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Molecular Medicine

, Volume 21, Issue 1, pp 833–846 | Cite as

Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation

  • Pim B. Olthof
  • Megan J. Reiniers
  • Marcel C. Dirkes
  • Thomas M. van Gulik
  • Michal Heger
  • Rowan F. van Golen
Review Article

Abstract

Hepatic ischemia/reperfusion (I/R) injury is a side effect of major liver surgery that often cannot be avoided. Prolonged periods of ischemia put a metabolic strain on hepatocytes and limit the tolerable ischemia and preservation times during liver resection and transplantation, respectively. In both surgical settings, temporarily lowering the metabolic demand of the organ by reducing organ temperature effectively counteracts the negative consequences of an ischemic insult. Despite its routine use, the application of liver cooling is predicated on an incomplete understanding of the underlying protective mechanisms, which has limited a uniform and widespread implementation of liver-cooling techniques. This review therefore addresses how hypothermia-induced hypometabolism modulates hepatocyte metabolism during ischemia and thereby reduces hepatic I/R injury. The mechanisms underlying hypothermia-mediated reduction in energy expenditure during ischemia and the attenuation of mitochondrial production of reactive oxygen species during early reperfusion are described. It is further addressed how hypothermia suppresses the sterile hepatic I/R immune response and preserves the metabolic functionality of hepatocytes. Lastly, a summary of the clinical status quo of the use of liver cooling for liver resection and transplantation is provided.

Notes

Acknowledgments

The authors thank Inge Kos from the medical illustration service for some of the artwork. RF van Golen was supported by a PhD scholarship and the Young Talent Fund, both from the Academic Medical Center in Amsterdam. M Heger was supported by grants from the Dutch Anti-Cancer Foundation (Stichting Nationaal Fonds Tegen Kanker) in Amsterdam, the Phospholipid Research Center in Heidelberg, the Nijbakker-Morra Foundation in Leiden, and Stichting Technologische Wetenschap (STW).

References

  1. 1.
    Farges O, Goutte N, Bendersky N, Falissard B, Group AC-FHS. (2012) Incidence and risks of liver resection: an all-inclusive French nationwide study. Ann. Surg. 256:697–704.PubMedCrossRefGoogle Scholar
  2. 2.
    Breitenstein S, et al. (2010) Novel and simple preoperative score predicting complications after liver resection in noncirrhotic patients. Ann. Surg. 252:726–34.PubMedCrossRefGoogle Scholar
  3. 3.
    Schiergens TS, et al. (2014) Liver resection in the elderly: significance of comorbidities and blood loss. J. Gastrointest. Surg. 18:1161–70.PubMedCrossRefGoogle Scholar
  4. 4.
    van Golen RF, Reiniers MJ, van Gulik TM, Heger M. (2015) Organ cooling in liver transplantation and resection: how low should we go? Hepatology. 61:395–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Fortner JG, et al. (1974) Major hepatic resection using vascular isolation and hypothermic perfusion. Ann. Surg. 180:644–52.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Azoulay D, et al. (2015) Complex liver resection using standard total vascular exclusion, venovenous bypass, and in situ hypothermic portal perfusion: an audit of 77 consecutive cases. Ann. Surg. 262:93–104.PubMedCrossRefGoogle Scholar
  7. 7.
    Reiniers MJ, et al. (2014) In situ hypothermic perfusion with retrograde outflow during right hemihepatectomy: first experiences with a new technique. J. Am. Coll. Surg. 218:e7–16.PubMedCrossRefGoogle Scholar
  8. 8.
    van Golen RF, van Gulik TM, Heger M. (2012) The sterile immune response during hepatic ischemia/reperfusion. Cytokine Growth Factor Rev. 23:69–84.PubMedCrossRefGoogle Scholar
  9. 9.
    van Golen RF, van Gulik TM, Heger M. (2012) Mechanistic overview of reactive species-induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury. Free Radic. Biol. Med. 52:1382–1402.PubMedCrossRefGoogle Scholar
  10. 10.
    Kloek JJ, et al. (2012) Cholestasis is associated with hepatic microvascular dysfunction and aberrant energy metabolism before and during ischemia-reperfusion. Antioxid. Redox Signal. 17:1109–23.PubMedCrossRefGoogle Scholar
  11. 11.
    Chouchani ET, et al. (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 515:431–5.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Murphy MP. (2009) How mitochondria produce reactive oxygen species. Biochem. J. 417:1–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Radi R, Rodriguez M, Castro L, Telleri R. (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch. Biochem. Biophys. 308:89–95.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim JS, Wang JH, Lemasters JJ. (2012) Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation: role of Ca2+-dependent mitochondrial formation of reactive oxygen species. Am. J. Physiol. 302:G723–31.CrossRefGoogle Scholar
  15. 15.
    Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. (2002) Cytochrome c release from mitochondria proceeds by a two-step process. Proc. Natl. Acad. Sci. U. S. A. 99:1259–63.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL. (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim. Biophys. Acta. 1787:1395–401.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Nieminen AL, Byrne AM, Herman B, Lemasters JJ. (1997) Mitochondrial permeability transition in hepatocytes induced by t-BuOOH: NAD(P)H and reactive oxygen species. Am. J. Physiol. 272: C1286–1294.PubMedCrossRefGoogle Scholar
  18. 18.
    van Golen RF, Reiniers MJ, Olthof PB, van Gulik TM, Heger M. (2013) Sterile inflammation in hepatic ischemia/reperfusion injury: present concepts and potential therapeutics. J. Gastroenterol. Hepatol. 28:394–400.CrossRefGoogle Scholar
  19. 19.
    de Graaf W, et al. (2012) Quantitative assessment of liver function after ischemia-reperfusion injury and partial hepatectomy in rats. J. Surg. Res. 172:85–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Lock JF, et al. (2009) The costs of postoperative liver failure and the economic impact of liver function capacity after extended liver resection: a single-center experience. Langenbecks Arch. Surg. 394:1047–56.PubMedCrossRefGoogle Scholar
  21. 21.
    Thorniley MS, Simpkin S, Fuller B, Jenabzadeh MZ, Green CJ. (1995) Monitoring of surface mitochondrial NADH levels as an indication of ischemia during liver isograft transplantation. Hepatology. 21:1602–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Caraceni P, Ryu HS, van Thiel DH, Borle AB. (1995) Source of oxygen free radicals produced by rat hepatocytes during postanoxic reoxygenation. Biochim. Biophys. Acta. 1268:249–54.PubMedCrossRefGoogle Scholar
  23. 23.
    Barron JT, Gu L, Parrillo JE. (1998) Malate-aspartate shuttle, cytoplasmic NADH redox potential, and energetics in vascular smooth muscle. J. Mol. Cell. Cardiol. 30:1571–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhou L, Stanley WC, Saidel GM, Yu X, Cabrera ME. (2005) Regulation of lactate production at the onset of ischaemia is independent of mitochondrial NADH/NAD+: insights from in silico studies. J. Physiol. 569:925–37.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Behrends M, et al. (2006) Mild hypothermia reduces the inflammatory response and hepatic ischemia/reperfusion injury in rats. Liver Int. 26:734–741.PubMedCrossRefGoogle Scholar
  26. 26.
    Niemann CU, et al. (2006) Mild hypothermia protects obese rats from fulminant hepatic necrosis induced by ischemia-reperfusion. Surgery. 140:404–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Khandoga A, et al. (2003) Impact of intraischemic temperature on oxidative stress during hepatic reperfusion. Free Radic. Biol. Med. 35:901–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Harrison R. (2002) Structure and function of xanthine oxidoreductase: where are we now? Free Radic. Biol. Med. 33:774–97.PubMedCrossRefGoogle Scholar
  29. 29.
    Biberthaler P, et al. (2001) The influence of organ temperature on hepatic ischemia-reperfusion injury: a systematic analysis. Transplantation. 72:1486–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Dinant S, van Veen SQ, Roseboom HJ, van Vliet AK, van Gulik TM. (2006) Liver protection by hypothermic perfusion at different temperatures during total vascular exclusion. Liver Int. 26:486–93.PubMedCrossRefGoogle Scholar
  31. 31.
    van Golen RF, Reiniers MJ, Heger M, Verheij J. (2015) Solutions to the discrepancies in the extent of liver damage following ischemia/reperfusion in standard mouse models. J. Hepatol. 62:975–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Churchill TA, Cheetham KM, Fuller BJ. (1994) Glycolysis and energy metabolism in rat liver during warm and cold ischemia: evidence of an activation of the regulatory enzyme phosphofructokinase. Cryobiology. 31:441–52.PubMedCrossRefGoogle Scholar
  33. 33.
    Reiniers MJ, van Golen RF, van Gulik TM, Heger M. (2014) Reactive oxygen and nitrogen species in steatotic hepatocytes: a molecular perspective on the pathophysiology of ischemia-reperfusion injury in the fatty liver. Antioxid. Redox Signal. 21:1119–42.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Moon KH, et al. (2008) Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion. Gastroenterology. 135:1344–57.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Jaeschke H, Lemasters JJ. (2003) Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology. 125:1246–57.PubMedCrossRefGoogle Scholar
  36. 36.
    Takahashi K, Morikawa S, Inubushi T, Nosaka S. (2004) Protective effects of moderate hypothermia on phosphoenergetic metabolism in rat liver during gradual hypoxia studied by in vivo 31P nuclear magnetic resonance spectroscopy. J. Surg. Res. 117:323–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Peralta C, et al. (2000) Hepatic preconditioning preserves energy metabolism during sustained ischemia. Am. J. Physiol. Gastrointest. Liver Physiol. 279:G163–71.PubMedCrossRefGoogle Scholar
  38. 38.
    Dutta A, et al. (2009) Impairment of mitochondrial beta-oxidation in rats under cold-hypoxic environment. Int. J. Biometeorol. 53:397–407.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Johannigman JA, Johnson DJ, Roettger R. (1992) The effect of hypothermia on liver adenosine triphosphate (ATP) recovery following combined shock and ischemia. J. Trauma. 32:190–5.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Niemann CU, et al. (2010) Short passive cooling protects rats during hepatectomy by inducing heat shock proteins and limiting the induction of pro-inflammatory cytokines. J. Surg. Res. 158:43–52.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    van Golen RF, Reiniers MJ, Verheij J, Heger M. (2015) Solutions to the discrepancies in liver damage profiles following ischemia/reperfusion in standardized mouse models. J. Hepatol. 62:975–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Kato A, Singh S, McLeish KR, Edwards MJ, Lentsch AB. (2002) Mechanisms of hypothermic protection against ischemic liver injury in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 282:G608–16.PubMedCrossRefGoogle Scholar
  43. 43.
    Seki E, Brenner DA, Karin M. (2012) A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology. 143:307–20.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Zwacka RM, et al. (1998) Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation. Nat. Med. 4:698–704.PubMedCrossRefGoogle Scholar
  45. 45.
    Kuboki S, et al. (2007) Hepatocyte NF-kappaB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia. Am. J. Physiol. Gastrointest. Liver Physiol. 292:G201–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Shin T, Kuboki S, Lentsch AB. (2008) Roles of nuclear factor-kappaB in postischemic liver. Hepatol. Res. 38:429–40.PubMedCrossRefGoogle Scholar
  47. 47.
    Yenari MA, et al. (2005) Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection. Ann. N. Y. Acad. Sci. 1053:74–83.PubMedCrossRefGoogle Scholar
  48. 48.
    Kuboki S, et al. (2007) Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 292:G1141–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Iimuro Y, et al. (1998) NFkappaB prevents apoptosis and liver dysfunction during liver regeneration. J. Clin. Invest. 101:802–11.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Konig M, Bulik S, Holzhutter HG. (2012) Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism. PLoS Comput. Biol. 8:e1002577.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Shi Z, et al. (2013) Prevalence of stress hyperglycemia among hepatopancreatobiliary postoperative patients. Int. J. Clin. Exp. Med. 6:799–803.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Huang PY, et al. (2015) Correlation of early postoperative blood glucose levels with postoperative complications, hospital costs, and length of hospital stay in patients with gastrointestinal malignancies. Endocrine. 48:187–94.PubMedCrossRefGoogle Scholar
  53. 53.
    Han S, et al. (2015) Glycemic responses to intermittent hepatic inflow occlusion in living liver donors. Liver Transpl. 21:180–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Little SA, Jarnagin WR, DeMatteo RP, Blumgart LH, Fong Y. (2002) Diabetes is associated with increased perioperative mortality but equivalent long-term outcome after hepatic resection for colorectal cancer. J. Gastrointest. Surg. 6:88–94.PubMedCrossRefGoogle Scholar
  55. 55.
    van den Berghe G, et al. (2001) Intensive insulin therapy in critically ill patients. N. Engl. J. Med. 345:1359–67.PubMedCrossRefGoogle Scholar
  56. 56.
    Durczynski A, et al. (2013) Major liver resection results in early exacerbation of insulin resistance, and may be a risk factor of developing overt diabetes in the future. Surg. Today. 43:534–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A. (2007) Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J. Hepatol. 47:142–56.PubMedCrossRefGoogle Scholar
  58. 58.
    Uehara T, et al. (2005) JNK mediates hepatic ischemia reperfusion injury. J. Hepatol. 42:850–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Michael MD, et al. (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell. 6:87–97.PubMedCrossRefGoogle Scholar
  60. 60.
    Kiuchi T, et al. (1990) Changes in arterial ketone body ratio in the phase immediately after hepatectomy: prognostic implications. Arch. Surg. 125:655–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Choi S, et al. (2005) Mild hypothermia provides significant protection against ischemia/reperfusion injury in livers of obese and lean rats. Ann. Surg. 241:470–6.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    International Transporter Consortium, et al. (2010) Membrane transporters in drug development. Nat. Rev. Drug Discov. 9:215–36.CrossRefGoogle Scholar
  63. 63.
    Huang W, et al. (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 312:233–6.PubMedCrossRefGoogle Scholar
  64. 64.
    de Graaf W, et al. (2011) Transporters involved in the hepatic uptake of (99m)Tc-mebrofenin and indocyanine green. J. Hepatol. 54:738–45.PubMedCrossRefGoogle Scholar
  65. 65.
    Hoekstra LT, et al. (2013) Physiological and biochemical basis of clinical liver function tests: a review. Ann. Surg. 257:27–36.PubMedCrossRefGoogle Scholar
  66. 66.
    Tanaka Y, Chen C, Maher JM, Klaassen CD. (2006) Kupffer cell-mediated downregulation of hepatic transporter expression in rat hepatic ischemia-reperfusion. Transplantation. 82:258–66.PubMedCrossRefGoogle Scholar
  67. 67.
    Tsujimoto T, et al. (2013) Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver. Int. J. Pharm. 458:262–71.PubMedCrossRefGoogle Scholar
  68. 68.
    Heijnen BH, Straatsburg IH, Gouma DJ, van Gulik TM. (2003) Decrease in core liver temperature with 10 degrees C by in situ hypothermic perfusion under total hepatic vascular exclusion reduces liver ischemia and reperfusion injury during partial hepatectomy in pigs. Surgery. 134:806–17.PubMedCrossRefGoogle Scholar
  69. 69.
    Roth M, Obaidat A, Hagenbuch B. (2012) OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br. J. Pharmacol. 165:1260–87.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Jonker JW, Stedman CA, Liddle C, Downes M. (2009) Hepatobiliary ABC transporters: physiology, regulation and implications for disease. Front. Biosci. 14:4904–20.CrossRefGoogle Scholar
  71. 71.
    Naugler WE. (2014) Bile acid flux is necessary for normal liver regeneration. PLoS One. 9:e97426.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Hoti E, Salloum C, Azoulay D. (2011) Hepatic resection with in situ hypothermic perfusion is superior to other resection techniques. Dig. Surg. 28:94–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Azoulay D, et al. (2005) In situ hypothermic perfusion of the liver versus standard total vascular exclusion for complex liver resection. Ann. Surg. 241:277–85.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Kurz A, Sessler DI, Lenhardt R. (1996) Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization: Study of Wound Infection and Temperature Group. N. Engl. J. Med. 334:1209–1215.PubMedCrossRefGoogle Scholar
  75. 75.
    Frank SM, et al. (1997) Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events: a randomized clinical trial. JAMA. 277:1127–34.PubMedCrossRefGoogle Scholar
  76. 76.
    Heijnen BH, et al. (2003) Effect of in situ hypothermic perfusion on intrahepatic pO2 and reactive oxygen species formation after partial hepatectomy under total hepatic vascular exclusion in pigs. Liver Int. 23:19–27.PubMedCrossRefGoogle Scholar
  77. 77.
    Dinant S, Roseboom HJ, Levi M, van Vliet AK, van Gulik TM. (2009) Hypothermic in situ perfusion of the porcine liver using Celsior or Ringer-lactate solution. Langenbecks Arch. Surg. 394:143–50.PubMedCrossRefGoogle Scholar
  78. 78.
    Azoulay D, et al. (2014) Liver resection using total vascular exclusion of the liver preserving the caval flow, in situ hypothermic portal perfusion and temporary porta-caval shunt: a new technique for central tumors. Hepatobiliary Surg. Nutr. 3:149–53.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Belzer FO, Southard JH. (1988) Principles of solid-organ preservation by cold storage. Transplantation. 45:673–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Clavien PA. (1998) Sinusoidal endothelial cell injury during hepatic preservation and reperfusion. Hepatology. 28:281–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Caldwell-Kenkel JC, Currin RT, Tanaka Y, Thurman RG, Lemasters JJ. (1991) Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion. Hepatology. 13:83–95.PubMedGoogle Scholar
  82. 82.
    Sindram D, Porte RJ, Hoffman MR, Bentley RC, Clavien PA. (2000) Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver. Gastroenterology. 118:183–91.PubMedCrossRefGoogle Scholar
  83. 83.
    van Golen RF, Stevens KM, Colarusso P, Jaeschke H, Heger M. (2015) Platelet aggregation but not activation and degranulation during the acute post-ischemic reperfusion phase in livers with no underlying disease. J. Clin. Transl. Res. 1:107–15.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Xu H, Lee CY, Clemens MG, Zhang JX. (2004) Pronlonged hypothermic machine perfusion preserves hepatocellular function but potentiates endothelial cell dysfunction in rat livers. Transplantation. 77:1676–82.PubMedCrossRefGoogle Scholar
  85. 85.
    Brunner SM, et al. (2013) Bile duct damage after cold storage of deceased donor livers predicts biliary complications after liver transplantation. J. Hepatol. 58:1133–9.PubMedCrossRefGoogle Scholar
  86. 86.
    van Golen RF, et al. (2014) The mechanisms and physiological relevance of glycocalyx degradation in hepatic ischemia/reperfusion injury. Antioxid. Redox Signal. 21:1098–118.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Schlegel A, Kron P, Dutkowski P. (2015) Hypothermic oxygenated liver perfusion: basic mechanisms and clinical application. Curr. Transplant. Rep. 2:52–62.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Westerkamp AC, et al. (2015) End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers. Liver Transpl. 21:1300–11.PubMedCrossRefGoogle Scholar
  89. 89.
    Nassar A, et al. (2015) Ex vivo normothermic machine perfusion is safe, simple, and reliable: results from a large animal model. Surg. Innov. 22:61–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Liu Q, et al. (2014) Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers. Liver Transpl. 20:987–99.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    op den Dries S, et al. (2013) Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am. J. Transplant. 13:1327–35.CrossRefGoogle Scholar
  92. 92.
    Schlegel A, Kron P, Graf R, Dutkowski P, Clavien PA. (2014) Warm vs. cold perfusion techniques to rescue rodent liver grafts. J. Hepatol. 61:1267–75.PubMedCrossRefGoogle Scholar
  93. 93.
    Moers C, et al. (2009) Machine perfusion or cold storage in deceased-donor kidney transplantation. N. Engl. J. Med. 360:7–19.PubMedCrossRefGoogle Scholar
  94. 94.
    Schlegel A, Graf R, Clavien PA, Dutkowski P. (2013) Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation. J. Hepatol. 59:984–91.PubMedCrossRefGoogle Scholar
  95. 95.
    Dutkowski P, Furrer K, Tian Y, Graf R, Clavien PA. (2006) Novel short-term hypothermic oxygenated perfusion (HOPE) system prevents injury in rat liver graft from non-heart beating donor. Ann. Surg. 244:968–76.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Graham JA, Guarrera JV. (2014) “Resuscitation” of marginal liver allografts for transplantation with machine perfusion technology. J. Hepatol. 61:418–31.PubMedCrossRefGoogle Scholar
  97. 97.
    Schlegel A, Rougemont O, Graf R, Clavien PA, Dutkowski P. (2013) Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts. J. Hepatol. 58:278–86.PubMedCrossRefGoogle Scholar
  98. 98.
    Guarrera JV, et al. (2010) Hypothermic machine preservation in human liver transplantation: the first clinical series. Am. J. Transplant. 10:372–81.PubMedCrossRefGoogle Scholar
  99. 99.
    Dutkowski P, et al. (2014) HOPE for human liver grafts obtained from donors after cardiac death. J. Hepatol. 60:765–72.PubMedCrossRefGoogle Scholar
  100. 100.
    Guarrera JV, et al. (2015) Hypothermic machine preservation facilitates successful transplantation of “orphan” extended criteria donor livers. Am. J. Transplant. 15:161–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Vairetti M, et al. (2009) Subnormothermic machine perfusion protects steatotic livers against preservation injury: a potential for donor pool increase? Liver Transpl. 15:20–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Bruinsma BG, et al. (2014) Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation. Am. J. Transplant. 14:1400–9.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Guarrera JV. (2014) Donation: where are our opportunities for expansion? Liver Transp. 20(S2):S2–4.CrossRefGoogle Scholar

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Authors and Affiliations

  • Pim B. Olthof
    • 1
  • Megan J. Reiniers
    • 1
  • Marcel C. Dirkes
    • 1
  • Thomas M. van Gulik
    • 1
  • Michal Heger
    • 1
  • Rowan F. van Golen
    • 1
  1. 1.Department of Experimental Surgery, Surgical Laboratory, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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