Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation (DHOPE-DCD)

Dual Hypothermic Oxygenated Perfusion of DCD Liver Grafts in Preventing Biliary Complications After Transplantation

A Multicenter Randomized Controlled Trial to Compare the Efficacy of End-ischemic Dual Hypothermic Oxygenated Perfusion With Standard Static Cold Storage of Liver Grafts Donated After Circulatory Death in Preventing Biliary Complications

Erasmus Medical Center, Leiden University Medical Center, Universitaire Ziekenhuizen KU Leuven, University Hospital, Ghent, King's College Hospital NHS Trust

Rationale: Recent publications report good results of controlled donation after circulatory death (DCD) Maastricht category III liver transplantation when strict donor-recipient matching is applied and ischemia times are kept to a minimum. However a major concern remains the high rate of biliary complications after transplantation of DCD livers. Non-anastomotic biliary strictures (NAS) occur in 29% of patients receiving a DCD graft whereas the incidence of NAS in recipients of donation after brain death (DBD) liver grafts is 11%. NAS are associated with higher morbidity and increased cost of liver transplantation. Injury to the biliary epithelium and the peribiliary vascular plexus occurring during donor warm ischemia and static cold storage (SCS) has been identified as a major risk factor for development of NAS. Machine perfusion has been proposed as an alternative strategy for organ preservation, offering the opportunity to improve the quality of the organ by providing oxygen to the graft. Experimental studies have shown that end-ischemic dual hypothermic oxygenated machine perfusion (DHOPE) helps liver grafts to recover from ischemia by restoring mitochondrial function. Moreover, DHOPE has been shown to provide better preservation of peribiliary vascular plexus of the bile ducts, which could be an important step forward in reducing the incidence of NAS after transplantation. Objective: To study the efficacy of end-ischemic DHOPE in reducing the incidence of NAS within six months after controlled DCD (Maastricht category III) liver transplantation. Study design: An international, multicenter, prospective, randomized, controlled, interventional, clinical trial with a two parallel arm approach (treatment/control). Study population: Adult patients (≥18 yrs old) undergoing a liver transplantation with a liver graft procured from a controlled DCD donor (Maastricht category III) with a body weight ≥40 kg. Intervention: In the intervention group liver grafts will be subjected to two hours of hypothermic, oxygenated perfusion at the end of SCS and before implantation. In the control group donor liver grafts will be preserved in accordance to standard practice by SCS only. Main study parameters/endpoints: The incidence and severity of symptomatic NAS as diagnosed by an Adjudication committee (who are blinded for the group assignment) by means of magnetic resonance cholangiopancreatography (MRCP).

The liver is procured with a segment of supratruncal aorta. The intervention is restricted to the liver graft after arrival in the transplant center and before implantation. The donor liver is subjected to 2 hours of hypothermic oxygenated perfusion via the portal vein and the supratruncal aorta applied by the Liver Assist®. Before perfusion, the liver is flushed via the portal vein with 1 L Belzer machine perfusion solution. The perfusion is pressure controlled and set to a mean of 25 mmHg (arterial) and 5 mm Hg (portal). The perfusion fluid is 4 L Belzer machine perfusion solution with additional 3 mmol/L glutathione. The perfusion fluid is 12°C, when the temperature is set at 10°C. The oxygen flow is set at 0.5 mL/min of 100% oxygen on each of the two membrane oxygenators.

The donor liver is procured with a segment of 5 cm circular supratruncal aorta left attached to the coeliac trunc. The patients randomized to the control group will receive a liver graft preserved by conventional SCS without any further intervention.

The perfusion fluid is Belzer machine perfusion solution University of Wisconsin (Bridge-to-Life, Ltd., Northbrook, IL).

Glutathione in a dosage of 3 mmol/ is added to the perfusion fluid according to the intention of use of the perfusion fluid.

NAS is defined as all of the following criteria: any irregularities or narrowing of the lumen of the intra- or extrahepatic donor bile ducts, but not at the anastomosis which are diagnosed by cholangiogram (preferably by MRCP) in the presence of a patent hepatic artery demonstrated by Doppler ultrasonography and if necessary, by computed tomography angiography and as assessed by the Adjudication Committee when imaging is indicated by clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up

Asymptomatic NAS is defined as all of the following: irregularities or narrowing of the lumen of the intra- or extrahepatic donor bile ducts, but not at the anastomosis which are diagnosed by cholangiogram (preferably by MRCP) in the presence of a patent hepatic artery demonstrated by Doppler ultrasonography and if necessary, by computed tomography angiography in the absence of clinical signs (i.e., jaundice, cholangitis) or elevation of cholestatic laboratory parameters in blood samples taken during follow-up

Severity and location of NAS is based on assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al. And required treatment for NAS (i.e. ursodeoxycholic acid, ERCP, retransplantation)

Assessment of the images of the MRCP obtained in all patients at six months after transplantation (time window of 15 days) which will be performed based on a scoring system described by Buis et. al.

Defined as liver failure requiring retransplantation or leading to death within seven days after transplantation without any identifiable cause such as surgical problems, hepatic artery thrombosis, portal vein thrombosis and acute rejection

Defined as a modification of the Olthoff criteria: Prothrombin time/ international normalized ratio (INR) >1.6 and or serum total bilirubin >10 mg/dL on postoperative day 7

serum levels of alanine aminotransferase (ALT), AST, alkaline phosphatase (AlkP), gamma-glutamyl transferase (γGT), and total bilirubin

Length of initial ICU and initial hospital stay is determined in days of admission following liver transplantation. Duration of follow-up hospital stay is determined in days of hospital admission after discharge and up to six months after liver transplantation

Estimated glomerular filtration rate (eGFR) according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation

Symptoms of diabetes and random plasma glucose ≥11.1 mmol/L. Symptoms include polyuria, polydipsia, and unexplained weight loss. OR Fasting plasma glucose ≥7.0 mmol/L. Fasting is defined as no caloric intake for at least eight hours. OR Two-hour plasma glucose ≥11.1 mmol/L during an oral glucose tolerance test. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

Inclusion Criteria: Adult patients (≥ 18 years old) Signed informed consent Willing and able to attend follow-up examinations Donor liver graft from a controlled donation after circulatory death (Maastricht category III) Donors with a body weight ≥40 kg Exclusion Criteria: Simultaneous participation in another clinical trial that might possibly influence this trial Mental conditions rendering the subject incapable to understand the nature, scope and consequences of the trial Listed for liver transplantation due to fulminant liver failure or retransplantation because of primary non-function Recipient positive test for HIV Donor positive for HIV antigen, hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody Simultaneous transplantation of another organ Patients with contra-indications for MRCP (i.e. pacemaker)

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van Rijn R, van den Berg AP, Erdmann JI, Heaton N, van Hoek B, de Jonge J, Leuvenink HGD, Mahesh SVK, Mertens S, Monbaliu D, Muiesan P, Perera MTPR, Polak WG, Rogiers X, Troisi RI, de Vries Y, Porte RJ. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol. 2019 Mar 12;19(1):40. doi: 10.1186/s12876-019-0956-6.