Ischemia-Reperfusion Injury and Therapeutic Strategy in Donation After Circulatory Death Liver Transplantation

  • Toru Goto
  • Markus SelznerEmail author


Ischemia-reperfusion injury (IRI) is an important problem in transplantation when blood flow is restored in damaged organs resulting in significant morbidity and mortality in recipient. Liver grafts from donation after circulatory death (DCD) have a more prolonged warm ischemia time that can result in decreased postoperative liver function and increased bile duct injury.

Liver IRI induces damage of hepatocytes and liver sinusoidal endothelial cells (SECs), which is regulated by several molecular pathways. During the ischemic period, there is a metabolic disturbance with adenosine triphosphate (ATP) depletion of cells and lactic acidosis, which induces mitochondrial dysfunction and production of reactive oxygen species (ROS). After reperfusion and restoration of oxygen supply, ROS and damage-associated molecular patterns (DAMPs) are produced. Damaged and activated SEC and liver macrophages (Kupffer cells) promote neutrophil migration and platelet activation by releasing pro-inflammatory mediators such as cytokines and chemokines. Migrated neutrophils secrete ROS, which further promotes cell death. Activated platelets induce a reduction of microcirculation by vasoconstriction and thrombosis in the sinusoid.

In the clinical setting, three main therapeutic strategies can be applied to protect the DCD liver graft from ischemic damage and to improve postoperative function: (1) minimizing the ischemia time, (2) providing thrombolytic therapy during the transplant procedure, and (3) carrying out in situ and ex situ machine perfusion. Especially, the ex situ machine perfusion is a promising approach for the protection from IRI with improved hepatic function and a reduction of biliary injury.


Ischemia-reperfusion injury Donation after circulatory death Liver sinusoidal endothelial cells Hepatocytes Warm ischemia time Cold ischemia time Ischemic-type biliary lesions Ischemic cholangiopathy Ex vivo machine perfusion Normothermic ex situ machine perfusion Hypothermic ex situ machine perfusion Normothermic regional machine perfusion 



Controlled DCD


Damage-associated molecular patterns


Donation after circulatory death


High-mobility group box 1


Hypothermic ex situ machine perfusion


Ischemic cholangiopathy


Ischemia-reperfusion injury


Ischemic-type biliary lesions


Machine perfusion


Normothermic ex situ machine perfusion


Normothermic regional machine perfusion


Reactive oxygen species


Liver sinusoidal endothelial cells


Toll-like receptor


Tissue plasminogen activator


Uncontrolled DCD


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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Multi-Organ Transplant Program, Department of SurgeryToronto General Hospital, University Health NetworkTorontoCanada
  2. 2.Department of Surgery, Division of Hepato-biliary-Pancreatic Surgery & TransplantationKyoto University Graduate School of MedicineTorontoCanada
  3. 3.Department of General Surgery & Multi-Organ TransplantToronto General HospitalTorontoCanada

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