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O'Brien Laramy M, Robinson J, Venkatramani CJ, Horn S, Steiner C, Son YJ. Drug Development Considerations for Additives to Organ Preservation Solutions. Transplantation 2025; 109:764-773. [PMID: 39375888 DOI: 10.1097/tp.0000000000005221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified. We have supplemented this strategy with a comparison to available regulatory guidance from the US Food and Drug Administration to highlight potential areas for further clarification. The strategy articulated here is based on Genentech's internal experience for a program intended for use in kidney transplantation.
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Affiliation(s)
| | - Jamie Robinson
- Pharma Technical Regulatory, Genentech, Inc., South San Francisco, CA
| | - C J Venkatramani
- Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA
| | - Stephanie Horn
- Pharma Technical Regulatory-Device and Combination Products, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Carine Steiner
- Analytical Research & Development, Pharma Technical Development, F. Hoffmann-La Roche, Basel, Switzerland
| | - Yoen-Ju Son
- Pharma Technical Development Project and Portfolio Development, South San Francisco, CA
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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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Kazemi K, Nikeghbalian Z, Yaghmaei S, Nikeghbalian S, Shamsaeifar A, Asgharnia Y, Dehghankhalili M, Golchini A, Malekhosseini SA. University of Wisconsin vs normal saline solutions for preservation of blood vessels of brain dead donors: A histopathological study. Clin Transplant 2018; 32:e13241. [PMID: 29573462 DOI: 10.1111/ctr.13241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2018] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To compare the cellular changes of harvested arteries which were preserved in normal saline (NS) and the standard and routinely used University of Wisconsin (UW) solution. METHODS This experimental study was conducted on 20 brain dead patients. The femoral and iliac arteries were bilaterally removed and were placed in NS and UW solutions. The vascular change indices including endothelial detachment (ED), medial detachment (MD), and internal elastic membrane disruption (IEMD) were surveyed for each preserver in the first, 5th, 10th, and 21st day. RESULTS The mean age of the included patients was 32.28 ± 8.88 years, and there were 13 (65.0%) men and 7 (35.0%) women among the patients. The NS and UW preservation solutions were comparable regarding the indices of vascular changes at first, 5th, and 10th day of the study. Only in 21st day of the study, there was a significant difference between 2 group regarding MD changes (P = .049). CONCLUSION The results of this in vitro study demonstrated that NS can be used as a worthy preserver for harvested vessels for up to 21 days, especially in resource-limited transplantation centers.
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Affiliation(s)
- Kourosh Kazemi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Nikeghbalian
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shekoofeh Yaghmaei
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Shamsaeifar
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Yasaman Asgharnia
- Student Research Committee, Guilan University of Medical Sciences, Rasht, Iran
| | - Maryam Dehghankhalili
- Resident of General Surgery, Department of General Surgery, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Golchini
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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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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Folch-Puy E, Panisello A, Oliva J, Lopez A, Castro Benítez C, Adam R, Roselló-Catafau J. Relevance of Endoplasmic Reticulum Stress Cell Signaling in Liver Cold Ischemia Reperfusion Injury. Int J Mol Sci 2016; 17:807. [PMID: 27231901 PMCID: PMC4926341 DOI: 10.3390/ijms17060807] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 05/15/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023] Open
Abstract
The endoplasmic reticulum (ER) is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS). This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR), which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI) of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes.
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Affiliation(s)
- Emma Folch-Puy
- Experimental Pathology Department, Instituto de Investigaciones Biomédicas de Barcelona, Spanish Research Council (IIBB-CSIC), Rosselló 161, 08036-Barcelona, Catalonia, Spain.
| | - Arnau Panisello
- Experimental Pathology Department, Instituto de Investigaciones Biomédicas de Barcelona, Spanish Research Council (IIBB-CSIC), Rosselló 161, 08036-Barcelona, Catalonia, Spain.
| | - Joan Oliva
- Department of Medicine, LaBioMed at Harbor UCLA Medical Center, Torrance, 90502 CA, USA.
| | - Alexandre Lopez
- Centre Hépatobiliaire, AP-HP Hôpital Paul Brousse, Inserm U935, Université Paris-Sud, Villejuif, 75008 Paris, France.
| | - Carlos Castro Benítez
- Centre Hépatobiliaire, AP-HP Hôpital Paul Brousse, Inserm U935, Université Paris-Sud, Villejuif, 75008 Paris, France.
| | - René Adam
- Centre Hépatobiliaire, AP-HP Hôpital Paul Brousse, Inserm U935, Université Paris-Sud, Villejuif, 75008 Paris, France.
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Instituto de Investigaciones Biomédicas de Barcelona, Spanish Research Council (IIBB-CSIC), Rosselló 161, 08036-Barcelona, Catalonia, Spain.
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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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Abstract
PURPOSE OF REVIEW To summarize the history of organ preservation and place into this context the current trends in preservation. RECENT FINDINGS Multiple large retrospective studies have analyzed cold preservation solutions in an attempt to determine superiority with largely negative results. Experimental and some clinical studies have examined machine perfusion of procured grafts, in both hypothermic and normothermic contexts with variable, but promising, results. Lastly, there are experimental efforts to evaluate mesenchymal stem cell therapy on rehabilitation of marginal donor organs. SUMMARY New trends in organ preservation may soon translate into more efficient use of the limited donor pool.
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Savier E, Granger B, Charlotte F, Cormillot N, Siksik JM, Vaillant JC, Hannoun L. Liver preservation with SCOT 15 solution decreases posttransplantation cholestasis compared with University of Wisconsin solution: a retrospective study. Transplant Proc 2014; 43:3402-7. [PMID: 22099807 DOI: 10.1016/j.transproceed.2011.09.054] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND SCOT 15 is a new solution to preserve abdominal organs for transplantation. Its principal characteristic is the use of polyethylene glycol. Herein We report our experience using SCOT 15 compared with the reference University of Wisconsin (UW) solution for hepatic transplantation. METHODS We compared 2 groups: SCOT 15 (n = 33; 2009-2010) versus UW (n = 34; 2008-2010), which were paired for cold and warm ischemic times, donor ages, and graft weights. Endpoints were biologic tests in the first 2 months after the operation. A linear mixed model was used to evaluate longitudinal changes and influences of each solution. RESULTS No primary failure was observed. At postoperative day 0, transaminase values were higher in the SCOT 15 than in the UW group: aspartate transaminase: 2,435 ± 399 vs 589 ± 83 IU/L (P < .01); alanine transaminase: ALT: 1,207 ± 191 vs 484 ± 64 IU/L (P < .05), then returned to low levels in both groups. From day 0 to 8, coagulation factors reached normal values; there was no difference between the 2 groups. Total bilirubin decreased similarly in the 2 groups. However, from the second postoperative week (W1) to W8, the SCOT 15 group showed a slow decrease in the mean values of gamma-glutamyltranspeptidase (gGT) from 233 ± 125 to 130 ± 161 IU/L, which were significantly lower than those in the UW group, where the gGT remained around 300 IU/L (P < .01). The End-Stage Liver Disease, Child-Pugh, or United Network for Organ Sharing scores, primary liver diseases, hepatitic C virus status, arterial or biliary complications, and male/female ratio, which was different in the 2 groups, did not statistically influence these results. CONCLUSIONS The main effect of cold storage of human liver using SCOT 15 compared with UW solution was to decrease cholestasis following transplantation.
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Affiliation(s)
- E Savier
- Service de Chirurgie Digestive et Hépato-Bilio-Pancréatique-Transplantation Hépatique, Groupe Hospitalier Pitié-Salpêtrière, Paris, 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 static cold storage of abdominal allografts: which is best? Curr Opin Organ Transplant 2014; 19:100-7. [PMID: 24553501 DOI: 10.1097/mot.0000000000000063] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW To update the reader on the recent literature in liver, kidney, pancreas, and intestine static cold preservation, and to identify which solutions are most advantageous for each organ. RECENT FINDINGS The comparison of randomized trials of histidine-tryptophan-ketoglutarate (HTK), Celsior, and University of Wisconsin solutions has shown equivalent risk of delayed graft function after kidney transplantation. Similar outcomes have been observed after pancreas preservation with University of Wisconsin, HTK, and Celsior solution. In live-donor liver transplantation, University of Wisconsin and HTK solution have shown equivalent results, whereas in the recent trials of deceased-donor liver transplantation, University of Wisconsin, HTK, and Celsior solutions have shown equivalence. Contrary to the most clinical trials, national registry data in kidney, pancreas, and liver transplantation demonstrate more detrimental effects and earlier graft loss after preservation with HTK versus University of Wisconsin solution. Early outcomes after intestinal transplantation with University of Wisconsin or HTK solution have shown no significant difference and animal studies indicate intraluminal preservation may be beneficial. SUMMARY The University of Wisconsin solution is the standard criterion static cold preservation for the procurement of liver, kidney, pancreas, and intestine. University of Wisconsin, HTK, and Celsior solutions all provide similar allograft outcomes in most clinical trials, but subtle differences have become more apparent in the recent studies and registry reports.
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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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Boudjema K, Grandadam S, Compagnon P, Salamé E, Wolf P, Ducerf C, Le Treut P, Soubrane O, Cherqui D, Mouchel C, Renault A, Bellissant E. Efficacy and safety of Celsior preservation fluid in liver transplantation: one-year follow up of a prospective, multicenter, non-randomized study. Clin Transplant 2011; 26:199-207. [PMID: 21517997 DOI: 10.1111/j.1399-0012.2011.01447.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The purpose of this prospective, nine-center, non-randomized study was to assess the efficacy and safety of Celsior preservation fluid in liver transplantation using unselected donors. As data comparing allograft outcomes following liver transplantation using Celsior and University of Wisconsin (UW) preservation fluids are limited, we also compared our cohort with matched controls selected from the European Liver Transplant Registry (ELTR) who received total liver grafts preserved with UW solution during the same period. One hundred and forty patients who received livers preserved with Celsior were included. The primary endpoint, graft loss at one-yr post-transplantation, was observed in 24 patients (17.1%) which was not significantly different from the 20.0% pre-defined threshold rate (95% confidence interval [CI] 10.9, 23.4; p=0.398). Predictive factors for graft loss on univariate analysis were moderate-to-severe steatosis on the donor graft (5/22 patients with graft loss vs. 8/107 patients without, p=0.046) and duration of warm ischemia (1.4±1.1 h in patients with graft loss vs. 0.9±0.5 h in patients without, p=0.034). Hepatic artery thrombosis and stenosis occurred in seven (5.0%) and six (4.3%) patients, respectively. The comparison of our patients to 420 ELTR controls showed that one-yr graft survival rates (Celsior: 82.9%, 95% CI 75.8, 88.2; UW: 78.6%, 95% CI 74.4, 82.2) and Kaplan-Meier one-yr graft survival distributions (p=0.285) were similar. Within the cold ischemia time achieved in our study, liver preservation with Celsior appeared efficient and safe. Comparison with ELTR patients suggested that liver allograft survival was similar using Celsior or UW solution for preservation of unselected donor grafts.
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Affiliation(s)
- Karim Boudjema
- Service de Chirurgie Hépatobiliaire et Digestive, Hôpital de Pontchaillou, Centre Hospitalier Universitaire de Rennes & Université de Rennes 1, Rennes, France.
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15
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Abstract
During liver resection surgery for cancer or liver transplantation, the liver is subject to ischaemia (reduction in blood flow) followed by reperfusion (restoration of blood flow), which results in liver injury [ischemia-reperfusion (IR) or IR injury]. Modulation of IR injury can be achieved in various ways. These include hypothermia, ischaemic preconditioning (IPC) (brief cycles of ischaemia followed by reperfusion of the organ before the prolonged period of ischaemia i.e. a conditioning response), ischaemic postconditioning (conditioning after the prolonged period of ischaemia but before the reperfusion), pharmacological agents to decrease IR injury, genetic modulation of IR injury, and machine perfusion (pulsatile perfusion). Hypothermia decreases the metabolic functions and the oxygen consumption of organs. Static cold storage in University of Wisconsin solution reduces IR injury and has prolonged organ storage and improved the function of transplanted grafts. There is currently no evidence for any clinical advantage in the use of alternate solutions for static cold storage. Although experimental data from animal models suggest that IPC, ischaemic postconditioning, various pharmacological agents, gene therapy, and machine perfusion decrease IR injury, none of these interventions can be recommended in clinical practice. This is because of the lack of randomized controlled trials assessing the safety and efficacy of ischaemic postconditioning, gene therapy, and machine perfusion. Randomized controlled trials and systematic reviews of randomized controlled trials assessing the safety and efficacy of IPC and various pharmacological agents have demonstrated biochemical or histological improvements but this has not translated to clinical benefit. Further well designed randomized controlled trials are necessary to assess the various new protective strategies in liver resection.
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Liver transplantation using University of Wisconsin or Celsior preserving solutions in the portal vein and Euro-Collins in the aorta. Transplant Proc 2010; 42:429-34. [PMID: 20304157 DOI: 10.1016/j.transproceed.2010.01.035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Orthotopic liver transplantation (OLT) is today the gold standard treatment of the end-stage liver disease. Different solutions are used for graft preservation. Our objective was to compare the results of cadaveric donor OLT, preserved with the University of Wisconsin (UW) or Celsior solutions in the portal vein and Euro-Collins in the aorta. METHODS We evaluated retrospectively 72 OLT recipients, including 36 with UW solution (group UW) and 36 with Celsior (group CS). Donors were perfused in situ with 1000 mL UW or Celsior in the portal vein of and 3000 mL of Euro-Collins in the aortia and on the back table managed with 500 mL UW or Celsior in the portal vein, 250 mL in the hepatic artery, and 250 mL in the biliary duct. We evaluated the following variables: donor characteristics, recipient features, intraoperative details, reperfusion injury, and steatosis via a biopsy after reperfusion. We noted grafts with primary nonfunction (PNF), initial poor function (IPF), rejection episodes, biliary duct complications, hepatic artery complications, re-OLT, and recipient death in the first year after OLT. RESULTS The average age was 33.6 years in the UW group versus 41 years in the CS group (P = .048). There was a longer duration of surgery in the UW group (P = .001). The other recipient characteristics, ischemia-reperfusion injury, steatosis, PNF, IPF, rejection, re-OLT, and recipient survival were not different. Stenosis of the biliary duct occured in 3 (8.3%) cases in the UW group and 8 (22.2%) in the CS (P = .19) with hepatic artery thrombosis in 4 (11.1%) CS versus none in the UW group (P = .11). CONCLUSION Cadaveric donor OLT showed similar results with organs preserved with UW or Celsior in the portal vein and Euro-Collins in the aorta.
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Lopez-Andujar R, Deusa S, Montalvá E, San Juan F, Moya A, Pareja E, DeJuan M, Berenguer M, Prieto M, Mir J. Comparative prospective study of two liver graft preservation solutions: University of Wisconsin and Celsior. Liver Transpl 2009; 15:1709-17. [PMID: 19938119 DOI: 10.1002/lt.21945] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
University of Wisconsin solution (UWS) is the gold standard for graft preservation. Celsior solution (CS) is a new solution not as yet widely used in liver grafts. The aim of this study was to compare the liver function of transplanted grafts stored in these 2 preservation solutions. The primary endpoints were the rates of primary nonfunction (PNF) and primary dysfunction (PDF). We performed a prospective and pseudorandomized study that included 196 patients (representing 104 and 92 livers preserved in UWS and CS, respectively) at La Fe University Hospital (Valencia, Spain) between March 2003 and May 2005. PNF and PDF rates, liver function laboratory parameters, postoperative bleeding, vascular and biliary complications, and patient and graft survival at 3 years were compared for the 2 groups. The 2 groups were similar in terms of donor variables, recipient variables, and surgical techniques. The PNF rates were 2.2% and 1.9% in the CS and UWS groups, respectively (P = not significant), and the PDF rates were 15.2% and 15.5% in the CS and UWS groups, respectively (P = not significant). There were no significant differences in the laboratory parameters for the 2 groups, except for alanine aminotransferase levels in month 3, which were lower in the CS group (P = 0.01). No significant differences were observed in terms of complications. Three-year patient and graft survival rates were as follows for years 1, 2, and 3: 83%, 80%, and 76% (patient) and 80%, 77%, and 73% (graft) for the UWS group and 83%, 77%, and 70% (patient) and 81%, 73%, and 67% (graft) for the CS group (P = not significant). In conclusion, this study shows that CS is as effective as UWS in liver preservation.
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Affiliation(s)
- Rafael Lopez-Andujar
- Hepatic Surgery and Liver Transplant Unit, La Fe University Hospital, Valencia, Spain.
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de Rougemont O, Lehmann K, Clavien PA. Preconditioning, organ preservation, and postconditioning to prevent ischemia-reperfusion injury to the liver. Liver Transpl 2009; 15:1172-82. [PMID: 19790166 DOI: 10.1002/lt.21876] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ischemia and reperfusion lead to injury of the liver. Ischemia-reperfusion injury is inevitable in liver transplantation and trauma and, to a great extent, in liver resection. This article gives an overview of the mechanisms involved in this type of injury and summarizes protective and treatment strategies in clinical use today. Intervention is possible at different time points: during harvesting, during the period of preservation, and during implantation. Liver preconditioning and postconditioning can be applied in the transplant setting and for liver resection. Graft optimization is merely possible in the period between the harvest and the implantation. Given that there are 3 stages in which a surgeon can intervene against ischemia-reperfusion injury, we have structured the review as follows. The first section reviews the approaches using surgical interventions, such as ischemic preconditioning, as well as pharmacological applications. In the second section, static organ preservation and machine perfusion are addressed. Finally, the possibility of treating the recipient or postconditioning is discussed.
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Affiliation(s)
- Olivier de Rougemont
- Swiss Hepato-Pancreatico-Biliary Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland
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19
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Abstract
PURPOSE OF REVIEW To provide an update on recent developments in liver preservation through a comprehensive review of the literature. RECENT FINDINGS Comparisons of the available preservation solutions for liver transplantation based on recent trials suggest clinical equivalence. The debate continues regarding risk of biliary-tract complications. Development of new preservation solutions and agents that target specific mechanisms of steatotic and donors after cardiac death pathophysiology is showing promise in a variety of preclinical and clinical studies. Early clinical results of ischemic preconditioning are conflicting and so there is the need for additional clinical studies. The most important developments have been in the machine perfusion of the liver. New portable perfusion systems have shown promise in preclinical studies and may allow rapid evolution of clinical liver machine perfusion. The first human clinical trial is well underway with results showing safety and improved efficacy of preservation of transplanted human liver allografts. SUMMARY Liver preservation is in a period of rapid advance. In the future, a multifaceted liver-preservation strategy that integrates pharmacologic agents and hypothermic machine perfusion is likely to minimize organ injury and maximize patient outcomes. An ongoing challenge is to increase the number of innovations entering prospective and randomized clinical trials.
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Jeon H, Ranjan D. The easiest way to improve the outcome of suboptimal liver grafts. Liver Transpl 2008; 14:905; author reply 906-7. [PMID: 18508378 DOI: 10.1002/lt.21464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Pradeau D, Stocco J, Chaumeil JC. [Solutions for organ preservation and other cardioplegic liquid formulations. Role of the hospital pharmacist]. ANNALES PHARMACEUTIQUES FRANÇAISES 2008; 66:1-18. [PMID: 18435981 DOI: 10.1016/j.pharma.2007.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2007] [Indexed: 11/19/2022]
Abstract
Solid organ transplantation is an increasing need and a well-established activity which requires maintaining the quality of the transplant from procurement through the entire, storage, transport and graft procedure. Solutions for organ preservation play a key role in this procedure, by minimizing the deleterious effects of both ischemia and reperfusion. As such, their qualitative and quantitative compositions have to be optimized and validated. The development strategy and formulations proposed for these solutions are analyzed in this review as well as the results of the clinical studies which have set up the relevant pharmacological and physicochemical criteria. The French regulatory status of these products is also discussed. A clear distinction has to be made between solutions for organ preservation which are classified as produits thérapeutiques annexes (therapeutic ancillary products) and cardioplegic liquid formulations which are considered as medicinal products and are subject to marketing approval. Finally, the roles of the hospital pharmacist in the evaluation, selection, purchase and proper use of these products are described.
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Affiliation(s)
- D Pradeau
- Laboratoire de développement analytique et galénique, Ageps, 7, rue du Fer à Moulin, 75221 Paris cedex 05, France.
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Registry of Randomized Controlled Trials in Transplantation: July 1 to December 31, 2006. Transplantation 2007; 84:940-53. [DOI: 10.1097/01.tp.0000286319.97951.45] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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