Abstract
Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20–25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.
Highlights
Since the ground-breaking efforts of the pioneering group of Thomas Starzl in 1963, orthotopic liver transplantation (OLT) has evolved as the treatment of choice for patients with chronic liver disease and acute liver failure [1,2]
The microcirculation data of the donation after circulatory death (DCD) + A2 group stayed around the preischemic baseline values, there was a prominent decrease in microcirculation and tissue perfusion in the DCD group, with significant between-group differences (103% ± 5% vs. 38% ± 4%, DCD + A2 vs. DCD; p < 0.05; see Figure 1)
Even more pronounced functional deterioration was observed in the DCD control animals following 3 h of reperfusion, whereas an improvement of allograft clearance capacity was documented in the treated DCD + A2 group (44% ± 15% vs. 81% ± 18%; p < 0.05, see Figure 2)
Summary
Since the ground-breaking efforts of the pioneering group of Thomas Starzl in 1963, orthotopic liver transplantation (OLT) has evolved as the treatment of choice for patients with chronic liver disease and acute liver failure [1,2]. Despite many improvements in terms of surgical techniques, peri-operative intensive therapy, and organ preservation, ischemic-reperfusion injury (IRI) still represents a major source of allograft dysfunction and inferior outcomes following OLT [1,2,3,4]. Aside from advanced donor age, long cold preservation, or the presence of a significant macrosteatosis, donation after circulatory death (DCD) is one of the most frequently employed features to define marginal ECD allografts [1,6,7]. Many centers successfully transplant a high number of liver allografts from DCD donors, in the case of these particular livers, the additional period of in situ warm ischemia time during retrieval exposes the recipient to an increased risk of developing graft-related complications, such as delayed graft function-DGF, primary non-function-PNF, or biliary complications, leading to inferior long-term outcomes [8,9,10]
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