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Geng H, Chen J, Tu K, Tuo H, Wu Q, Guo J, Zhu Q, Zhang Z, Zhang Y, Huang D, Zhang M, Xu Q. Carbon dot nanozymes as free radicals scavengers for the management of hepatic ischemia-reperfusion injury by regulating the liver inflammatory network and inhibiting apoptosis. J Nanobiotechnology 2023; 21:500. [PMID: 38129928 PMCID: PMC10734184 DOI: 10.1186/s12951-023-02234-1] [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: 08/02/2023] [Accepted: 11/29/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) is a pathophysiological process during liver transplantation, characterized by insufficient oxygen supply and subsequent restoration of blood flow leading to an overproduction of reactive oxygen species (ROS), which in turn activates the inflammatory response and leads to cellular damage. Therefore, reducing excess ROS production in the hepatic microenvironment would provide an effective way to mitigate oxidative stress injury and apoptosis during HIRI. Nanozymes with outstanding free radical scavenging activities have aroused great interest and enthusiasm in oxidative stress treatment. RESULTS We previously demonstrated that carbon-dots (C-dots) nanozymes with SOD-like activity could serve as free radicals scavengers. Herein, we proposed that C-dots could protect the liver from ROS-mediated inflammatory responses and apoptosis in HIRI, thereby improving the therapeutic effect. We demonstrated that C-dots with anti-oxidative stress and anti-inflammatory properties improved the survival of L-02 cells under H2O2 and LPS-treated conditions. In the animal model, Our results showed that the impregnation of C-dots could effectively scavenge ROS and reduce the expression of inflammatory cytokines, such as IL-1β, IL-6, IL-12, and TNF-α, resulting in a profound therapeutic effect in the HIRI. To reveal the potential therapeutic mechanism, transcriptome sequencing was performed and the relevant genes were validated, showing that the C-dots exert hepatoprotective effects by modulating the hepatic inflammatory network and inhibiting apoptosis. CONCLUSIONS With negligible systemic toxicity, our findings substantiate the potential of C-dots as a therapeutic approach for HIRI, thereby offering a promising intervention strategy for clinical implementation.
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Affiliation(s)
- Haoge Geng
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Jiayu Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
| | - Hang Tuo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Qingsong Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Jinhui Guo
- Qingdao Medical College, Qingdao University, Qingdao, Shandong, 266071, China
| | - Qingwei Zhu
- Qingdao Medical College, Qingdao University, Qingdao, Shandong, 266071, China
| | - Zhe Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Yujie Zhang
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Dongsheng Huang
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
| | - Mingzhen Zhang
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
| | - Qiuran Xu
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
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Abstract
The past decade has been the foreground for a radical revolution in the field of preservation in abdominal organ transplantation. Perfusion has increasingly replaced static cold storage as the preferred and even gold standard preservation method for marginal-quality organs. Perfusion is dynamic and offers several advantages in comparison with static cold storage. These include the ability to provide a continuous supply of new metabolic substrates, clear metabolic waste products, and perform some degree of organ viability assessment before actual transplantation in the recipient. At the same time, the ongoing importance of static cold storage cannot be overlooked, in particular when it comes to logistical and technical convenience and cost, not to mention the fact that it continues to work well for the majority of transplant allografts. The present review article provides an overview of the fundamental concepts of organ preservation, providing a brief history of static cold preservation and description of the principles behind and basic components of cold preservation solutions. An evaluation of current evidence supporting the use of different preservation solutions in abdominal organ transplantation is provided. As well, the range of solutions used for machine perfusion of abdominal organs is described, as are variations in their compositions related to changing metabolic needs paralleling the raising of the temperature of the perfusate from hypothermic to normothermic range. Finally, appraisal of new preservation solutions that are on the horizon is provided.
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Methane Admixture Protects Liver Mitochondria and Improves Graft Function after Static Cold Storage and Reperfusion. Antioxidants (Basel) 2023; 12:antiox12020271. [PMID: 36829829 PMCID: PMC9951982 DOI: 10.3390/antiox12020271] [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: 12/01/2022] [Revised: 01/21/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023] Open
Abstract
Mitochondria are targets of cold ischemia-reperfusion (IR), the major cause of cell damage during static cold preservation of liver allografts. The bioactivity of methane (CH4) has recently been recognized in various hypoxic and IR conditions as having influence on many aspects of mitochondrial biology. We therefore hypothesized that cold storage of liver grafts in CH4-enriched preservation solution can provide an increased defence against organ dysfunction in a preclinical rat model of liver transplantation. Livers were preserved for 24 h in cold histidine-tryptophan-ketoglutarate (HTK) or CH4-enriched HTK solution (HTK-CH4) (n = 24 each); then, viability parameters were monitored for 60 min during normothermic isolated reperfusion and perfusate and liver tissue were collected. The oxidative phosphorylation capacity and extramitochondrial Ca2+ movement were measured by high resolution respirometry. Oxygen and glucose consumption increased significantly while hepatocellular damage was decreased in the HTK-CH4 grafts compared to the HTK group. Mitochondrial oxidative phosphorylation capacity was more preserved (128.8 ± 31.5 pmol/s/mL vs 201.3 ± 54.8 pmol/s/mL) and a significantly higher Ca2+ flux was detected in HTK-CH4 storage (2.9 ± 0.1 mV/s) compared to HTK (2.3 ± 0.09 mV/s). These results demonstrate the direct effect of CH4 on hepatic mitochondrial function and extramitochondrial Ca2+ fluxes, which may have contributed to improved graft functions and a preserved histomorphology after cold IR.
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Malekhosseini SA, Ghasemi Y, Rousta J, Aghaei R, Kianpour S, Negahdaripour M, Heidari R, Shamsaeefar A, Gholami S, Nikeghbalian S. Clinical Evaluation of an HTK Solution for Liver Transplantation: A Phase 3 Randomized Pilot Clinical Trial Study. ARCHIVES OF IRANIAN MEDICINE 2022; 25:617-623. [PMID: 37543887 PMCID: PMC10685771 DOI: 10.34172/aim.2022.97] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 02/27/2022] [Indexed: 08/07/2023]
Abstract
BACKGROUND Organ preservation solutions are not easily accessible in Iran, similar to many resource-limited countries. We aimed to evaluate the efficacy of a locally-produced HTK solution among adult liver transplantation candidates in a pilot clinical trial study. METHODS Adult patients undergoing liver transplantation were randomly allocated into two groups. One received the HTK solution (PharMedCina Inc., Shiraz, Iran), and the second received the commercially available HTK solution (Custodiol ®). RESULTS Overall, 28 individuals entered the study, including 11 and 9 males (78.6% and 64.3%) in the Custodiol® and local HTK groups, respectively. Clinical characteristics, including postoperative biliary complications, reperfusion syndrome, infection and primary non-function (PNF) rates, amount of intraoperative bleeding, length of hospital and ICU stay, peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and duration of follow-up were similar between the two groups (P>0.05). One patient died in the locally-produced HTK group. The patient underwent re-transplantation 20 days after his first liver transplantation due to PNF. Two patients died in the Custodiol group, both due to PNF of the liver, which occurred five and three days after transplantation. The two groups did not show any difference regarding serum levels of AST, ALT, alkaline phosphatase (ALP), bilirubin, platelet count, prothrombin time and international normalized ratio, white blood cell count, blood urea nitrogen, and creatinine on the first postoperative day and on the day of discharge (P>0.05). CONCLUSION Based on the findings of this pilot study with the current sample size, no statistically significant difference was found between our locally-produced HTK solution and Custodiol® regarding clinical outcomes.
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Affiliation(s)
- Seyed Ali Malekhosseini
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Younes Ghasemi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Javad Rousta
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roghayyeh Aghaei
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sedigheh Kianpour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Manica Negahdaripour
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Shamsaeefar
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Siavash Gholami
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
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Teodoro JS, Da Silva RT, Machado IF, Panisello-Roselló A, Roselló-Catafau J, Rolo AP, Palmeira CM. Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria. Cells 2022; 11:688. [PMID: 35203337 PMCID: PMC8870414 DOI: 10.3390/cells11040688] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/10/2022] Open
Abstract
Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.
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Affiliation(s)
- João S. Teodoro
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Rui T. Da Silva
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Ivo F. Machado
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Anabela P. Rolo
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
| | - Carlos M. Palmeira
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
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Rao F, Yang J, Gong C, Huang R, Wang Q, Shen J. Systematic review of preservation solutions for allografts for liver transplantation based on a network meta-analysis. Int J Surg 2018; 54:1-6. [PMID: 29684666 DOI: 10.1016/j.ijsu.2018.04.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 04/09/2018] [Accepted: 04/12/2018] [Indexed: 01/20/2023]
Abstract
AIMS The aim of this work was to determine the best preservation solutions for allografts for liver transplantation by quantitative network meta-analysis. METHODS Global electronic databases including PubMed, EMBASE, and Cochrane Library were searched for relevant randomized controlled trials. Seven pieces of parametric data were extracted from included studies for pooled estimation. A consistency model was used for direct and indirect comparisons. The cumulative probability P value was utilized to rank the solutions. A node-splitting model was utilized for testing the consistency of final data. Quality of evidence was assessed using the GRADE (Grades of Recommendations Assessment, Development and Evaluation) system. RESULTS Eleven 2-arm trials including 1319 patients and 5 different solutions were finally included. HTK (Histidine-tryptophan-ketoglutarate) solution exhibited the best efficacy for decreasing the primary dysfunction rate, biliary complications and ICU-stay time (probability P = 0.43, 0.45 and 0.58, respectively). Celsior solution significantly decreased the rate of rejection and early retransplantation (probability P = 0.73 and 0.38, respectively), and enhanced patient and graft survival (probability P = 0.90 and 0.98, respectively) more than did other solutions. Overall, the quality of evidence was rated high or moderate. CONCLUSIONS We suggested that HTK solution may offer the best safety during the perioperative period. However, Celsior solution led to better graft tolerance and exhibited greater benefit for long-term outcomes. And our conclusions still need to be further validated.
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Affiliation(s)
- Fengying Rao
- School of Nursing, Huanggang Polytechnic College, Huanggang, 438002, PR China
| | - Jian Yang
- School of Nursing, Huanggang Polytechnic College, Huanggang, 438002, PR China
| | - Cheng Gong
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China
| | - Rong Huang
- School of Nursing, Huanggang Polytechnic College, Huanggang, 438002, PR China
| | - Qi Wang
- The 1st Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, PR China.
| | - Jun Shen
- Emergency Center, Zhongnan Hospital of Wuhan University, 430071, Hubei Province, PR China.
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Szilágyi ÁL, Mátrai P, Hegyi P, Tuboly E, Pécz D, Garami A, Solymár M, Pétervári E, Balaskó M, Veres G, Czopf L, Wobbe B, Szabó D, Wagner J, Hartmann P. Compared efficacy of preservation solutions on the outcome of liver transplantation: Meta-analysis. World J Gastroenterol 2018; 24:1812-1824. [PMID: 29713134 PMCID: PMC5922999 DOI: 10.3748/wjg.v24.i16.1812] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/02/2018] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To compare the effects of the four most commonly used preservation solutions on the outcome of liver transplantations. METHODS A systematic literature search was performed using MEDLINE, Scopus, EMBASE and the Cochrane Library databases up to January 31st, 2017. The inclusion criteria were comparative, randomized controlled trials (RCTs) for deceased donor liver (DDL) allografts with adult and pediatric donors using the gold standard University of Wisconsin (UW) solution or histidine-tryptophan-ketoglutarate (HTK), Celsior (CS) and Institut Georges Lopez (IGL-1) solutions. Fifteen RCTs (1830 livers) were included; the primary outcomes were primary non-function (PNF) and one-year post-transplant graft survival (OGS-1). RESULTS All trials were homogenous with respect to donor and recipient characteristics. There was no statistical difference in the incidence of PNF with the use of UW, HTK, CS and IGL-1 (RR = 0.02, 95%CI: 0.01-0.03, P = 0.356). Comparing OGS-1 also failed to reveal any difference between UW, HTK, CS and IGL-1 (RR = 0.80, 95%CI: 0.80-0.80, P = 0.369). Two trials demonstrated higher PNF levels for UW in comparison with the HTK group, and individual studies described higher rates of biliary complications where HTK and CS were used compared to the UW and IGL-1 solutions. However, the meta-analysis of the data did not prove a statistically significant difference: the UW, CS, HTK and IGL-1 solutions were associated with nearly equivalent outcomes. CONCLUSION Alternative solutions for UW yield the same degree of safety and effectiveness for the preservation of DDLs, but further well-designed clinical trials are warranted.
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Affiliation(s)
| | - Péter Mátrai
- Institute of Bioanalysis, University of Pécs, Pécs H-7624, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs H-7624, Hungary
- MTA-SZTE Translational Gastroenterology Research Group, Szeged H-6720, Hungary
- János Szentágothai Research Center, University of Pécs, Pécs H-7624, Hungary
| | - Eszter Tuboly
- Institute of Surgical Research, University of Szeged, Szeged H-6720, Hungary
| | - Daniella Pécz
- Institute of Surgical Research, University of Szeged, Szeged H-6720, Hungary
| | - András Garami
- Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Margit Solymár
- Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Erika Pétervári
- Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Márta Balaskó
- Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Gábor Veres
- 1st Department of Paediatrics, University of Semmelweis, Budapest H-1085, Hungary
| | - László Czopf
- Department of Cardiology, 1st Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Bastian Wobbe
- Department of Cardiology, 1st Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Dorottya Szabó
- Department of Cardiology, 1st Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Juliane Wagner
- Department of Cardiology, 1st Department of Medicine, University of Pécs, Pécs H-7624, Hungary
| | - Petra Hartmann
- Institute of Surgical Research, University of Szeged, Szeged H-6720, Hungary
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Hameed AM, Laurence JM, Lam VWT, Pleass HC, Hawthorne WJ. A systematic review and meta-analysis of cold in situ perfusion and preservation of the hepatic allograft: Working toward a unified approach. Liver Transpl 2017; 23:1615-1627. [PMID: 28734125 PMCID: PMC5725662 DOI: 10.1002/lt.24829] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 05/03/2017] [Accepted: 07/16/2017] [Indexed: 01/01/2023]
Abstract
The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route (aortic or dual) or perfusion/preservation solution in donation after brain death (DBD) liver transplantation. The Embase, MEDLINE, and Cochrane databases were used (1980-2017). Random effects modeling was used to estimate effects on transplantation outcomes based on (1) aortic or dual in situ perfusion and (2) the use of University of Wisconsin (UW), histidine tryptophan ketoglutarate (HTK), Celsior, and/or Institut Georges Lopez-1 (IGL-1) solutions for perfusion/preservation. A total of 22 articles were included (2294 liver transplants). The quality of evidence ranged from very low to moderate Grading of Recommendations, Assessment, Development and Evaluations score. Meta-analyses were conducted for 14 eligible studies. Although there was no difference in the primary nonfunction (PNF) rate, a higher peak alanine aminotransferase (ALT) was recorded in dual compared with aortic-only UW-perfused livers (standardized mean difference, 0.24; 95% confidence interval, 0.01-0.47); a back-table portal venous flush was undertaken in the majority of aortic-only perfused livers. There were no relevant differences in peak enzymes, PNF, thrombotic graft loss, biliary complications, or 1-year graft survival in comparisons between dual-perfused livers using UW, HTK, Celsior, or IGL-1. In conclusion, there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes, and it may be favored because of its simplicity. However, there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others. Liver Transplantation 23 1615-1627 2017 AASLD.
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Affiliation(s)
- Ahmer M. Hameed
- Centre for Transplant and Renal Research, Westmead Institute for Medical ResearchWestmeadNew South WalesAustralia,Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia
| | - Jerome M. Laurence
- Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia,Department of Surgery,Institute of Academic Surgery, Royal Prince Alfred HospitalUniversity of SydneyCamperdownNew South WalesAustralia
| | - Vincent W. T. Lam
- Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia
| | - Henry C. Pleass
- Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia,Department of Surgery
| | - Wayne J. Hawthorne
- Centre for Transplant and Renal Research, Westmead Institute for Medical ResearchWestmeadNew South WalesAustralia,Department of SurgeryWestmead HospitalWestmeadNew South WalesAustralia,Sydney Medical SchoolUniversity of SydneySydneyNew South WalesAustralia
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9
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Cannistrà M, Ruggiero M, Zullo A, Gallelli G, Serafini S, Maria M, Naso A, Grande R, Serra R, Nardo B. Hepatic ischemia reperfusion injury: A systematic review of literature and the role of current drugs and biomarkers. Int J Surg 2016; 33 Suppl 1:S57-70. [PMID: 27255130 DOI: 10.1016/j.ijsu.2016.05.050] [Citation(s) in RCA: 254] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic ischemia reperfusion injury (IRI) is not only a pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues and organs. Hepatic IRI can seriously impair liver function, even producing irreversible damage, which causes a cascade of multiple organ dysfunction. Many factors, including anaerobic metabolism, mitochondrial damage, oxidative stress and secretion of ROS, intracellular Ca(2+) overload, cytokines and chemokines produced by KCs and neutrophils, and NO, are involved in the regulation of hepatic IRI processes. Matrix Metalloproteinases (MMPs) can be an important mediator of early leukocyte recruitment and target in acute and chronic liver injury associated to ischemia. MMPs and neutrophil gelatinase-associated lipocalin (NGAL) could be used as markers of I-R injury severity stages. This review explores the relationship between factors and inflammatory pathways that characterize hepatic IRI, MMPs and current pharmacological approaches to this disease.
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Affiliation(s)
- Marco Cannistrà
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Michele Ruggiero
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Alessandra Zullo
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Giuseppe Gallelli
- Department of Emergency, Pugliese-Ciaccio Hospital, Catanzaro, Italy.
| | - Simone Serafini
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Mazzitelli Maria
- Department of Primary Care, Provincial Health Authority of Vibo Valentia, 89900 Vibo Valentia, Italy.
| | - Agostino Naso
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Grande
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Bruno Nardo
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy; Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
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10
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Latchana N, Peck JR, Whitson BA, Henry ML, Elkhammas EA, Black SM. Preservation solutions used during abdominal transplantation: Current status and outcomes. World J Transplant 2015; 5:154-164. [PMID: 26722644 PMCID: PMC4689927 DOI: 10.5500/wjt.v5.i4.154] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/01/2015] [Accepted: 11/11/2015] [Indexed: 02/05/2023] Open
Abstract
Organ preservation remains an important contributing factor to graft and patient outcomes. During donor organ procurement and transportation, cellular injury is mitigated through the use of preservation solutions in conjunction with hypothermia. Various preservation solutions and protocols exist with widespread variability among transplant centers. In this review of abdominal organ preservation solutions, evolution of transplantation and graft preservation are discussed followed by classification of preservation solutions according to the composition of electrolytes, impermeants, buffers, antioxidants, and energy precursors. Lastly, pertinent clinical studies in the setting of hepatic, renal, pancreas, and intestinal transplantation are reviewed for patient and graft survival as well as financial considerations. In liver transplants there may be some benefit with the use of histidine-tryptophan-ketoglutarate (HTK) over University of Wisconsin solution in terms of biliary complications and potential cost savings. Renal grafts may experience increased initial graft dysfunction with the use of Euro-Collins thereby dissuading its use in support of HTK which can lead to substantial cost savings. University of Wisconsin solution and Celsior are favored in pancreas transplants given the concern for pancreatitis and graft thrombosis associated with HTK. No difference was observed with preservation solutions with respect to graft and patient survival in liver, renal, and pancreas transplants. Studies involving intestinal transplants are sparse but University of Wisconsin solution infused intraluminally in combination with an intra-vascular washout is a reasonable option until further evidence can be generated. Available literature can be used to ameliorate extensive variation across centers while potentially minimizing graft dysfunction and improving associated costs.
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Adam R, Delvart V, Karam V, Ducerf C, Navarro F, Letoublon C, Belghiti J, Pezet D, Castaing D, Le Treut YP, Gugenheim J, Bachellier P, Pirenne J, Muiesan P. Compared efficacy of preservation solutions in liver transplantation: a long-term graft outcome study from the European Liver Transplant Registry. Am J Transplant 2015; 15:395-406. [PMID: 25612492 DOI: 10.1111/ajt.13060] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 08/08/2014] [Accepted: 08/09/2014] [Indexed: 01/25/2023]
Abstract
Between 2003 and 2012, 42 869 first liver transplantations performed in Europe with the use of either University of Wisconsin solution (UW; N = 24 562), histidine-tryptophan-ketoglutarate(HTK; N = 8696), Celsior solution (CE; N = 7756) or Institute Georges Lopez preservation solution (IGL-1; N = 1855) preserved grafts. Alternative solutions to the UW were increasingly used during the last decade. Overall, 3-year graft survival was higher with UW, IGL-1 and CE (75%, 75% and 73%, respectively), compared to the HTK (69%) (p < 0.0001). The same trend was observed with a total ischemia time (TIT) >12 h or grafts used for patients with cancer (p < 0.0001). For partial grafts, 3-year graft survival was 89% for IGL-1, 67% for UW, 68% for CE and 64% for HTK (p = 0.009). Multivariate analysis identified HTK as an independent factor of graft loss, with recipient HIV (+), donor age ≥65 years, recipient HCV (+), main disease acute hepatic failure, use of a partial liver graft, recipient age ≥60 years, no identical ABO compatibility, recipient hepatitis B surface antigen (-), TIT ≥ 12 h, male recipient and main disease other than cirrhosis. HTK appears to be an independent risk factor of graft loss. Both UW and IGL-1, and CE to a lesser extent, provides similar results for full size grafts. For partial deceased donor liver grafts, IGL-1 tends to offer the best graft outcome.
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Affiliation(s)
- R Adam
- Centre Hépatobiliaire, AP-HP Hôpital Paul Brousse, Inserm U 776, Univ Paris Sud, Villejuif, France
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The effect of preservation solutions for storage of liver allografts on transplant outcomes: a systematic review and meta-analysis. Ann Surg 2014; 260:46-55. [PMID: 24374537 DOI: 10.1097/sla.0000000000000402] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The objective of this review was to systematically evaluate the evidence comparing preservation fluids for liver allografts on transplant outcomes. BACKGROUND Adequate preservation of liver allografts for transplantation is essential for successful transplant outcomes. There are several preservation fluids available that have been specifically designed for the static cold storage of livers. These fluids differ in composition and cost. METHODS literature search was performed using MEDLINE, EMBASE, Cochrane Library, Transplant Library, and the International Clinical Trials Registry Platform. Only randomized controlled trials were included. Studies were assessed for methodological quality. Primary outcomes were the risk of early dysfunction, primary nonfunction, retransplantation, patient survival, and graft survival. Secondary outcomes were serum biochemical parameters in the first week and biliary complications. Summary effects were calculated as relative risk and relative log survival with 95% confidence intervals (95% CIs). RESULTS Sixteen randomized controlled trials met the full inclusion criteria (1619 livers). There is good evidence that the University of Wisconsin and Celsior solutions are associated with the same rates of early dysfunction (relative risk = 1.08, 95% CI = 0.63-1.86, P = 0.77), primary nonfunction (relative risk = 0.73, 95% CI = 0.22-2.40, P = 0.60), patient survival (relative log survival = 0.86, 95% CI = 0.58-1.28, P = 0.46), and graft survival (relative log survival = 0.85, 95% CI = 0.59-1.23, P = 0.39). There was no good evidence of any difference in outcomes when comparing histidine-tryptophan-ketoglutarate with either of the University of Wisconsin or Celsior solution, although data were limited. CONCLUSIONS Data from included studies suggest that preservation of deceased donor livers with the University of Wisconsin or Celsior solution results in equivalent outcomes.
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Preservation solutions for liver transplantation in adults: celsior versus custodiol: a systematic review and meta-analysis with an indirect comparison of randomized trials. Transplant Proc 2012; 45:25-32. [PMID: 23267794 DOI: 10.1016/j.transproceed.2012.02.031] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Accepted: 02/28/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND The University of Wisconsin (UW) solution has been recognized as the gold standard for liver preservation; however, it possesses some limitations, and other solutions exist for organ preservation. The aim of this study was to compare the liver functions of transplanted grafts that had been stored in Celsior and Custodiol solutions. METHODS We searched the MEDLINE, EMBASE, LILACS, Cochrane Central Register of Controlled Trials, and SCIELO databases. We included randomized and quasi-randomized, controlled trials that compared the efficacy and safety of Celsior and Custodiol with UW solution for liver preservation in adults. The factors that were considered for analysis were their impacts on primary dysfunction (primary nonfunction and initial poor function), ischemic-type biliary lesions, and patient and graft survival rates. Because of the lack of direct evidence, an indirect comparison of Celsior and Custodiol was calculated. RESULTS We identified 3 randomized controlled trials and 1 quasi-randomized, controlled trial to pool in a meta-analysis of Celsior versus UW solutions. The number of episodes of primary dysfunction was lower in the Celsior group (7.4%) than in the UW group (9.8%), but the difference was not significant (relative risk [RR], 0.68; 95% confidence interval [CI], 0.22-1.97). Two randomized controlled trials compared Custodiol and Wisconsin solutions were identified. The number of episodes of primary dysfunction was also lower in the Custodiol group (3.0%) compared with the Wisconsin group (8.4%), but the difference was not significant (RR, 0.36; 95% CI, 0.08-1.70). An indirect comparison using data from the main analysis revealed no difference between the Celsior and Custodiol solutions (RR, 1.88; 95% CI, 0.57-6.16). CONCLUSION The Celsior and Custodiol solutions performed similarly to UW solution as preservation solutions in liver transplantation clinical settings.
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Review of Randomized Clinical Trials of Donor Management and Organ Preservation in Deceased Donors. Transplantation 2012; 94:425-41. [DOI: 10.1097/tp.0b013e3182547537] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Rudd DM, Dobson GP. Eight hours of cold static storage with adenosine and lidocaine (Adenocaine) heart preservation solutions: Toward therapeutic suspended animation. J Thorac Cardiovasc Surg 2011; 142:1552-61. [DOI: 10.1016/j.jtcvs.2011.05.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2010] [Revised: 04/19/2011] [Accepted: 05/05/2011] [Indexed: 10/18/2022]
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García-Gil FA, Serrano MT, Fuentes-Broto L, Arenas J, García JJ, Güemes A, Bernal V, Campillo A, Sostres C, Araiz JJ, Royo P, Simón MA. Celsior versus University of Wisconsin preserving solutions for liver transplantation: postreperfusion syndrome and outcome of a 5-year prospective randomized controlled study. World J Surg 2011; 35:1598-607. [PMID: 21487851 DOI: 10.1007/s00268-011-1078-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Celsior solution (CS) is a high-sodium, low-potassium, low-viscosity extracellular solution that has been used for liver graft preservation in recent years, although experience with it is still limited. We performed an open-label randomized active-controlled trial comparing CS with the University of Wisconsin solution (UW) for liver transplantation (LT), with a follow-up period of 5 years. METHODS Adult transplant recipients (n=102) were prospectively randomized to receive either CS (n=51) or UW (n=51). The two groups were comparable with respect to donor and recipient characteristics. The primary outcome measure was the incidence of postreperfusion syndrome (PRS). Secondary outcome measures included primary nonfunction (PNF) or primary dysfunction (PDF), liver retransplantation, and graft and patient survival. Other secondary outcome measures were days in the intensive care unit (ICU) and the rates of acute rejection, chronic rejection, infectious complications, postoperative reoperations, and vascular and biliary complications. RESULTS In all, 14 posttransplant variables revealed no significant differences between the groups. There were no cases of PNF or PDF. The incidence of PRS was 5.9% in the CS group and 21.6% in the UW group (P=0.041). After reperfusion, CS revealed greater control of serum potassium (P=0.015), magnesium levels (P=0.005), and plasma glucose (P=0.042) than UW. Respective patient survivals at 3, 12, and 60 months were 95.7, 87.2, and 82.0% for the CS group and 95.7, 83.3, and 66.6% for the UW group (P=0.123). CONCLUSIONS While retaining the same degree of safety and effectiveness as UW for LT, CS may yield postliver graft reperfusion benefits, as shown in this study by a significant reduction in the incidence of PRS and greater metabolic control.
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Affiliation(s)
- Francisco A García-Gil
- Department of Surgery, University of Zaragoza, Domingo Miral s/n, 50009, Zaragoza, Spain.
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Lee S, Huang CS, Kawamura T, Shigemura N, Stolz DB, Billiar TR, Luketich JD, Nakao A, Toyoda Y. Superior myocardial preservation with HTK solution over Celsior in rat hearts with prolonged cold ischemia. Surgery 2010; 148:463-473. [PMID: 20627336 DOI: 10.1016/j.surg.2010.04.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 04/13/2010] [Indexed: 11/30/2022]
Abstract
BACKGROUND Increasing allograft ischemic time is a significant risk factor for mortality following heart transplantation (HTx). The purpose of this study was to evaluate the protective effects of histidine-tryptophan-ketoglutarate (HTK) and Celsior (CEL) using a rat HTx model with prolonged cold storage. METHODS The hearts were excised from donor rats, stored in cold preservation solution for either 6 or 18 hours, and heterotopically transplanted into syngeneic recipients. Serum creatine phosphokinase (CPK), serum troponin I, graft-infiltrating cells, graft mRNA levels for inflammatory mediators, and tissue adenosine triphosphate (ATP) levels were analyzed, as markers of graft injury. RESULTS The recipients of grafts stored in HTK for 18 hours of prolonged cold ischemia had lower levels of serum CPK and tissue malondialdehyde, less upregulation of the mRNAs for IL-6 and inducible nitric oxide synthase, less apoptosis, and higher ATP levels than those receiving grafts stored in CEL and Saline. Cardiac contraction 3 hours after reperfusion was observed in 43% of the cardiac grafts stored in HTK for 18 hours, while no cardiac wall movement was seen in grafts stored in either saline or CEL. CONCLUSION Cold storage in HTK exhibited superior protective effects against prolonged cold ischemia in a syngeneic rat transplantation model.
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Affiliation(s)
- Sungsoo Lee
- The Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittsburgh, PA, USA
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Stahl JE, Kreke JE, Malek FAA, Schaefer AJ, Vacanti J. Consequences of cold-ischemia time on primary nonfunction and patient and graft survival in liver transplantation: a meta-analysis. PLoS One 2008; 3:e2468. [PMID: 18575623 PMCID: PMC2430537 DOI: 10.1371/journal.pone.0002468] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Accepted: 05/07/2008] [Indexed: 12/23/2022] Open
Abstract
Introduction The ability to preserve organs prior to transplant is essential to the organ allocation process. Objective The purpose of this study is to describe the functional relationship between cold-ischemia time (CIT) and primary nonfunction (PNF), patient and graft survival in liver transplant. Methods To identify relevant articles Medline, EMBASE and the Cochrane database, including the non-English literature identified in these databases, was searched from 1966 to April 2008. Two independent reviewers screened and extracted the data. CIT was analyzed both as a continuous variable and stratified by clinically relevant intervals. Nondichotomous variables were weighted by sample size. Percent variables were weighted by the inverse of the binomial variance. Results Twenty-six studies met criteria. Functionally, PNF% = −6.678281+0.9134701*CIT Mean+0.1250879*(CIT Mean−9.89535)2−0.0067663*(CIT Mean−9.89535)3, r2 = .625, , p<.0001. Mean patient survival: 93 % (1 month), 88 % (3 months), 83 % (6 months) and 83 % (12 months). Mean graft survival: 85.9 % (1 month), 80.5 % (3 months), 78.1 % (6 months) and 76.8 % (12 months). Maximum patient and graft survival occurred with CITs between 7.5–12.5 hrs at each survival interval. PNF was also significantly correlated with ICU time, % first time grafts and % immunologic mismatches. Conclusion The results of this work imply that CIT may be the most important pre-transplant information needed in the decision to accept an organ.
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Affiliation(s)
- James E Stahl
- MGH-Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
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Pengel L, Barcena L, Morris PJ. Registry of randomized controlled trials in transplantation: January 1 to June 30, 2005. Transplantation 2006; 81:1071-86. [PMID: 16641590 DOI: 10.1097/01.tp.0000221632.63426.5c] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Liset Pengel
- Centre for Evidence in Transplantation, Clinical Effectiveness Unit, Royal College of Surgeons of England and London School of Hygiene and Tropical Medicine, University of London, London, UK
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Lledó García E, Berenguer García I, Rodríguez Martínez D, Pedemonte G, Hernández Fernández C, Del Cañizo López JF. [Recent advances in the comprehension of the effects of cold ischemia in kidney graft]. Actas Urol Esp 2005; 29:392-400. [PMID: 15981428 DOI: 10.1016/s0210-4806(05)73261-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Cold ischemia is the best known method to preserve kidneys for transplant. However, it produces several detrimental effects. First, cellular necrosis. Secondarily, during the hypothermic period a mitochondrial injury process develops which makes the cell entering a pre-apoptotic state. This apoptosis occurs definitively in the reperfusion. Preservation solutions currently available are not perfect and are not able to avoid cold-related cell injuries. The addition of certain substances to UW solution (desferrioxamine) has shown experimentally a reduction in mitochondrial cold-related lesions. Isolated hypothermic kidney perfusion reduces initial graft dysfunction about 20% in comparison to hypothermic storage. This fact relates to important either economical as functional consequences.
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Affiliation(s)
- E Lledó García
- Servicio de Urología, Unidad de Preservación Renal Experimental, Hosp. Univ. Gregorio Marañón, Madrid
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