Long-term liver preservation technology shows promise for daytime transplantation

In a recent study published in e-clinical medicine, researchers conducted a phase II clinical trial evaluating the safety and feasibility of prolonged double hypothermic oxygenation machine perfusion (DHOPE) to extend preservation of human donor livers by 20 hours, and specifically The aim is to promote daytime donation for donor livers after brain death (DBD). transplant.

study: Prolonged hypothermic machine perfusion enables daytime liver transplantation – an ideal stage 2 prospective clinical trial. Image credit: Dmitry Kandinsky / Shutterstock.com

save organs for transplant

Liver transplantation is an important emergency procedure because the donor liver deteriorates when stored on ice. Long-term liver preservation is critical for logistics and organ waste reduction.

DHOPE can improve transplant outcomes by reducing ischemia-reperfusion injury. Preclinical evaluations have reported that DHOPE can extend preservation by up to 24 hours, and multicenter observational cohort studies have shown excellent outcomes for preserved liver transplantation. However, the prolongation of DHOPE requires further evidence for widespread clinical application.

About research

In this prospective study, researchers are comparing the safety and feasibility of long-term DHOPE treatment to conventional DHOPE treatment for brain-dead donor livers to enable next-day transplantation.

The study was conducted at the University Medical Center Groningen (UMCG). The researchers divided the livers into two groups based on donor liver resection completion time: extended DHOPE of at least 4 hours and conventional DHOPE of 1 to 2 hours.

Participants included adults undergoing only liver transplants and excluded those with high-accuracy conditions, Model for End-Stage Liver Disease (MELD) scores >3, or multiple organ transplants. Individuals receiving grafts due to post-circulatory death, donors weighing less than 40 kg, untreated hepatitis B, hepatitis C, human immunodeficiency virus (HIV) infection, or graft steatosis account for 30% Donors with more than 10% were also excluded from the study.

The safety endpoint was defined as a composite measure of serious adverse events (SAEs) during long-term conventional DHOPE up to 30 days after liver transplantation. The feasibility endpoint was defined as successful long-term DHOPE therapy perfused liver transplantation.

Secondary endpoints of the study included patient survival, biliary complications, incidence of acute kidney injury, graft function analysis, intensive care unit (ICU) and non-ICU length of stay, perfusion factors during DHOPE, Clavien – Major types of postoperative complications indicated by Dindo grade were included. 3b or higher, and comprehensive comorbidity index score after 30 days.

The DHOPE device enabled liver perfusion through the hepatic artery and portal vein using two pumps and a pressure control system with automatic flow adjustment. Perfusion pressures were 3 to 5 millimeters (mm) of mercury in the portal vein and 18 to 25 mm of mercury in the hepatic artery, and flow rates were 50 to 200 mL/min in the portal vein and 20 to 80 mL/min in the hepatic artery.

Cell-free deoxyribonucleic acid DNA (cfDNA), D-dimer, tissue plasminogen activator (tPA), and thiobarbituric acid-reactive substances (TBARS) levels in plasma and perfusate were determined by adenosine trinucleotides in liver grafts. It was measured along with phosphate (ATP) concentration.

Intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), high mobility group box 1 (HMGB-1), and hyaluronic acid levels in perfusate was also measured. Measured using enzyme-linked immunosorbent assay (ELISA). Liver biopsies were used for immunohistochemical analysis of caspase-3 and von Willebrand factor (VWF) expression.

research result

From November 1, 2020 to July 16, 2022, 24 people were enrolled in the study with a 1:1 ratio in study groups. Median liver preservation time was 15 hours for long-term His DHOPE recipients and 8 hours for conventional His DHOPE recipients.

Three patients in both groups experienced SAEs within 30 days after transplantation. However, no significant differences in liver transplant-related complications or patient and graft survival were observed between groups.

All participants in the long-term and control groups underwent liver transplantation with their respective DHOPE perfusions. The extension group had shorter operative time and higher risk of biliary anastomotic stricture after 19 months.

Despite a minimum follow-up period of 1 year, none of the grafts showed signs of non-anastomotic biliary stricture. In all study participants, patient and graft survival rates at 1 year after liver transplantation were 100%. However, 3 long-term DHOPE recipients experienced acute kidney injury, whereas 5 control patients experienced postoperative complications.

During long-term DHOPE, ischemia-reperfusion injury markers such as cfDNA, lactate, IL-6, and TNF-α were slightly increased in the perfusate, whereas oxidative stress markers such as TBARS, HMGB-1, and ICAM-1 markers were not affected. Endothelial damage markers were not increased. However, D-dimer and his VWF levels increased. ATP levels in liver biopsies were higher after long-term DHOPE compared to controls.

Serum markers of ischemia-reperfusion injury, oxidative stress, and endothelial injury did not differ between groups after reperfusion. However, median serum IL-6 levels were slightly higher in long-term DHOPE recipients compared to conventional DHOPE recipients after surgery.

Postoperative days showed no biochemical differences between groups. However, alkaline phosphatase (ALP) levels were higher in controls. Histology showed that the liver was intact and the neutrophils were indicative of surgical hepatitis.

conclusion

Study results demonstrate the feasibility and safety of DHOPE therapy, which extends donor liver preservation and allows daytime transplantation. Using a temperature of 10 °C can extend storage time to 20 hours, potentially revolutionizing liver transplantation.

There were no significant adverse events, and the patient did not have any signs of non-anastomotic biliary stricture. DHOPE can provide training opportunities for transplant teams and promote a healthier work-life balance while optimizing logistical efficiency, improving performance, and reducing night surgeries.