Hypothermic Oxygenated Machine Perfusion Prevents Arteriolonecrosis of the Peribiliary Plexus in Pig Livers Donated after Circulatory Death

BACKGROUND: Livers derived from donation after circulatory death (DCD) are increasingly accepted for transplantation. However, DCD livers suffer additional donor warm ischemia, leading to biliary injury and more biliary complications after transplantation. It is unknown whether oxygenated machine perfusion results in better preservation of biliary epithelium and the peribiliary vasculature. We compared oxygenated hypothermic machine perfusion (HMP) with static cold storage (SCS) in a porcine DCD model. METHODS: After 30 min of cardiac arrest, livers were perfused in situ with HTK solution (4°C) and preserved for 4 h by either SCS (n = 9) or oxygenated HMP (10°C; n = 9), using pressure-controlled arterial and portal venous perfusion. To simulate transplantation, livers were reperfused ex vivo at 37°C with oxygenated autologous blood. Bile duct injury and function were determined by biochemical and molecular markers, and a systematic histological scoring system. RESULTS: After reperfusion, arterial flow was higher in the HMP group, compared to SCS (251±28 vs 166±28 mL/min, respectively, after 1 hour of reperfusion; p = 0.003). Release of hepatocellular enzymes was significantly higher in the SCS group. Markers of biliary epithelial injury (biliary LDH, gamma-GT) and function (biliary pH and bicarbonate, and biliary transporter expression) were similar in the two groups. However, histology of bile ducts revealed significantly less arteriolonecrosis of the peribiliary vascular plexus in HMP preserved livers (>50% arteriolonecrosis was observed in 7 bile ducts of the SCS preserved livers versus only 1 bile duct of the HMP preserved livers; p = 0.024). CONCLUSIONS: Oxygenated HMP prevents arteriolonecrosis of the peribiliary vascular plexus of the bile ducts of DCD pig livers and results in higher arterial flow after reperfusion. Together this may contribute to better perfusion of the bile ducts, providing a potential advantage in the post-ischemic recovery of bile ducts

Criteria for Viability Assessment of Discarded Human Donor Livers during Ex Vivo Normothermic Machine Perfusion

Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37 °C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥ 30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial

Bile duct injury in liver transplantation: studies on etiology and the protective role of machine perfusion

Het ontstaan van non-anastomotische galwegstricturen (NAS) is een veel voorkomend en moeilijk behandelbaar probleem na levertransplantatie. Kenmerkend voor deze complicatie is het ontstaan van vernauwingen (stricturen) van de galwegen in of net buiten de lever (extrahepatisch). De studies beschreven in dit proefschrift hebben bijgedragen aan een beter inzicht in de onderliggende etiologieën van galwegschade en het daaropvolgende ontstaan van NAS na levertransplantatie. Daarnaast werd met dit onderzoek het eerste bewijs geleverd dat machinepreservatie, vergeleken met de klassieke koude preservatie, superieure bescherming van de galwegen van donorlevers biedt

Protection of Bile Ducts in Liver Transplantation:Looking Beyond Ischemia

Biliary complications, especially nonanastomotic biliary strictures (NAS), are a major cause of morbidity after orthotopic liver transplantation. Of all donor and recipient characteristics known to increase the risk of developing NAS, the role of prolonged ischemia times is most extensively described in the literature. However, there is increasing evidence that several other, non-ischemia-related factors play a critical role in the pathogenesis of NAS as well. The clinical presentation of NAS may vary considerably among liver transplant recipients, including large variations in time of occurrence, and in location and severity of the strictures. Additional underlying causes such as bile salt toxicity and immune-mediated injury are believed to explain the wide spectrum of biliary strictures after orthotopic liver transplantation. Current and emerging insight in the pathogenesis of NAS and potential targets to reduce biliary injury and preserve bile ducts are discussed in this overview

Shared Decision Making in Transplantation:How Patients See Their Role in the Decision Process of Accepting a Donor Liver

At the time of the organ offer for transplantation, donor-related risks such as disease transmission and graft failure are weighed against the patient's risk of remaining on the waiting list. The patient's commonly inactive role in decision making and the timing and extent of donor-specific risk information have been discussed in the medical literature. This is the first study revealing the opinions of liver patients on these issues. Forty patients listed for liver transplantation and 179 liver transplant patients participated in an anonymous questionnaire-based survey. The majority of the patients wanted to be informed about donor-related risks (59.8%-74.8%). The preferred timing for being informed about donor-related risks was the time of the organ offer for 53.3% of the patients. Among these patients, 79.8% wished to be involved in making the decision to accept or not accept a liver for transplantation, 10.6% wished to make the final decision alone, and only 9.6% did not want to be involved in the decision-making process. Implementing this knowledge through the standardization of the content, the manner of transfer, and the amount of information that we provide to our patients will improve opportunities for shared decision making at different time points during the transplant allocation process. This will enable us to provide the same opportunities and care to every patient on the waiting list. (C) 2014 AASLD