group A and B were comparatively analyzed by using osmium-maceration scanning electron microscopy with complementary transmission electron microscopy methods.
RESULTS An analysis of the LSEC after warm ischemia revealed that mitochondria with condensed-shaped cristae, abnormal vesicles, reduction of ribosomes and the endoplasmic reticulum (ER) surround the mitochondria appeared. The MP subsequent after warm ischemia alleviate the abnormal vesicles and reduction of ribosomes in LSEC, which indicated the reduction of the ER damage. However, MMP could restore the tubular mitochondrial cristae, while after HMP the condensed and narrow mitochondrial cristae remained. In addition, the volume of the sinusoidal space in the liver grafts after MMP were restored, which indicated a lower risk of pressure injury than HMP.
CONCLUSION MMP alleviates the ER damage of LSEC by warm ischemia, additionally restore the metabolism of LSEC via the normalization of mitochondria and prevent the share stress damage of liver grafts.
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Affiliation(s)
- Hiroki Bochimoto
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku 105-8461, Tokyo, Japan
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Yo Ishihara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Nur Khatijah Mohd Zin
- Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku 105-8461, Tokyo, Japan
| | - Hiroyoshi Iwata
- Department of Surgery, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
| | - Daisuke Kondoh
- Laboratory of Veterinary Anatomy, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Hokkaido, Japan
| | - Hiromichi Obara
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
- Department of Mechanical Engineering, Tokyo Metropolitan University, Hachioji 192-0397, Tokyo, Japan
| | - Naoto Matsuno
- Department of Transplantation Technology and Therapeutic Development, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
- Department of Surgery, Asahikawa Medical University, Asahikawa 078-8510, Hokkaido, Japan
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Kirste G. Cold but not too cold: advances in hypothermic and normothermic organ perfusion. KOREAN JOURNAL OF TRANSPLANTATION 2022; 36:2-14. [PMID: 35769433 PMCID: PMC9235527 DOI: 10.4285/kjt.22.0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 02/21/2022] [Indexed: 11/24/2022] Open
Abstract
Transplantation is the method of choice and, in many cases, the only method of treatment for patients with end-stage organ disease. Excellent results have been achieved, and the main focus today is to extend the number of available donors. The use of extended-criteria donors or donors after circulatory death is standard, but is accompanied by an increased risk of ischemia reperfusion injury. This review presents newly developed machine perfusion techniques using hypothermic, subnormothermic, or normothermic conditions, with or without oxygenation. Possibilities for treatment and quality assessment in decision-making about organ acceptability are also discussed.
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Affiliation(s)
- Guenter Kirste
- Department of Surgery, University Hospital of Freiburg, Albert Ludwig University of Freiburg, Freiburg im Breisgau, Germany
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Machine perfusion of the liver: applications in transplantation and beyond. Nat Rev Gastroenterol Hepatol 2022; 19:199-209. [PMID: 34997204 DOI: 10.1038/s41575-021-00557-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/17/2021] [Indexed: 12/14/2022]
Abstract
The shortage of donor livers considered suitable for transplantation has driven the development of novel methods for organ preservation and reconditioning. Machine perfusion techniques can improve the quality of marginal livers, extend the time for which they can be preserved and enable an objective assessment of their quality and viability. These benefits can help avoid the needless wastage of organs based on hypothetical concerns regarding quality. As machine perfusion techniques are gaining traction in clinical practice, attention has now shifted to their potential applications beyond transplantation. As well as providing an update on the current status of machine perfusion in clinical practice, this Perspective discusses how this technology is being used as a tool for therapeutic interventions including defatting of steatotic livers, immunomodulation and gene therapies.
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Fodor M, Woerdehoff A, Peter W, Esser H, Oberhuber R, Margreiter C, Maglione M, Cardini B, Resch T, Weissenbacher A, Sucher R, Zoller H, Tilg H, Öfner D, Schneeberger S. Reassessment of Relevance and Predictive Value of Parameters Indicating Early Graft Dysfunction in Liver Transplantation: AST Is a Weak, but Bilirubin and INR Strong Predictors of Mortality. Front Surg 2021; 8:693288. [PMID: 34869549 PMCID: PMC8634944 DOI: 10.3389/fsurg.2021.693288] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 10/27/2021] [Indexed: 01/14/2023] Open
Abstract
Introduction: Early graft dysfunction (EAD) complicates liver transplantation (LT). The aim of this analysis was to discriminate between the weight of each variable as for its predictive value toward patient and graft survival. Methods: We reviewed all LT performed at the Medical University of Innsbruck between 2007 and 2018. EAD was recorded when one of the following criteria was present: (i) aspartate aminotransferase (AST) levels >2,000 IU/L within the first 7 days, (ii) bilirubin levels ≥10mg/dL or (iii) international normalized ratio (INR) ≥1.6 on postoperative day 7. Results: Of 616 LT, 30.7% developed EAD. Patient survival did not differ significantly (P = 0.092; log rank-test = 2.87), graft survival was significantly higher in non-EAD patients (P = 0.008; log rank-test = 7.13). Bilirubin and INR on postoperative day 7 were identified as strong mortality predictors (Bilirubin HR = 1.71 [1.34, 2.16]; INR HR = 2.69 [0.51, 14.31]), in contrast to AST (HR = 0.91 [0.75, 1.10]). Similar results were achieved for graft loss estimation. A comparison with the Model for Early Allograft Function (MEAF) and the Liver Graft Assessment Following Transplantation (L-GrAFT) score identified a superior discrimination potential but lower specificity. Conclusion: Contrarily to AST, bilirubin and INR have strong predictive capacity for patient and graft survival. This fits well with the understanding, that bile duct injury and deprivation of synthetic function rather than hepatocyte injury are key factors in LT.
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Affiliation(s)
- Margot Fodor
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Adriana Woerdehoff
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Wolfgang Peter
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Hannah Esser
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Resch
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Annemarie Weissenbacher
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Robert Sucher
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Leipzig, Germany
| | - Heinz Zoller
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
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11
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Mitochondrial respiratory chain and Krebs cycle enzyme function in human donor livers subjected to end-ischaemic hypothermic machine perfusion. PLoS One 2021; 16:e0257783. [PMID: 34710117 PMCID: PMC8553115 DOI: 10.1371/journal.pone.0257783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/09/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Marginal human donor livers are highly susceptible to ischaemia reperfusion injury and mitochondrial dysfunction. Oxygenation during hypothermic machine perfusion (HMP) was proposed to protect the mitochondria but the mechanism is unclear. Additionally, the distribution and uptake of perfusate oxygen during HMP are unknown. This study aimed to examine the feasibility of mitochondrial function analysis during end-ischaemic HMP, assess potential mitochondrial viability biomarkers, and record oxygenation kinetics. METHODS This was a randomised pilot study using human livers retrieved for transplant but not utilised. Livers (n = 38) were randomised at stage 1 into static cold storage (n = 6), hepatic artery HMP (n = 7), and non-oxygen supplemented portal vein HMP (n = 7) and at stage 2 into oxygen supplemented and non-oxygen supplemented portal vein HMP (n = 11 and 7, respectively). Mitochondrial parameters were compared between the groups and between low- and high-risk marginal livers based on donor history, organ steatosis and preservation period. The oxygen delivery efficiency was assessed in additional 6 livers using real-time measurements of perfusate and parenchymal oxygen. RESULTS The change in mitochondrial respiratory chain (complex I, II, III, IV) and Krebs cycle enzyme activity (aconitase, citrate synthase) before and after 4-hour preservation was not different between groups in both study stages (p > 0.05). Low-risk livers that could have been used clinically (n = 8) had lower complex II-III activities after 4-hour perfusion, compared with high-risk livers (73 nmol/mg/min vs. 113 nmol/mg/min, p = 0.01). Parenchymal pO2 was consistently lower than perfusate pO2 (p ≤ 0.001), stabilised in 28 minutes compared to 3 minutes in perfusate (p = 0.003), and decreased faster upon oxygen cessation (75 vs. 36 minutes, p = 0.003). CONCLUSIONS Actively oxygenated and air-equilibrated end-ischaemic HMP did not induce oxidative damage of aconitase, and respiratory chain complexes remained intact. Mitochondria likely respond to variable perfusate oxygen levels by adapting their respiratory function during end-ischaemic HMP. Complex II-III activities should be further investigated as viability biomarkers.
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12
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Meister FA, Bednarsch J, Amygdalos I, Boecker J, Strnad P, Bruners P, Lang SA, Ulmer TF, Heij L, Santana DAM, Liu WJ, Lurje G, Neumann UP, Czigany Z. Various myosteatosis selection criteria and their value in the assessment of short- and long-term outcomes following liver transplantation. Sci Rep 2021; 11:13368. [PMID: 34183733 PMCID: PMC8239038 DOI: 10.1038/s41598-021-92798-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 06/07/2021] [Indexed: 02/07/2023] Open
Abstract
Body composition and myosteatosis affect clinical outcomes in orthotopic liver transplantation (OLT). Here we aimed to compare the value and limitations of various selection criteria to define pre-transplant myosteatosis in the assessment of short- and long-term outcomes following OLT. We retrospectively analyzed the data of 264 consecutive recipients who underwent deceased donor OLT at a German university medical centre. Myosteatosis was evaluated by preoperative computed-tomography-based segmentation. Patients were stratified using muscle radiation attenuation of the whole muscle area (L3Muslce-RA), psoas RA (L3Psoas-RA) and intramuscular adipose tissue content (IMAC) values. L3Muslce-RA, L3Psoas-RA and IMAC performed well without major differences and identified patients at risk for inferior outcomes in the group analysis. Quartile-based analyses, receiver operating characteristic curve and correlation analyses showed a superior association of L3Muslce-RA with perioperative outcomes when compared to L3Psoas-RA and L3IMAC. Long-term outcome did not show any major differences between the used selection criteria. This study confirms the prognostic role of myosteatosis in OLT with a particularly strong value in the perioperative phase. Although, based on our data, L3Muscle-RA might be the most suitable and recommended selection criterion to assess CT-based myosteatosis when compared to L3Psoas-RA and L3IMAC, further studies are warranted to validate these findings.
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Affiliation(s)
- Franziska Alexandra Meister
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Joerg Boecker
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Philipp Bruners
- Institute of Radiology, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Sven Arke Lang
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Lara Heij
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Institute for Pathology, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Daniel Antonio Morales Santana
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Wen-Jia Liu
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Georg Lurje
- Department of Surgery, Campus Charité Mitte
- Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.,Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Zoltan Czigany
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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13
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Ivanics T, Abreu P, De Martin E, Sapisochin G. Changing Trends in Liver Transplantation: Challenges and Solutions. Transplantation 2021; 105:743-756. [PMID: 32910093 DOI: 10.1097/tp.0000000000003454] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite improvements in postliver transplant outcomes through refinements in perioperative management and surgical techniques, several changing trends in liver transplantation have presented challenges. Mortality on the waitlist remains high. In the United States, Europe, and the United Kingdom, there is an increasing need for liver transplantation, primarily as a result of increased incidence of nonalcoholic steatohepatitis-related cirrhosis and cancer indications. Meanwhile, donor suitability has decreased, as donors are often older and have more comorbidities. Despite a mismatch between organ need and availability, many organs are discarded. Notwithstanding this, many solutions have been developed to overcome these challenges. Innovative techniques in allograft preservation, viability assessment, and reconditioning have allowed the use of suboptimal organs with adequate results. Refinements in surgical procedures, including live donor liver transplantations, have increased the organ pool and are decreasing the time and mortality on the waitlist. Despite many challenges, a similar number of solutions and prospects are on the horizon. This review seeks to explore the changing trends and challenges in liver transplantation and highlight possible solutions and future directions.
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Affiliation(s)
- Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Phillipe Abreu
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Eleonora De Martin
- APHP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM 1193, Université Paris-Sud, DHU Hepatinov, Villejuif, France
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
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14
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Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies. Int J Mol Sci 2021; 22:ijms22041864. [PMID: 33668478 PMCID: PMC7918617 DOI: 10.3390/ijms22041864] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular–pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
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15
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Rayar M, Beaurepaire JM, Bajeux E, Hamonic S, Renard T, Locher C, Desfourneaux V, Merdrignac A, Bergeat D, Lakehal M, Sulpice L, Houssel-Debry P, Jezequel C, Camus C, Bardou-Jacquet E, Meunier B. Hypothermic Oxygenated Perfusion Improves Extended Criteria Donor Liver Graft Function and Reduces Duration of Hospitalization Without Extra Cost: The PERPHO Study. Liver Transpl 2021; 27:349-362. [PMID: 33237618 DOI: 10.1002/lt.25955] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 10/19/2020] [Accepted: 11/05/2020] [Indexed: 12/14/2022]
Abstract
Few studies have evaluated the efficacy or the cost of hypothermic oxygenated perfusion (HOPE) in the conservation of extended criteria donor (ECD) grafts from donation after brain death (DBD) donors during liver transplantation (LT). We performed a prospective, monocentric study (NCT03376074) designed to evaluate the interest of HOPE for ECD-DBD grafts. For comparison, a control group was selected after propensity score matching among patients who received transplants between 2010 and 2017. Between February and November 2018, the HOPE procedure was used in 25 LTs. Immediately after LT, the median aspartate aminotransferase (AST) level was significantly lower in the HOPE group (724UI versus 1284UI; P = 0.046) as were the alanine aminotransferase (ALT; 392UI versus 720UI; P = 0.01), lactate (2.2 versus 2.7; P = 0.01) There was a significant reduction in intensive care unit stay (3 versus 5 days; P = 0.01) and hospitalization (15 versus 20 days; P = 0.01). The incidence of early allograft dysfunction (EAD; 28% versus 42%; P = 0.22) was similar . A level of AST or ALT in perfusate >800UI was found to be highly predictive of EAD occurrence (areas under the curve, 0.92 and 0.91, respectively). The 12-month graft (88% versus 89.5%; P = 1.00) and patient survival rates (91% versus 91.3%; P = 1.00) were similar. The additional cost of HOPE was estimated at € 5298 per patient. The difference between costs and revenues, from the hospital's perspective, was not different between the HOPE and control groups (respectively, € 3023 versus € 4059]; IC, -€ 5470 and € 8652). HOPE may improve ECD graft function and reduce hospitalization stay without extra cost. These results must be confirmed in a randomized trial.
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Affiliation(s)
- Michel Rayar
- Service de Chirurgie Hépato-Biliaire et DigestiveCHU RennesRennesFrance
- Faculté de MédecineUniversité Rennes 1RennesFrance
- INSERM, CIC 1414RennesFrance
| | | | - Emma Bajeux
- Service d'Epidémiologie et de Santé PubliqueCHU RennesRennesFrance
| | | | - Thomas Renard
- Service de Chirurgie Hépato-Biliaire et DigestiveCHU RennesRennesFrance
| | - Clara Locher
- Faculté de MédecineUniversité Rennes 1RennesFrance
- Service de Pharmacologie Clinique, Centre Hospitalo- Universitaire RennesRennesFrance
| | | | - Aude Merdrignac
- Service de Chirurgie Hépato-Biliaire et DigestiveCHU RennesRennesFrance
- Faculté de MédecineUniversité Rennes 1RennesFrance
| | - Damien Bergeat
- Service de Chirurgie Hépato-Biliaire et DigestiveCHU RennesRennesFrance
| | - Mohamed Lakehal
- Service de Chirurgie Hépato-Biliaire et DigestiveCHU RennesRennesFrance
| | - Laurent Sulpice
- Service de Chirurgie Hépato-Biliaire et DigestiveCHU RennesRennesFrance
- Faculté de MédecineUniversité Rennes 1RennesFrance
| | | | - Caroline Jezequel
- Service des Maladies du FoieCentre Hospitalo-Universitaire RennesRennesFrance
| | - Christophe Camus
- Service de Maladies Infectieuses et Réanimation MédicaleCHU RennesRennesFrance
| | - Edouard Bardou-Jacquet
- Faculté de MédecineUniversité Rennes 1RennesFrance
- INSERM, CIC 1414RennesFrance
- Service des Maladies du FoieCentre Hospitalo-Universitaire RennesRennesFrance
| | - Bernard Meunier
- Service de Chirurgie Hépato-Biliaire et DigestiveCHU RennesRennesFrance
- Faculté de MédecineUniversité Rennes 1RennesFrance
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16
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Bonaccorsi-Riani E, Brüggenwirth IMA, Buchwald JE, Iesari S, Martins PN. Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials. Semin Liver Dis 2020; 40:264-281. [PMID: 32557478 DOI: 10.1055/s-0040-1713118] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.
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Affiliation(s)
- E Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.,Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium
| | - I M A Brüggenwirth
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J E Buchwald
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
| | - S Iesari
- Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - P N Martins
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
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17
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Hu X, Wang W, Zeng C, He W, Zhong Z, Liu Z, Wang Y, Ye Q. Appropriate timing for hypothermic machine perfusion to preserve livers donated after circulatory death. Mol Med Rep 2020; 22:2003-2011. [PMID: 32582977 PMCID: PMC7411412 DOI: 10.3892/mmr.2020.11257] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 05/28/2020] [Indexed: 12/17/2022] Open
Abstract
Hypothermic machine perfusion (HMP) is a method that can be more effective in preserving donor organs compared with cold storage (CS). However, the optimal duration and the exact mechanisms of the protevtive effects of HMP remain unknow. The present study aimed to investigate the adequate perfusion time and mechanisms underlying HMP to protect livers donated after circulatory death (DCD). After circulatory death, adult male Sprague-Dawley rat livers were subjected to 30 min of warm ischemia (WI) and were subsequently preserved by HMP or CS. To determine the optimal perfusion time, liver tissues were analyzed at 0, 1, 3, 5, 12 and 24 h post-preservation to evaluate injury and assess the expression of relevant proteins. WI livers were preserved by HMP or CS for 3 h, and liver viability was evaluated by normothermic reperfusion (NR). During NR, oxygen consumption, bile production and the activities of hepatic enzymes in the perfusate were assessed. Following 2 h of NR, levels of inflammation and oxidative stress were determined in the livers and perfusate. HMP for 3 h resulted in the highest expression of myocyte enhancer factor 2C (MEF2C) and kruppel-like factor 2 (KLF2) and the lowest expression of NF-κB p65, tumor necrosis factor (TNF)-α and interleukin (IL)-1β among the different timepoints, which indicated that 3 h may be the optimal time for HMP induction of the KLF2-dependent signaling pathway. Compared with CS-preserved livers, HMP-preserved livers displayed significantly higher oxygen consumption, lower hepatic enzyme levels in the perfusate following NR. Following HMP preservation, the expression levels of MEF2C, KLF2, endothelial nitric oxide synthase and nitric oxide were increased, whereas the expression levels of NF-κB p65, IL-1β and TNF-α were decreased compared with CS preservation. The results indicated that 3 h may be the optimal time for HMP to protect DCD rat livers. Furthermore, HMP may significantly reduce liver inflammation and oxidative stress injury by mediating the KLF2/NF-κB/eNOS-dependent signaling pathway.
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Affiliation(s)
- Xiaoyan Hu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Wei Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Cheng Zeng
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Weiyang He
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Zibiao Zhong
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Zhongzhong Liu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei 430071, P.R. China
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18
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Brüggenwirth IMA, van Leeuwen OB, de Vries Y, Bodewes SB, Adelmeijer J, Wiersema-Buist J, Lisman T, Martins PN, de Meijer VE, Porte RJ. Extended hypothermic oxygenated machine perfusion enables ex situ preservation of porcine livers for up to 24 hours. JHEP Rep 2020; 2:100092. [PMID: 32195456 PMCID: PMC7078381 DOI: 10.1016/j.jhepr.2020.100092] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 01/16/2020] [Indexed: 12/19/2022] Open
Abstract
Background & Aims End-ischemic hypothermic oxygenated machine perfusion (HOPE) of the donor liver for 1-2 h mitigates ischemia-reperfusion injury during subsequent liver transplantation. Extended preservation time may be preferred to facilitate difficult recipient hepatectomy or to optimize logistics. We therefore investigated whether end-ischemic dual HOPE (DHOPE) could extend preservation time for up to 24 h using a porcine liver reperfusion model. Methods Following 30 min warm ischemia, porcine livers were subjected to 2 h static cold storage (SCS), followed by 2 h, 6 h, or 24 h DHOPE (n = 6 per group). Subsequent normothermic reperfusion was performed for 4 h using autologous blood. Two livers preserved by 24 h SCS served as additional controls. A proof of principle confirmation was carried out in 2 discarded human livers subjected to extended DHOPE. Hepatocellular and cholangiocyte injury and function were assessed. Oxidative stress levels and histology were compared between groups. Results Perfusion flows remained stable during DHOPE, regardless of duration. After normothermic reperfusion, livers perfused for 24 h by DHOPE had similar lactate clearance, blood pH, glucose, and alanine aminotransferase levels, and biliary pH, bicarbonate, and LDH levels, as livers perfused for 2 h and 6 h. Levels of malondialdehyde and high-mobility group box 1 in serum and liver parenchyma were similar for all groups. Histological analysis of bile ducts and liver parenchyma revealed no differences between the groups. Extended DHOPE in discarded human livers preserved hepatocellular and cholangiocyte function and histology after reperfusion. In contrast, livers preserved by 24 h SCS were non-functioning. Conclusion Extended end-ischemic DHOPE enabled successful preservation of porcine and discarded human donor livers for up to 24 h. Extended DHOPE enables safe extension of preservation time, which may facilitate allocation and transplantation from a logistical perspective, and further expand the donor pool. Lay summary It has been suggested that preserving liver grafts with a technique called (dual) hypothermic oxygenated machine perfusion ([D]HOPE) leads to better outcomes after transplantation than if livers are stored on ice, especially if an organ is of lesser quality. In this study, we showed that DHOPE could be used to preserve liver grafts for up to 24 h. This extended procedure could be used globally to facilitate transplantation and expand the donor pool.
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Key Words
- 8-OHdG, 8-hydroxydeoxyguanosine
- ALT, alanine aminotransferase
- DCD, donation after circulatory death
- DHOPE, dual hypothermic oxygenated machine perfusion
- ECD, extended criteria donor
- HMGB-1, high-mobility group box 1
- HMP, hypothermic machine perfusion
- HOPE, hypothermic oxygenated machine perfusion
- HPF, high-powered field
- IL-6, interleukin 6
- LDH, lactate dehydrogenase
- MDA, malondialdehyde
- NMP, normothermic machine perfusion
- SCS, static cold storage
- SEM, standard error of the mean
- TNFα, tumor necrosis factor-alpha
- UW, University of Wisconsin
- VWF, von Willebrand factor
- cfDNA, cell-free DNA
- donation after circulatory death
- extended preservation
- hypothermic machine perfusion
- liver preservation
- sTM, soluble thrombomodulin
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Affiliation(s)
- Isabel M A Brüggenwirth
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Otto B van Leeuwen
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Yvonne de Vries
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Silke B Bodewes
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Jelle Adelmeijer
- Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Janneke Wiersema-Buist
- Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ton Lisman
- Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Paulo N Martins
- Division of Organ Transplantation, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, MA, United States
| | - Vincent E de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
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19
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Tan L, Yang Y, Ma G, Zhu T, Yang J, Liu H, Zhang W. Early acute kidney injury after liver transplantation in patients with normal preoperative renal function. Clin Res Hepatol Gastroenterol 2019; 43:475-482. [PMID: 31126850 DOI: 10.1016/j.clinre.2018.07.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 07/21/2018] [Accepted: 07/24/2018] [Indexed: 02/05/2023]
Abstract
AIM Acute kidney injury (AKI) commonly occurs in patients after liver transplantation (LT). However, few studies have focused on AKI and its correlation with clinical outcomes under the Kidney Disease Improving Global Outcomes (KDIGO) criteria. This study aimed to identity the incidence, risk factors, and impacts of early AKI on outcomes in LT recipients with normal preoperative renal function, according to the KDIGO criteria. METHODS Clinical and laboratory data of 227 patients with normal preoperative renal function who underwent LT from January 2011 to January 2015 were retrospectively analyzed. RESULTS During the first week after LT, 106 patients (46.7%) developed AKI based on the KDIGO criteria. A multivariate analysis revealed that BMI of > 25, prolonged inferior vena cava clamping, prolonged cold ischemia time, and post-operative RBC requirements > 10 units were independent risk factors for AKI after LT. The area under the receiver operating characteristic curve for the predictive ability of AKI under these risk factors was 0.748. The occurrence of AKI was associated with longer mechanical ventilation time and post-operative ICU stay, increased post-operative 30-day mortality and decreased long-term patient survival. CONCLUSIONS Even in patients with normal preoperative renal function, AKI was a frequent complication in LT recipients and had both negative short- or long-term effects on patient outcomes, also the severity of AKI had a dose-response relationship with worse outcomes. Patients with BMI > 25, prolonged inferior vena cava clamping, prolonged cold ischemia time, or post-operative RBC requirement > 10 units should be pay particular attention, which may assist in achieving better clinical outcomes.
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Affiliation(s)
- Lingcan Tan
- Department of Anesthesiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu 610041, China.
| | - Yaoxin Yang
- Department of Anesthesiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu 610041, China
| | - Gang Ma
- Department of Anesthesiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu 610041, China
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu 610041, China.
| | - Jiayin Yang
- Department of Liver Surgery, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu 610041, China.
| | - Haibei Liu
- Department of Anesthesiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu 610041, China
| | - Weiyi Zhang
- Department of Anesthesiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu 610041, China
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20
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Zeng X, Wang S, Li S, Yang Y, Fang Z, Huang H, Wang Y, Fan X, Ye Q. Hypothermic oxygenated machine perfusion alleviates liver injury in donation after circulatory death through activating autophagy in mice. Artif Organs 2019; 43:E320-E332. [PMID: 31237688 DOI: 10.1111/aor.13525] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/12/2019] [Accepted: 06/13/2019] [Indexed: 12/13/2022]
Abstract
Hypothermic oxygenated machine perfusion (HOPE) is a safe and reliable method that could alleviate liver injury in donation after circulatory death (DCD). This study focuses on the role of autophagy in HOPE's protective effect on DCD liver injury. A 30-minute warm ischemic liver model was established in mice. After 4 hours of cold storage (CS), 1 hour of hypothermic machine perfusion (HMP) with 100% O2 or 100% N2 was employed. During 2 hours of reperfusion, liver tissue and perfusate were collected to evaluate liver function, oxidative stress level, apoptosis, and necrosis. Western blotting was used to explore the level of autophagy. When the liver experienced warm ischemic injury, LC3B-II expression was significantly enhanced. Compared with the CS, HOPE induced lower release of AST and ALT, as well as lower oxidative stress levels, apoptosis, and necrosis cell numbers, and led to higher tissue ATP content. Meanwhile, expression of autophagy-related proteins, such as ULK1, Atg5, and LC3B-II, increased. When oxygen was completely replaced by nitrogen, the washout effect of HMP did not activate autophagy and did not relieve DCD liver injury. When the autophagy inhibitor 3-methyladenine was used in HOPE, the protective effect of HOPE was attenuated. In conclusion, DCD liver injury activated autophagy compared with healthy liver, while HOPE alleviated DCD liver injury by increasing autophagy levels further in this mouse model. However, HMP with 100% of N2 had no beneficial effect on DCD liver injury or on autophagy levels compared with CS. The research on autophagy may provide a new strategy for alleviating DCD liver injury in clinical practice.
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Affiliation(s)
- Xianpeng Zeng
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Shengjie Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Shiyi Li
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Yunying Yang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Zehong Fang
- The Third General Surgery Department of Jiangxi Provincial People's Hospital, Organ Transplant Department of Jiangxi Provincial People's Hospital, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Honglei Huang
- Nuffield Department of Surgical Sciences, Oxford University, Oxford, United Kingdom
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Xiaoli Fan
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China.,Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The 3rd Xiangya Hospital of Central South University, Changsha, China
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21
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Combined kidney‑liver perfusion enhances the proliferation effects of hypothermic perfusion on liver grafts via upregulation of IL‑6/Stat3 signaling. Mol Med Rep 2019; 20:1663-1671. [PMID: 31257470 PMCID: PMC6625442 DOI: 10.3892/mmr.2019.10379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 12/19/2018] [Indexed: 12/02/2022] Open
Abstract
A limited number of studies have revealed that adding kidneys to liver perfusion may maintain an improved physiological balance; however, the underlying mechanism remains to be elucidated. The preset study confirmed the protective role of this new model and investigated the underlying mechanisms. Methods: A total of 12 rats were randomly assigned into two groups (n=6 for each group): The kidney-liver perfusion (KL) group and liver perfusion (LP) group. Perfusate samples were collected during the perfusion process for the analysis of pH, K+ and liver function. Liver tissues were obtained for the evaluation of adenosine triphosphate (ATP), terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling and immunohistochemistry of Ki67. Cell cycle inhibitors, apoptosis-associated genes and signal transducer and activator of transcription 3 (Stat3) were analyzed using quantitative polymerase chain reaction and western blot analysis. Results: Overall pH and K+ values of the KL group were significantly different from the LP group and more stable; aspartate aminotransferase, alanine transaminase and lactate dehydrogenase levels increased progressively over time in the LP group and were significantly different at different time points compared with pre-perfusion levels and the KL group, which suggested the KL group was superior to the LP group. In addition, KL reduced portal vein resistance and was associated with lower ATP consumption compared with the LP group. Furthermore, liver proliferation was upregulated with the upregulation of the interleukin 6 (IL-6)/Stat3 signaling pathway in KL compared with LP. The present study revealed for the first time that KL and hypothermic machine perfusion demonstrated a more proactive repair capability by maintaining liver regeneration via the upregulation of the IL-6/Stat3 signaling pathway.
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22
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Weissenbacher A, Vrakas G, Nasralla D, Ceresa CDL. The future of organ perfusion and re-conditioning. Transpl Int 2019; 32:586-597. [PMID: 30980772 PMCID: PMC6850430 DOI: 10.1111/tri.13441] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/25/2019] [Accepted: 04/09/2019] [Indexed: 12/14/2022]
Abstract
Organ preservation and re‐conditioning using machine perfusion technologies continue to generate promising results in terms of viability assessment, organ utilization and improved initial graft function. Here, we summarize the latest findings and study the results of ex‐vivo/ex‐situ hypothermic (HMP) and normothermic machine perfusion (NMP) in the area of abdominal organ transplantation (kidney, liver, pancreas and intestine). We also consider the potential role of normothermic regional perfusion (NRP) to re‐condition donors after circulatory death organs before retrieval. The findings from clinical studies reported to date suggest that machine perfusion will offer real benefits when compared with conventional cold preservation. Several randomized trials are expected to report their findings within the next 2 years which may shed light on the relative merits of different perfusion methods and could indicate which perfusion parameters may be most useful to predict organ quality and viability. Further work is needed to identify composite endpoints that are relevant for transplanted organs that have undergone machine preservation. Multi‐centre trials to compare and analyse the combinations of NRP followed by HMP and/or NMP, either directly after organ retrieval using transportable devices or when back‐to‐base, are needed. The potential applications of machine preservation technology beyond the field of solid organ transplantation are also considered.
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Affiliation(s)
- Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.,Nuffield Department of Surgical Sciences, Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Georgios Vrakas
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - David Nasralla
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Carlo D L Ceresa
- Nuffield Department of Surgical Sciences, Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals, University of Oxford, Oxford, UK
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23
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Werner MJM, van Leeuwen OB, de Jong IEM, Bodewes FAJA, Fujiyoshi M, Luhker OC, Scheenstra R, de Vries Y, de Kleine RHJ, Porte RJ. First report of successful transplantation of a pediatric donor liver graft after hypothermic machine perfusion. Pediatr Transplant 2019; 23:e13362. [PMID: 30801955 DOI: 10.1111/petr.13362] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/07/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022]
Abstract
One of the main limiting factors in pediatric liver transplantation is donor availability. For adults, DCD liver grafts are increasingly used to expand the donor pool. To improve outcome after DCD liver transplantation, ex situ machine perfusion is used as an alternative organ preservation strategy, with the supplemental value of providing oxygen to the graft during preservation. We here report the first successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion. The full-size liver graft was derived from a 13-year-old, female DCD donor and was end-ischemic pretreated with dual hypothermic oxygenated machine perfusion. Arterial and portal pressures were set at 18 and 4 mm Hg, slightly lower than protocolized settings for adult livers. During 2 hours of machine perfusion, portal and arterial flows increased from 100 to 210 mL/min and 30 to 63 mL/min, respectively. The pretreated liver graft was implanted in a 16-year-old girl with progressive familial intrahepatic cholestasis type 2. Postoperative AST, ALT, and prothrombin time normalized within a week. The recipient quickly recovered and was discharged from the hospital after 18 days. One year after transplantation, she is in excellent condition with a completely normal liver function and histology. This case is the first report of successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion and illustrates the potential role of ex situ machine perfusion in expanding the donor pool and improving outcome after pediatric liver transplantation.
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Affiliation(s)
- Maureen J M Werner
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Otto B van Leeuwen
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Iris E M de Jong
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Frank A J A Bodewes
- Department of Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Masato Fujiyoshi
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Olaf C Luhker
- Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - René Scheenstra
- Department of Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Yvonne de Vries
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Ruben H J de Kleine
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Department of Surgery, Section of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, Groningen, The Netherlands
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24
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Tchilikidi KY. Liver graft preservation methods during cold ischemia phase and normothermic machine perfusion. World J Gastrointest Surg 2019; 11:126-142. [PMID: 31057698 PMCID: PMC6478595 DOI: 10.4240/wjgs.v11.i3.126] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/21/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023] Open
Abstract
The growing demand for donor organs requires measures to expand donor pool. Those include extended criteria donors, such as elderly people, steatotic livers, donation after cardiac death, etc. Static cold storage to reduce metabolic requirements developed by Collins in late 1960s is the mainstay and the golden standard for donated organ protection. Hypothermic machine perfusion provides dynamic organ preservation at 4°C with protracted infusion of metabolic substrates to the graft during the ex vivo period. It has been used instead of static cold storage or after it as short perfusion in transplant center. Normothermic machine perfusion (NMP) delivers oxygen, and nutrition at physiological temperature mimicking regular environment in order to support cellular function. This would minimize effects of ischemia/reperfusion injury. Potentially, NMP may help to estimate graft functionality before implantation into a recipient. Clinical studies demonstrated at least its non-inferiority or better outcomes vs static cold storage. Regular grafts donated after brain death could be safely preserved with convenient static cold storage. Except for prolonged ischemia time where hypothermic machine perfusion started in transplant center could be estimated to provide possible positive reconditioning effect. Use of hypothermic machine perfusion in regular donation instead of static cold storage or in extended criteria donors requires further investigation. Multicenter randomized clinical trial supposed to be completed in December 2021. Extended criteria donors need additional measures for graft storage and assessment until its implantation. NMP is actively evaluating promising method for this purpose. Future studies are necessary for precise estimation and confirmation to issue clinical practice recommendations.
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25
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van Rijn R, van den Berg AP, Erdmann JI, Heaton N, van Hoek B, de Jonge J, Leuvenink HGD, Mahesh SVK, Mertens S, Monbaliu D, Muiesan P, Perera MTPR, Polak WG, Rogiers X, Troisi RI, de Vries Y, Porte RJ. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol 2019; 19:40. [PMID: 30866837 PMCID: PMC6416838 DOI: 10.1186/s12876-019-0956-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 02/22/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The major concern in liver transplantation of grafts from donation after circulatory death (DCD) donors remains the high incidence of non-anastomotic biliary strictures (NAS). Machine perfusion has been proposed as an alternative strategy for organ preservation which reduces ischemia-reperfusion injury (IRI). Experimental studies have shown that dual hypothermic oxygenated machine perfusion (DHOPE) is associated with less IRI, improved hepatocellular function, and better preserved mitochondrial and endothelial function compared to conventional static cold storage (SCS). Moreover, DHOPE was safely applied with promising results in a recently performed phase-1 study. The aim of the current study is to determine the efficacy of DHOPE in reducing the incidence of NAS after DCD liver transplantation. METHODS This is an international multicenter randomized controlled trial. Adult patients (≥18 yrs. old) undergoing transplantation of a DCD donor liver (Maastricht category III) will be randomized between the intervention and control group. In the intervention group, livers will be subjected to two hours of end-ischemic DHOPE after SCS and before implantation. In the control group, livers will be subjected to care as usual with conventional SCS only. Primary outcome is the incidence of symptomatic NAS diagnosed by a blinded adjudication committee. In all patients, magnetic resonance cholangiography will be obtained at six months after transplantation. DISCUSSION DHOPE is associated with reduced IRI of the bile ducts. Whether reduced IRI of the bile ducts leads to lower incidence of NAS after DCD liver transplantation can only be examined in a randomized controlled trial. TRIAL REGISTRATION The trial was registered in Clinicaltrials.gov in September 2015 with the identifier NCT02584283 .
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Affiliation(s)
- Rianne van Rijn
- Section Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Aad P. van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Joris I. Erdmann
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Nigel Heaton
- Institute of Liver Studies, Kings College Hospital NHS Foundation Trust, London, UK
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeroen de Jonge
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Henri G. D. Leuvenink
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Shekar V. K. Mahesh
- Department of Radiology, University Medical Center Groningen, Groningen, The Netherlands
| | - Sarah Mertens
- Department of Abdominal Transplantation Surgery, University Hospitals of Leuven, Leuven, Belgium
| | - Diethard Monbaliu
- Department of Abdominal Transplantation Surgery, University Hospitals of Leuven, Leuven, Belgium
| | - Paolo Muiesan
- Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - M. Thamara P. R. Perera
- Liver Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Wojciech G. Polak
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Xavier Rogiers
- Department of Transplant Surgery, Ghent University Hospital, Ghent, Belgium
| | - Roberto I. Troisi
- Department of Transplant Surgery, Ghent University Hospital, Ghent, Belgium
| | - Yvonne de Vries
- Section Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J. Porte
- Section Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
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26
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Czigany Z, Lurje I, Tolba RH, Neumann UP, Tacke F, Lurje G. Machine perfusion for liver transplantation in the era of marginal organs-New kids on the block. Liver Int 2019; 39:228-249. [PMID: 30129192 DOI: 10.1111/liv.13946] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/26/2018] [Accepted: 08/16/2018] [Indexed: 12/12/2022]
Abstract
In the face of a critical organ shortage in the Western world, various strategies are employed to expand the donor pool for orthotopic liver transplantation (OLT). Among them is the transplantation of organs from extended criteria donors, a valuable source of liver allografts, however, characterized by potential risks for post-OLT complications and inferior outcomes. In recent years, machine perfusion (MP) of the explanted donor liver as well as regional perfusion techniques has witnessed significant advancements. Here, we aim to discuss different modes of dynamic organ preservation in OLT. These include hypothermic and normothermic MP, hypothermic oxygenated machine perfusion (HOPE), controlled oxygenated rewarming as well as regional perfusion protocols. Over recent years, multiple feasibility trials have demonstrated the clinical prospects of MP. In the context of OLT using organs from extended criteria donors, MP has numerous advantages compared to conventional cold storage, some of which include the preservation and reconditioning of borderline transplantable organs and the viability assessment of high-risk donor allografts. This review aims to address the topic of liver allograft MP, highlighting particularly the current trends in clinical applications and future perspectives. Furthermore, different approaches of liver storage and reconditioning are reviewed in the context of ongoing research.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Isabella Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Rene H Tolba
- Institute for Laboratory Animal Science, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.,Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Frank Tacke
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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27
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Boteon YL, Laing RW, Schlegel A, Wallace L, Smith A, Attard J, Bhogal RH, Neil DAH, Hübscher S, Perera MTPR, Mirza DF, Afford SC, Mergental H. Combined Hypothermic and Normothermic Machine Perfusion Improves Functional Recovery of Extended Criteria Donor Livers. Liver Transpl 2018; 24:1699-1715. [PMID: 30058119 PMCID: PMC6588092 DOI: 10.1002/lt.25315] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/03/2018] [Indexed: 12/23/2022]
Abstract
Hypothermic oxygenated perfusion (HOPE) and normothermic perfusion are seen as distinct techniques of ex situ machine perfusion of the liver. We aimed to demonstrate the feasibility of combining both techniques and whether it would improve functional parameters of donor livers into transplant standards. Ten discarded human donor livers had either 6 hours of normothermic perfusion (n = 5) or 2 hours of HOPE followed by 4 hours of normothermic perfusion (n = 5). Liver function was assessed according to our viability criteria; markers of tissue injury and hepatic metabolic activity were compared between groups. Donor characteristics were comparable. During the hypothermic perfusion phase, livers down-regulated mitochondrial respiration (oxygen uptake, P = 0.04; partial pressure of carbon dioxide perfusate, P = 0.04) and increased adenosine triphosphate levels 1.8-fold. Following normothermic perfusion, those organs achieved lower tissue expression of markers of oxidative injury (4-hydroxynonenal, P = 0.008; CD14 expression, P = 0.008) and inflammation (CD11b, P = 0.02; vascular cell adhesion molecule 1, P = 0.05) compared with livers that had normothermic perfusion alone. All livers in the combined group achieved viability criteria, whereas 40% (2/5) in the normothermic group failed (P = 0.22). In conclusion, this study suggests that a combined protocol of hypothermic oxygenated and normothermic perfusions might attenuate oxidative stress, tissue inflammation, and improve metabolic recovery of the highest-risk donor livers compared with normothermic perfusion alone.
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Affiliation(s)
- Yuri L. Boteon
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Richard W. Laing
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | | | - Lorraine Wallace
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | | | | | - Ricky H. Bhogal
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Desley A. H. Neil
- Department of PathologyQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
| | - Stefan Hübscher
- Department of PathologyQueen Elizabeth Hospital, University Hospitals Birmingham National Health Service Foundation TrustBirminghamUnited Kingdom
| | | | - Darius F. Mirza
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Simon C. Afford
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
| | - Hynek Mergental
- Liver Unit
- National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUnited Kingdom
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Alva N, Panisello-Roselló A, Flores M, Roselló-Catafau J, Carbonell T. Ubiquitin-proteasome system and oxidative stress in liver transplantation. World J Gastroenterol 2018; 24:3521-3530. [PMID: 30131658 PMCID: PMC6102496 DOI: 10.3748/wjg.v24.i31.3521] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/28/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
A major issue in organ transplantation is the development of a protocol that can preserve organs under optimal conditions. Damage to organs is commonly a consequence of flow deprivation and oxygen starvation following the restoration of blood flow and reoxygenation. This is known as ischemia-reperfusion injury (IRI): a complex multifactorial process that causes cell damage. While the oxygen deprivation due to ischemia depletes cell energy, subsequent tissue oxygenation due to reperfusion induces many cascades, from reactive oxygen species production to apoptosis initiation. Autophagy has also been identified in the pathogenesis of IRI, although such alterations and their subsequent functional significance are controversial. Moreover, proteasome activation may be a relevant pathophysiological mechanism. Different strategies have been adopted to limit IRI damage, including the supplementation of commercial preservation media with pharmacological agents or additives. In this review, we focus on novel strategies related to the ubiquitin proteasome system and oxidative stress inhibition, which have been used to minimize damage in liver transplantation.
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Affiliation(s)
- Norma Alva
- Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona 08028, Spain
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona, Barcelona 08036, Spain
| | - Marta Flores
- Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona 08028, Spain
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona, Barcelona 08036, Spain
| | - Teresa Carbonell
- Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona 08028, Spain
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Morito N, Obara H, Matsuno N, Enosawa S, Furukawa H. Oxygen consumption during hypothermic and subnormothermic machine perfusions of porcine liver grafts after cardiac death. J Artif Organs 2018; 21:450-457. [DOI: 10.1007/s10047-018-1063-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/17/2018] [Indexed: 12/14/2022]
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Bral M, Gala-Lopez B, Bigam DL, Freed DH, Shapiro AMJ. Ex situ liver perfusion: Organ preservation into the future. Transplant Rev (Orlando) 2018; 32:132-141. [PMID: 29691119 DOI: 10.1016/j.trre.2018.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 03/27/2018] [Accepted: 03/27/2018] [Indexed: 12/15/2022]
Abstract
In recent years, remarkable progress has occurred in the development of technologies to support ex situ liver perfusion. Building upon extensive preclinical studies in large animal models, pilot and randomized clinical trials have been initiated, and preliminary outcomes suggest more optimal protection of both standard and extended criteria liver grafts. There currently exists an incredible opportunity and need to further refine this technology, determine appropriate viability measures to predict usable liver grafts, and to explore potent protective additive strategies to further optimize the quality of extended criteria organs. These findings will have major bearing in expanding the limited liver donor pool, and may save lives where up to a quarter of listed patients die on wait-lists. Herein we offer a brief overview of the history and current status of ex situ liver perfusion, and discuss future directions that will likely have major impact on the practice of clinical liver transplantation.
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Affiliation(s)
- Mariusz Bral
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - Boris Gala-Lopez
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - David L Bigam
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - Darren H Freed
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
| | - A M James Shapiro
- Department of Surgery, University of Alberta, 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada; Members of the Canadian National Transplant Research Program (CNTRP), 2D4.43 Walter D MacKenzie Health Sciences Centre, 8440 112 St, Edmonton, Alberta T6G2B7, Canada.
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Schlegel A, Muller X, Dutkowski P. Hypothermic Machine Preservation of the Liver: State of the Art. CURRENT TRANSPLANTATION REPORTS 2018; 5:93-102. [PMID: 29564206 PMCID: PMC5843682 DOI: 10.1007/s40472-018-0183-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW In this review, we highlight which livers may benefit from additional treatment before implantation and describe the concept of hypothermic machine liver perfusion. Furthermore, we explain why cold oxygenated perfusion concepts could potentially lead to a breakthrough in this challenging field of transplantation. Accordingly, we summarize recent clinical applications of different hypothermic perfusion approaches. RECENT FINDINGS The impact of end-ischemic, hypothermic liver perfusion in liver transplantation is currently assessed by two multicenter, randomized controlled trials. Recently, new applications of hypothermic perfusion showed promising results and recipients were protected from severe intrahepatic biliary complications, despite the use of very extended criteria grafts including donation after circulatory death livers. SUMMARY Hypothermic machine liver perfusion is beneficial for high-risk livers and protects recipients from most feared complications. Importantly, such easy approach is currently implemented in several European centers and new markers obtained from perfusate may improve the prediction of liver function in the future.
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Affiliation(s)
- Andrea Schlegel
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham, UK
- NIHR Liver Biomedical Research Unit, University Hospitals Birmingham, Birmingham, UK
| | - Xavier Muller
- Department of Surgery & Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery & Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland
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Martins RM, Teodoro JS, Furtado E, Rolo AP, Palmeira CM, Tralhão JG. Recent insights into mitochondrial targeting strategies in liver transplantation. Int J Med Sci 2018; 15:248-256. [PMID: 29483816 PMCID: PMC5820854 DOI: 10.7150/ijms.22891] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 12/21/2017] [Indexed: 12/22/2022] Open
Abstract
Ischemia/reperfusion (I/R) injury in liver transplantation can disrupt the normal activity of mitochondria in the hepatic parenchyma. This potential dysfunction of mitochondria after I/R injury could be responsible for the initial poor graft function or primary nonfunction observed after liver transplantation. Thus, determining the mechanisms that lead to human hepatic mitochondrial dysfunction might contribute to improving the outcome of liver transplantation. Furthermore, early identification of novel prognostic factors involved in I/R injury could serve as a key endpoint to predict the outcome of liver grafts and also to promote the early adoption of novel strategies that protect against I/R injury. Here, we briefly review recent advances in the study of mitochondrial dysfunction and I/R injury, particularly in relation to liver transplantation. Next, we highlight various pharmacological therapeutic strategies that could be applied, and discuss their relationship to relevant mitochondrion-related processes and targets. Lastly, we note that although considerable progress has been made in our understanding of I/R injury and mitochondrial dysfunction, further investigation is required to elucidate the cellular and molecular mechanisms underlying these processes, thereby identifying biomarkers that can help in evaluating donor organs.
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Affiliation(s)
- Rui Miguel Martins
- Department of Surgery, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal
| | - João Soeiro Teodoro
- Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal; and Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Emanuel Furtado
- Unidade de Transplantação Hepática de Crianças e Adultos, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Anabela Pinto Rolo
- Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal; and Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Carlos Marques Palmeira
- Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal; and Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - José Guilherme Tralhão
- Department of Surgery A, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Clínica Universitária de Cirurgia III, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; and Center for Investigation on Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Czigany Z, Schöning W, Ulmer TF, Bednarsch J, Amygdalos I, Cramer T, Rogiers X, Popescu I, Botea F, Froněk J, Kroy D, Koch A, Tacke F, Trautwein C, Tolba RH, Hein M, Koek GH, Dejong CHC, Neumann UP, Lurje G. Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): a prospective multicentre randomised controlled trial (HOPE ECD-DBD). BMJ Open 2017; 7:e017558. [PMID: 29018070 PMCID: PMC5652559 DOI: 10.1136/bmjopen-2017-017558] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. In an attempt to improve the availability of donor allografts and reduce waiting list mortality, graft acceptance criteria were extended increasingly over the decades. The use of extended criteria donor (ECD) allografts is associated with a higher incidence of primary graft non-function and/or delayed graft function. As such, several strategies have been developed aiming at reconditioning poor quality ECD liver allografts. Hypothermic oxygenated machine perfusion (HOPE) has been successfully tested in preclinical experiments and in few clinical series of donation after cardiac death OLT. METHODS AND ANALYSIS HOPE ECD-DBD is an investigator-initiated, open-label, phase-II, prospective multicentre randomised controlled trial on the effects of HOPE on ECD allografts in donation after brain death (DBD) OLT. Human whole organ liver grafts will be submitted to 1-2 hours of HOPE (n=23) via the portal vein before implantation and are going to be compared with a control group (n=23) of patients transplanted after conventional cold storage. Primary (peak and Δ peak alanine aminotransferase within 7 days) and secondary (aspartate aminotransferase, bilirubin and international normalised ratio, postoperative complications, early allograft dysfunction, duration of hospital and intensive care unit stay, 1-year patient and graft survival) endpoints will be analysed within a 12-month follow-up. Extent of ischaemia-reperfusion (I/R) injury will be assessed using liver tissue, perfusate, bile and serum samples taken during the perioperative phase of OLT. ETHICS AND DISSEMINATION The study was approved by the institutional review board of the RWTH Aachen University, Aachen, Germany (EK 049/17). The current paper represent the pre-results phase. First results are expected in 2018. TRIAL REGISTRATION NUMBER NCT03124641.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Wenzel Schöning
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Tom Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Thorsten Cramer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
| | - Xavier Rogiers
- Department of Solid Organ Transplantation, Ghent University Hospital and Medical School, Ghent, Belgium
| | - Irinel Popescu
- Department of General Surgery and Liver transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Florin Botea
- Department of General Surgery and Liver transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Jiří Froněk
- Department of Transplantation Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Daniela Kroy
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Alexander Koch
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Rene H Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Marc Hein
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ger H Koek
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
| | - Cornelis H C Dejong
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany
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Clavien PA, Dutkowski P. Advances in hypothermic perfusion. Liver Transpl 2017; 23:S52-S55. [PMID: 28815993 DOI: 10.1002/lt.24844] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 08/04/2017] [Accepted: 08/08/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Pierre-Alain Clavien
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
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Kron P, Schlegel A, Mancina L, Clavien PA, Dutkowski P. Hypothermic oxygenated perfusion (HOPE) for fatty liver grafts in rats and humans. J Hepatol 2017; 68:S0168-8278(17)32268-7. [PMID: 28870676 DOI: 10.1016/j.jhep.2017.08.028] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 08/16/2017] [Accepted: 08/18/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS Pretreatment of marginal organs by perfusion is a promising opportunity to make more organs available for transplantation. Protection of human donation after cardiac death (DCD) livers by a novel machine perfusion technique, hypothermic oxygenated perfusion (HOPE), was recently established. Herein, we tested whether HOPE is also useful for fatty liver grafts, using a rodent transplant model. METHODS Rats were fed over three weeks with a special methionine-choline-deficient diet (MCDD) to induce severe hepatic macrosteatosis (≥60%). Afterwards, livers were transplanted with either minimal or 12h cold storage. Additional liver grafts were treated after 12h cold storage with 1h HOPE before transplantation. Graft injury after orthotopic liver transplantation (OLT) was assessed in terms of oxidative stress, damage-associated molecular patterns release, toll-like receptor-4 activation, cytokine release, endothelial activation, and the development of necrosis and fibrosis. RESULTS Implantation of cold stored macrosteatotic liver grafts induced massive reperfusion injury after OLT, compared to controls (non-fatty livers). HOPE treatment after cold storage failed to change the degree of steatosis itself, but markedly decreased reperfusion injury after OLT, as detected by less oxidative stress, less nuclear injury, less Kupffer- and endothelial cell activation, as well as less fibrosis within one week after OLT. Protective effects were lost in the absence of oxygen in the HOPE perfusate. CONCLUSION HOPE after cold storage of fatty livers prevents significant reperfusion injury and improves graft function, comparable to the effects of HOPE in DCD livers and DCD kidneys. HOPE treatment is easy and may become a universal concept to further expand the donor pool. LAY SUMMARY An increasing number of donor livers contain fat. It is important to harness marginal livers, which may contain fat, as the stock of donor livers is limited. Hypothermic oxygenated perfusion (HOPE) prevents reperfusion injury and improves liver graft function. HOPE offers a simple and low-cost option for treating liver grafts in transplant centers, even after cold storage, instead of transporting machines to the place of procurement. HOPE could be used globally to expand the donor pool.
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Affiliation(s)
- Philipp Kron
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Andrea Schlegel
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Leandro Mancina
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Pierre-Alain Clavien
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery & Transplantation, University Hospital Zurich, Switzerland.
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An Oxygenated and Transportable Machine Perfusion System Fully Rescues Liver Grafts Exposed to Lethal Ischemic Damage in a Pig Model of DCD Liver Transplantation. Transplantation 2017; 101:e205-e213. [PMID: 28403128 DOI: 10.1097/tp.0000000000001764] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Control of warm ischemia (WI) lesions that occur with donation after circulatory death (DCD) would significantly increase the donor pool for liver transplantation. We aimed to determine whether a novel, oxygenated and hypothermic machine perfusion device (HMP Airdrive system) improves the quality of livers derived from DCDs using a large animal model. METHODS Cardiac arrest was induced in female large white pigs by intravenous injection of potassium chloride. After 60 minutes of WI, livers were flushed in situ with histidine-tryptophan-ketoglutarate and subsequently preserved either by simple cold storage (WI-SCS group) or HMP (WI-HMP group) using Belzer-MPS solution. Liver grafts procured from heart-beating donors and preserved by SCS served as controls. After 4 hours of preservation, all livers were transplanted. RESULTS All recipients in WI-SCS group died within 6 hours after transplantation. In contrast, the HMP device fully protected the liver against lethal ischemia/reperfusion injury, allowing 100% survival rate. A postreperfusion syndrome was observed in all animals of the WI-SCS group but none of the control or WI-HMP groups. After reperfusion, HMP-preserved livers functioned better and showed less hepatocellular and endothelial cell injury, in agreement with better-preserved liver histology relative to WI-SCS group. In addition to improved energy metabolism, this protective effect was associated with an attenuation of inflammatory response, oxidative load, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. CONCLUSIONS This study demonstrates for the first time the efficacy of the HMP Airdrive system to protect liver grafts from lethal ischemic damage before transplantation in a clinically relevant DCD model.
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Nickkholgh A, Maluf D. Emerging graft protective strategies in clinical liver transplantation. Expert Rev Gastroenterol Hepatol 2017; 11:623-631. [PMID: 28438069 DOI: 10.1080/17474124.2017.1322901] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
There have been remarkable efforts to characterize the key responsible pathophysiologic mechanisms, as well as to ameliorate the organ preservation and ischemia reperfusion injury with the ultimate goal of expanding the donor pool and further improvement of the outcomes of liver transplantation. Attempts to translate the experimental results from bench to bedside have yielded no valid protective concepts in the field of clinical liver transplantation yet. Nonetheless, there has been a considerable amount of ongoing clinical research to develop clinically relevant graft protective strategies. Areas covered: This review focuses on the most recent evidence based findings and ongoing clinical trials that might lead to emerging graft protective strategies in the field of clinical liver transplantation. New evidence-based findings in the donor preconditioning, organ preservation, and perioperative pharmacologic graft protection strategies in the recipient are reviewed. Expert commentary: Few strategies have been shown to exert some graft protective effects against ischemia reperfusion injury in recent clinical trials in liver transplantation. Among others, 'dynamic graft preservation' techniques have been emerging as more promising graft optimization strategies.
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Affiliation(s)
- Arash Nickkholgh
- a Department of Surgery , University of Virginia , Charlottesville , VA , USA
| | - Daniel Maluf
- a Department of Surgery , University of Virginia , Charlottesville , VA , USA
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Cippà PE, Fehr T. Pharmacological modulation of cell death in organ transplantation. Transpl Int 2017; 30:851-859. [PMID: 28480540 DOI: 10.1111/tri.12977] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 02/20/2017] [Accepted: 04/29/2017] [Indexed: 12/22/2022]
Abstract
New options to pharmacologically modulate fundamental mechanisms of regulated cell death are rapidly evolving and found first clinical applications in cancer therapy. Here, we present an overview on how the recent advances in the understanding of the biology and pharmacology of cell death might influence research and clinical practice in solid organ transplantation. Of particular interest are the novel opportunities related to organ preservation and immunomodulation, which might contribute to promote organ repair and to develop more selective ways to modulate allogeneic immune responses to prevent rejection and induce immunological tolerance.
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Affiliation(s)
- Pietro E Cippà
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Fehr
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.,Department of Internal Medicine, Cantonal Hospital Graubuenden, Chur, Switzerland
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Short, Cool, and Well Oxygenated - HOPE for Kidney Transplantation in a Rodent Model. Ann Surg 2017; 264:815-822. [PMID: 27584571 DOI: 10.1097/sla.0000000000001766] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVES The aim of this study was to investigate novel and easily applicable preservation perfusion techniques in kidney grafts obtained from donors after circulatory death (DCD). BACKGROUND A novel perfusion approach, hypothermic oxygenated perfusion (HOPE), used for DCD liver grafts, is based on cold perfusion for 1 hour by an oxygenated solution before implantation. Here, we aimed to test HOPE in a rodent model of kidney grafts associated with substantial warm ischemia. METHODS Rat kidneys were exposed to 30 minutes in situ warm ischemia, without application of heparin. Kidneys were removed and cold stored for 4 and 18 hours, mimicking DCD organ procurement and conventional preservation. In additional experiments, kidneys were normothermically perfused with oxygenated blood for 1 hour after cold storage. In a third group, kidneys were perfused by HOPE for 1 hour after cold storage. In each group, orthotopic kidney transplantation was performed after recipient nephrectomy. RESULTS HOPE-treated DCD kidneys showed dramatically better function after transplantation, than cold-stored grafts in terms of nuclear injury, macrophage activation, endothelium activation, tubulus damage, and graft function. A short period of warm oxygenated perfusion before implantation improved graft quality as compared with cold storage, but was significantly less effective in all endpoints compared with HOPE. The effect of HOPE was dependent on perfusate oxygenation in the cold. CONCLUSIONS HOPE of DCD kidneys was superior to other clinically used preservation approaches, consistent to earlier results in livers. On the basis of this, we assume a strong and generalized effect on solid organ viability by HOPE before transplantation. These results justify a clinical trial.
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Dasari BVM, Schlegel A, Mergental H, Perera MTPR. The use of old donors in liver transplantation. Best Pract Res Clin Gastroenterol 2017; 31:211-217. [PMID: 28624109 DOI: 10.1016/j.bpg.2017.03.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 03/24/2017] [Indexed: 01/31/2023]
Abstract
The process of ageing has an impact on the entire human body including the organ systems. In transplantation, professionals are daily faced with risk assessment of suitable donor offers , whether to accept a liver graft for a specific recipient. In this context, livers from elderly donors are more frequently accepted for transplantation, to increase the donor pool and compensate the high waiting list mortality. In the current practice it is not unusual to accept 60-year old donor livers for transplantation, as the donor demographics have significantly changed over the years. However, controversy exists regarding the use of livers from donors above 70 or 80 years, particular in combination with other risk factors, e.g. liver steatosis, warm ischaemia or long cold storage. This review focuses first on the impact of ageing on liver morphology and function. Second, we will highlight outcome after transplantation from elderly donors. Finally, we describe further risk factors and donor-recipient selection under the scope of old donor organs and include our institutional experience and policy.
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Affiliation(s)
- Bobby V M Dasari
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom.
| | - Andrea Schlegel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom.
| | - Hynek Mergental
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom.
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, United Kingdom.
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Abstract
The demand of donor livers for transplantation exceeds the supply. In an attempt to maximize the number of potentially usable donor livers, several centers are exploring the role of machine perfusion. This review provides an update on machine perfusion strategies and basic concepts, based on current clinical issues, and discuss challenges, including currently used biomarkers for assessing the quality and viability of perfused organs. The potential benefits of machine perfusion on immunogenicity and the consequences on post-operative immunosuppression management are discussed.
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Karangwa SA, Dutkowski P, Fontes P, Friend PJ, Guarrera JV, Markmann JF, Mergental H, Minor T, Quintini C, Selzner M, Uygun K, Watson CJ, Porte RJ. Machine Perfusion of Donor Livers for Transplantation: A Proposal for Standardized Nomenclature and Reporting Guidelines. Am J Transplant 2016; 16:2932-2942. [PMID: 27129409 PMCID: PMC5132023 DOI: 10.1111/ajt.13843] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/28/2016] [Accepted: 04/19/2016] [Indexed: 02/06/2023]
Abstract
With increasing demand for donor organs for transplantation, machine perfusion (MP) promises to be a beneficial alternative preservation method for donor livers, particularly those considered to be of suboptimal quality, also known as extended criteria donor livers. Over the last decade, numerous studies researching MP of donor livers have been published and incredible advances have been made in both experimental and clinical research in this area. With numerous research groups working on MP, various techniques are being explored, often applying different nomenclature. The objective of this review is to catalog the differences observed in the nomenclature used in the current literature to denote various MP techniques and the manner in which methodology is reported. From this analysis, we propose a standardization of nomenclature on liver MP to maximize consistency and to enable reliable comparison and meta-analyses of studies. In addition, we propose a standardized set of guidelines for reporting the methodology of future studies on liver MP that will facilitate comparison as well as clinical implementation of liver MP procedures.
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Affiliation(s)
- S. A. Karangwa
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
- Surgical Research LaboratoryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - P. Dutkowski
- Department of Surgery & TransplantationUniversity Hospital ZurichZurichSwitzerland
| | - P. Fontes
- Thomas E. Starzl Transplantation Institute Department of SurgeryUniversity of Pittsburgh Medical CenterPittsburghPA
- McGowan Institute of Regenerative MedicineUniversity of PittsburghPittsburghPA
| | - P. J. Friend
- Nuffield Department of SurgeryOxford Transplant CentreUniversity of OxfordChurchill HospitalOxfordUK
| | - J. V. Guarrera
- Department of SurgeryCenter for Liver Disease and TransplantationColumbia University Medical CenterNew YorkNY
| | | | - H. Mergental
- Liver UnitUniversity Hospital BirminghamBirminghamUK
| | - T. Minor
- Department of Surgical ResearchClinic for General Visceral and Transplantation SurgeryUniversity Hospital EssenEssenGermany
| | - C. Quintini
- Department of SurgeryTransplant CenterDigestive Disease InstituteCleveland Clinic FoundationClevelandOH
| | - M. Selzner
- Department of SurgeryMulti Organ Transplant ProgramToronto General HospitalTorontoONCanada
| | - K. Uygun
- Department of SurgeryCenter for Engineering in MedicineMassachusetts General HospitalHarvard Medical SchoolBostonMA
| | - C. J. Watson
- University of Cambridge Department of Surgery and the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation University of CambridgeAddenbrooke's HospitalCambridgeUK
| | - R. J. Porte
- Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
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Jochmans I, Akhtar MZ, Nasralla D, Kocabayoglu P, Boffa C, Kaisar M, Brat A, O'Callaghan J, Pengel LHM, Knight S, Ploeg RJ. Past, Present, and Future of Dynamic Kidney and Liver Preservation and Resuscitation. Am J Transplant 2016; 16:2545-55. [PMID: 26946212 DOI: 10.1111/ajt.13778] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 02/03/2016] [Accepted: 02/23/2016] [Indexed: 01/25/2023]
Abstract
The increased demand for organs has led to the increased usage of "higher risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, preimplantation) and temperatures (hypo-, sub, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes ongoing research and emerging clinical trials.
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Affiliation(s)
- I Jochmans
- Abdominal Transplant Surgery, KU Leuven, University Hospitals Leuven, Leuven, Belgium
| | - M Z Akhtar
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - D Nasralla
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - P Kocabayoglu
- Department of General, Visceral and Transplant Surgery, University Hospital Essen, Essen, Germany
| | - C Boffa
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - M Kaisar
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - A Brat
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - J O'Callaghan
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - L H M Pengel
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - S Knight
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.,Clinical Effectiveness Unit, Centre for Evidence in Transplantation, Royal College of Surgeons of England, London, University of Oxford, Oxford, UK
| | - R J Ploeg
- Biomedical Research Centre and Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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44
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Barbas AS, Goldaracena N, Dib MJ, Selzner M. Ex-vivo liver perfusion for organ preservation: Recent advances in the field. Transplant Rev (Orlando) 2016; 30:154-60. [PMID: 27158081 DOI: 10.1016/j.trre.2016.03.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 02/15/2016] [Accepted: 03/01/2016] [Indexed: 01/13/2023]
Abstract
Liver transplantation is the optimal treatment for end-stage liver disease but is limited by the severe shortage of donor organs. This shortage has prompted increased utilization of marginal grafts from DCD and extended criteria donors, which poorly tolerate cold storage in comparison to standard criteria grafts. Ex-vivo liver perfusion (EVLP) technology has emerged as a potential alternative to cold storage for organ preservation, but there is no consensus regarding the optimal temperature or conditions for EVLP. Herein, we review recent advances in both pre-clinical and clinical studies, organized by perfusion temperature (hypothermic, subnormothermic, normothermic).
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Affiliation(s)
- A S Barbas
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada.
| | - N Goldaracena
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
| | - M J Dib
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
| | - M Selzner
- University of Toronto, Multi-Organ Transplant Program, Department of Surgery, Canada
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45
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Pantazi E, Bejaoui M, Folch-Puy E, Adam R, Roselló-Catafau J. Advances in treatment strategies for ischemia reperfusion injury. Expert Opin Pharmacother 2016; 17:169-79. [PMID: 26745388 DOI: 10.1517/14656566.2016.1115015] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Ischemia-reperfusion injury (IRI) involves a complex sequence of events and limits the outcome of various surgical interventions. Clinical trials, based on the data of experimental models, aim to prove whether a pharmacological or technical approach could be suitable to provide a beneficial effect in humans. Due to the complexity of IRI, few pharmacological treatments have been investigated in clinical Phase III. AREAS COVERED In this review we report clinical trials that test specific drugs in clinical trials of organ transplantation. These studies form part of Phase II trials and examine the administration of caspase inhibitors, P-selectin antagonist or an antioxidant component in order to attenuate cold IRI during transplantation. Moreover, we provide a brief description of drugs tested on trials of different clinical situations associated to IRI, such as the coronary artery bypass graft surgery and percutaneous coronary intervention. EXPERT OPINION Future clinical trials could be centered on the application of techniques suitable for organs with increased vulnerability toward IRI. Furthermore, the standardization of reliable biomarkers and a careful estimation of the impact of high risk factors may be the key in order to achieve a more critical evaluation of the obtained results.
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Affiliation(s)
- Eirini Pantazi
- a Experimental Hepatic Ischemia-Reperfusion Unit , Institute of Biomedical Research of Barcelona (IIBB-CSIC) , Barcelona , Spain
| | - Mohamed Bejaoui
- a Experimental Hepatic Ischemia-Reperfusion Unit , Institute of Biomedical Research of Barcelona (IIBB-CSIC) , Barcelona , Spain
| | - Emma Folch-Puy
- a Experimental Hepatic Ischemia-Reperfusion Unit , Institute of Biomedical Research of Barcelona (IIBB-CSIC) , Barcelona , Spain
| | - René Adam
- b AP-HP Hôpital Paul Brousse , Centre Hepato-Biliaire, Univ Paris-Sud Villejuif , Paris , France
| | - Joan Roselló-Catafau
- a Experimental Hepatic Ischemia-Reperfusion Unit , Institute of Biomedical Research of Barcelona (IIBB-CSIC) , Barcelona , Spain
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46
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Grąt M, Wronka KM, Patkowski W, Stypułkowski J, Grąt K, Krasnodębski M, Masior Ł, Lewandowski Z, Krawczyk M. Effects of Donor Age and Cold Ischemia on Liver Transplantation Outcomes According to the Severity of Recipient Status. Dig Dis Sci 2016; 61:626-35. [PMID: 26499986 PMCID: PMC4729807 DOI: 10.1007/s10620-015-3910-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 09/28/2015] [Indexed: 02/07/2023]
Abstract
UNLABELLED BackgroundProlonged cold ischemic time (CIT) and increased donor age are well-known factors negatively influencing outcomes after liver transplantation (LT). AIMS The aim of this study was to evaluate whether the magnitude of their negative effects is related to recipient model for end-stage liver disease (MELD) score. METHODS This retrospective study was based on a cohort of 1402 LTs, divided into those performed in low-MELD (<10), moderate-MELD (10–20), and high-MELD (>20) recipients. RESULTS While neither donor age (p = 0.775) nor CIT (p = 0.561) was a significant risk factor for worse 5-year graft survival in low-MELD recipients, both were found to yield independent effects (p = 0.003 and p = 0.012, respectively) in moderate-MELD recipients, and only CIT (p = 0.004) in high-MELD recipients. However, increased donor age only triggered the negative effect of CIT in moderate-MELD recipients, which was limited to grafts recovered from donors aged ≥46 years (p = 0.019). Notably, utilization of grafts from donors aged ≥46 years with CIT ≥9 h in moderate-MELD recipients (p = 0.003) and those with CIT ≥9 h irrespective of donor age in high-MELD recipients (p = 0.031) was associated with particularly compromised outcomes. CONCLUSIONS In conclusion, the negative effects of prolonged CIT seem to be limited to patients with moderate MELD receiving organs procured from older donors and to high-MELD recipients, irrespective of donor age. Varying effects of donor age and CIT according to recipient MELD score should be considered during the allocation process in order to avoid high-risk matches.
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Affiliation(s)
- Michał Grąt
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Karolina M. Wronka
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Waldemar Patkowski
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Jan Stypułkowski
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Karolina Grąt
- />Second Department of Clinical Radiology, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Maciej Krasnodębski
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Łukasz Masior
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
| | - Zbigniew Lewandowski
- />Department of Epidemiology, Medical University of Warsaw, 3 Oczki Street, 02-007 Warsaw, Poland
| | - Marek Krawczyk
- />Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland
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Schlegel A, Kron P, De Oliveira ML, Clavien PA, Dutkowski P. Is single portal vein approach sufficient for hypothermic machine perfusion of DCD liver grafts? J Hepatol 2016; 64:239-41. [PMID: 26432684 DOI: 10.1016/j.jhep.2015.09.015] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 09/11/2015] [Accepted: 09/19/2015] [Indexed: 12/23/2022]
Affiliation(s)
- Andrea Schlegel
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Philipp Kron
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Michelle L De Oliveira
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
| | - Pierre-Alain Clavien
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland.
| | - Philipp Dutkowski
- Department of Visceral Surgery and Transplantation, University Hospital Zurich, Swiss HPB and Transplant Center, Zurich, Switzerland
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48
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Schlegel A, Dutkowski P. Hypothermic liver perfusion. Liver Transpl 2015; 21 Suppl 1:S8-12. [PMID: 26334767 DOI: 10.1002/lt.24321] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/26/2015] [Accepted: 08/31/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Andrea Schlegel
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
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49
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Westerkamp AC, Mahboub P, Meyer SL, Hottenrott M, Ottens PJ, Wiersema-Buist J, Gouw ASH, Lisman T, Leuvenink HGD, Porte RJ. End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature. Liver Transpl 2015; 21:1300-11. [PMID: 26097213 DOI: 10.1002/lt.24200] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/06/2015] [Accepted: 06/08/2015] [Indexed: 12/20/2022]
Abstract
A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation.
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Affiliation(s)
- Andrie C Westerkamp
- Surgical Research Laboratory.,Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
| | | | - Sophie L Meyer
- Surgical Research Laboratory.,Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
| | | | | | | | - Annette S H Gouw
- Departments of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ton Lisman
- Surgical Research Laboratory.,Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
| | | | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery
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50
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Li P, Liu YF, Yang L. Advantages of dual hypothermic oxygenated machine perfusion over simple cold storage in the preservation of liver from porcine donors after cardiac death. Clin Transplant 2015; 29:820-8. [PMID: 26147375 DOI: 10.1111/ctr.12586] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2015] [Indexed: 12/14/2022]
Affiliation(s)
- Peng Li
- Department of Organ Transplantation; First Affiliated Hospital; China Medical University; Shenyang China
| | - Yong-Feng Liu
- Department of Organ Transplantation; First Affiliated Hospital; China Medical University; Shenyang China
| | - Lei Yang
- Department of Organ Transplantation; First Affiliated Hospital; China Medical University; Shenyang China
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