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

  • Toru Goto
  • Markus SelznerEmail author
Chapter

Abstract

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.

Keywords

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 

Abbreviations

cDCD

Controlled DCD

DAMPs

Damage-associated molecular patterns

DCD

Donation after circulatory death

HMBG-1

High-mobility group box 1

HMP

Hypothermic ex situ machine perfusion

IC

Ischemic cholangiopathy

IRI

Ischemia-reperfusion injury

ITBLs

Ischemic-type biliary lesions

MP

Machine perfusion

NMP

Normothermic ex situ machine perfusion

NRP

Normothermic regional machine perfusion

ROS

Reactive oxygen species

SECs

Liver sinusoidal endothelial cells

TLR

Toll-like receptor

tPA

Tissue plasminogen activator

uDCD

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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