The Impact of Extended Preservation on Clinical Liver Transplantation

Stratta, Robert J.; Wood, Robert; Langnas, Alan Norman; Duckworth, R. M.; Markin, Rodney S.; Marujo, Wagner; Grazi, Gian Luca; Saito, Shinya; Dawidson, Ingemar; Rikkers, Layton F.; Pillen, Todd; Shaw, Byers W.

doi:10.1097/00007890-199009000-00015

Cited by 50 publications

(25 citation statements)

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“…Specifically, liver grafts cold stored in the presence of simvastatin and afterwards warm reperfused exhibited significantly reduced hepatic injury, normal hepatic resistance, and improved endothelial function as compared to grafts cold stored without simvastatin in the preservation solution. Remarkably, the protective effects of simvastatin were observed in liver grafts cold stored for 16 hours, a period of time where UWS no longer provides protection, 38,39 thus opening up the possibility to lengthen liver procurement periods.…”

Section: Discussionmentioning

confidence: 99%

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

et al. 2012

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Pathophysiological alterations in the endothelial phenotype result in endothelial dysfunction. Flow cessation, occurring during organ procurement for transplantation, triggers the endothelial dysfunction characteristic of ischemia/reperfusion injury, partly due to a reduction in the expression of the vasoprotective transcription factor Kruppel-like Factor 2 (KLF2). We aimed at (1) characterizing the effects of flow cessation and cold storage on hepatic endothelial phenotype, and (2) ascertaining if the consequences of cold stasis on the hepatic endothelium can be pharmacologically modulated, improving liver graft function. Expression of KLF2 and its vasoprotective programs was determined in (i) hepatic endothelial cells (HEC) incubated under cold storage conditions with or without the KLF2-inducer simvastatin, and (ii) rat livers not cold stored or preserved in cold University of Wisconsin solution (UWS) supplemented with simvastatin or its vehicle. In addition, upon warm reperfusion hepatic vascular resistance, endothelial function, nitric oxide vasodilator pathway, apoptosis, inflammation, and liver injury were evaluated in not cold stored livers or livers preserved in cold UWS supplemented with simvastatin or vehicle. Expression of KLF2 and its vasoprotective programs decrease in HEC incubated under cold storage conditions. Cold-stored rat livers exhibit a time-dependent decrease in KLF2 and its target genes, liver injury, increased hepatic vascular resistance, and endothelial dysfunction. The addition of simvastatin to the storage solution, maintained KLF2-dependent vasoprotective programs, prevented liver damage, inflammation, and oxidative stress and improved endothelial dysfunction. Conclusion: Our results provide a rationale to evaluate the beneficial effects of a vasoprotective preservation solution on human liver procurement for transplantation. (HEPATOLOGY 2012;55:921-930)

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Section: Discussionmentioning

confidence: 99%

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

et al. 2012

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“…University of Wisconsin solution enhanced the safe cold ischemia time and contributed to the improvements in reduced-size liver transplantation, including splitting the liver for two recipients. [35][36][37][38][39][40] The continuing improvement in surgical techniques, 3,38,41 immunosuppressive drugs, 4,6,29,33 experience with reduced-size grafts, 38 and better monitoring and follow-up of patients led not only to improved survival posttransplantation in children but also to a decrease in posttransplantation complications requiring ReTx. This study shows a significant reduction in primary graft failure and the necessity for ReTx with increasing experience.…”

Section: Discussionmentioning

confidence: 99%

Outcome of liver retransplantation in children

et al. 1999

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Irreversible liver graft failure is a life-threatening complication. We reviewed the first 200 pediatric liver transplantations in Birmingham. Forty-one children developed primary graft failure, 9 of whom developed secondary graft failure. The main indications for graft failure were primary nonfunction (PRNF; 8 patients), vascular complications (VASC; 23 patients), and chronic rejection (CHRE; 19 patients). Thirty-two children underwent retransplantation (ReTx) (21 children received reduced grafts; 11 children, whole hepatic grafts). Patient survival was significantly worse for retransplant recipients compared with children receiving a single graft (63% v 76.5% actuarial patient survival at 1 year; P F .05). Primary graft 1-year actuarial survival was 74% in first grafts compared with 47% for regrafts (P F .05), but improved with time. The graft 1-year survival rate was 55% for whole grafts and 45% for reduced and/or split grafts in the first 100 grafts compared with 83% and 66% in the second 100 grafts, respectively (P F .01). Emergency ReTx within a month of transplantation was associated with more complications and a worse outcome (1-year survival rate, 37%) compared with patients who underwent ReTx later (1-year survival rate, 72%; P F .01). The incidence of primary graft failure decreased from 33% in the first 100 grafts to 16% in the second 100 grafts (P F .01), as did the incidence of PRNF, which decreased from 8% to 0% (P F .05). Although the rates of graft failure from VASC decreased from 15% to 8% (P ‫؍‬ .2) and CHRE decreased from 11% to 8% (P ‫؍‬ .6), neither reached statistical significance. The improved results overall are because of advances in surgical techniques, intensive care management, and graft preservation and refinements in immunosuppression. We conclude that ReTx for a child with primary graft failure is justified.

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“…The introduction of the University of Wisconsin solution more than 10 years ago extended the time of cold storage between harvesting and transplantation. 1,2 Preservation of livers before transplantation for more than 12 to 18 hours still carries the risk for compromising the function of the future graft, [3][4][5][6] and favors posttransplantation infection. 7 One of the most promising strategies that lengthens the time of cold ischemia without risking reperfusion injury is preconditioning.…”

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Extended preservation of rat liver graft by induction of heme oxygenase-1

et al. 2002

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Livers can be preserved only for a short period without jeopardizing the transplantation outcome. Heat shock proteins (HSPs) protect against ischemia and reperfusion injury. We studied whether their induction and, in particular, the induction of heme oxygenase 1 (HO-1), improves transplantation survival after an extended time of cold storage. Rats were subjected to heat preconditioning (42°C for 20 minutes). Livers were harvested 24 hours later, preserved in cold University of Wisconsin solution for 44 hours, and transplanted in isogeneic rats (arterialized transplantation). HO-1 was specifically induced and inhibited by cobalt protoporphyrin and tin protoporphyrin, respectively. All animals receiving a graft without preconditioning and subjected to 44 hours of cold preservation died within 3 days, whereas 89% of rats who received a graft exposed to heat survived for 3 weeks (P ‫؍‬ .0004). Preconditioning reduced serum aspartate transaminase (AST) and lactate dehydrogenase activities after reperfusion, improved bile flow, and decreased the histologic lesions of reperfusion injury. These significant effects of heat preconditioning were prevented by administration of tin protoporphyrin and could be reproduced by administration of cobalt protoporphyrin. In grafts without preconditioning, only a small fraction (<5%) of hepatocytes were positive with the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay, and even less expressed activated caspase 3. Preconditioning tended to reduce the number of positive cells and to stimulate the expression of antiapoptotic Bcl-X L . In conclusion, heat preconditioning and, specifically, overexpression of HO-1 improve posttransplantation survival and graft function after prolonged cold ischemia preservation. The mechanism underlying these beneficial effects does not appear to be prevention of apoptosis. (HEPATOLOGY 2002;35:1082-1092

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The Impact of Extended Preservation on Clinical Liver Transplantation

Cited by 50 publications

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Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

Outcome of liver retransplantation in children

Extended preservation of rat liver graft by induction of heme oxygenase-1

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