Hypothermic Machine Preservation in Human Liver Transplantation: The First Clinical Series

Guarrera, James V.; Henry, Scot D.; Samstein, Benjamin; Odeh‐Ramadan, R.; Kinkhabwala, Milan; Goldstein, Michael J.; Ratner, Lloyd E.; Renz, John F.; Lee, H. T.; Brown, Robert S.; Emond, Jean C.

doi:10.1111/j.1600-6143.2009.02932.x

Cited by 489 publications

(535 citation statements)

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“…11 This pioneering study created the rationale to investigate strategies for organ preservation based on machine perfusion of kidney or liver grafts. 24,25 Furthermore, it allows study of the molecular mechanisms leading to increased endothelial sensitivity to injury in the absence of shear stress, with the aim of discovery druggable targets to prevent endothelial and tissue damage during organ procurement. For this purpose, we analyzed the effects of shear stress interruption and cold storage on the hepatic endothelial phenotype and function, and developed a pharmacological strategy to maintain endothelial health in the setting of organ transplantation.…”

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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“…Matched control patients were identified as described above; to find two matched controls, preset criteria were extended in some cases, MELD was 12 in NMP versus 14 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) in matched controls (p = 0.55).…”

Section: Donor and Recipient Characteristicsmentioning

confidence: 99%

“…Investigators around the world are exploring novel preservation methods in an attempt to enable greater use of such high-risk organs without compromising outcomes. Recent advances include the demonstration of the benefit of cold continuous machine perfusion for the kidney (6) and the first use of a similar strategy in the liver (7,8). Early clinical investigations by the Zurich group suggest that oxygenated hypothermic liver perfusion at the end of cold preservation is beneficial (9,10).…”

Section: Introductionmentioning

confidence: 99%

Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial

Ravikumar

Jassem

Mergental

et al. 2016

American Journal of Transplantation

418

412

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Joint first authors. ISRCTN 14355416.The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury. We present the first patients transplanted using a normothermic machine perfusion (NMP) device that transports and stores an organ in a fully functioning state at 37°C. In this Phase 1 trial, organs were retrieved using standard techniques, attached to the perfusion device at the donor hospital, and transported to the implanting center in a functioning state. NMP livers were matched 1:2 to cold-stored livers. Twenty patients underwent liver transplantation after NMP. Median NMP time was 9.3 (3.5-18.5) h versus median cold ischaemia time of 8.9 (4.2-11.4) h. Thirty-day graft survival was similar (100% NMP vs. 97.5% control, p = 1.00). Median peak aspartate aminotransferase in the first 7 days was significantly lower in the NMP group ) versus , p = 0.03). This first report of liver transplantation using NMP-preserved livers demonstrates the safety and feasibility of using this technology from retrieval to transplantation, including transportation. NMP may be valuable in increasing the number of donor livers and improving the function of transplantable organs.Abbreviations: AST, aspartate transaminase; DBD, donation after brain death; DCD, donation after circulatory death; IRI, ischemia-reperfusion injury; IVC, inferior vena cava; MELD, model for end-stage liver disease; NHSBT, National Health Service Blood and Transplant; NMP, normothermic machine perfusion

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“…5,6 Although recent data from animal models and (discarded) human donor livers have provided promising results suggesting that endischemic MP has relevant protective effects on the bile ducts of donation after cardiac death (DCD) liver grafts, the most optimal perfusion temperature during end-ischemic MP has not been investigated. [7][8][9][10][11][12][13][14][15][16][17] The aim of this study was, therefore, to assess the optimal perfusion temperature during end-ischemic oxygenated MP for protection of the large bile ducts against I/R injury in a DCD rat liver model.…”

mentioning

confidence: 99%

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Westerkamp

Mahboub²,

Meyer

et al. 2015

Liver Transpl

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A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation. Liver Transpl 21:1300-1311, 2015. V C 2015 AASLD.Received March 17, 2015; accepted June 8, 2015.Ischemic cholangiopathy, also known as nonanastomotic biliary strictures (NAS), is one of the most prevalent and troublesome complications after liver transplantation. During NAS formation, in particular, the large (extrahepatic) bile ducts become fibrotic and/or necrotic. Patients with NAS may suffer from recurrent jaundice and episodes of cholangitis, and retransplantation may be the only curative treatment. 1 The combination of ischemia and ischemia/ reperfusion (I/R) injury has been shown to be a major Additional supporting information may be found in the online version of this article.

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Hypothermic Machine Preservation in Human Liver Transplantation: The First Clinical Series

Cited by 489 publications

References 20 publications

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

Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

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