Hypothermic Machine Perfusion for Liver Graft Preservation

Official title

Prospective and Randomized Clinical Study of the Effect of Hypothermic Machine Perfusion on Liver Graft Preservation

Overview

The goal of this clinical trial is to evaluate whether hypothermic machine perfusion improves liver graft preservation and post-transplant outcomes compared to conventional static cold storage in adult patients undergoing liver transplantation. This study focuses on liver grafts from deceased donors, including those with extended criteria, which are more susceptible to ischemia-reperfusion injury and early graft dysfunction. The main questions it aims to answer are: Does hypothermic machine perfusion reduce ischemia-reperfusion injury and improve early graft function after liver transplantation? Does this preservation strategy improve clinical outcomes, including graft survival, complication rates, and post-transplant recovery, compared to static cold storage? Researchers will compare hypothermic machine perfusion (ex situ, oxygenated perfusion at low temperature) to standard static cold storage to assess differences in graft preservation quality and post-transplant outcomes. Participants will: Receive a liver graft preserved either by hypothermic machine perfusion or static cold storage, according to a 1:1 randomization protocol Undergo standard liver transplantation procedures Be followed after transplantation with clinical, laboratory, imaging, and biomarker assessments at predefined time points (7 days, 30 days, 6 months, and 1 year) Additional evaluations will include biochemical markers of liver function, inflammatory and immunological mediators, mitochondrial function assessment, and histological analysis to better characterize graft injury and recovery.

Detailed description

This is a prospective, single-center, randomized controlled clinical trial designed to evaluate the impact of hypothermic machine perfusion on liver graft preservation and post-transplant outcomes in adult liver transplantation.

Liver transplantation is the standard treatment for end-stage liver disease; however, outcomes are strongly influenced by graft quality. The increasing use of extended criteria donors has introduced additional challenges, as these grafts are more susceptible to ischemia-reperfusion injury, a key determinant of early graft dysfunction and post-transplant complications. Conventional static cold storage, although widely used, does not prevent ongoing anaerobic metabolism and progressive depletion of cellular energy stores, contributing to mitochondrial dysfunction, oxidative stress, and inflammatory activation upon reperfusion.

Hypothermic machine perfusion has emerged as an alternative preservation strategy by providing continuous oxygenated perfusion under controlled hypothermic conditions. This approach aims to preserve mitochondrial integrity, reduce metabolic stress, and mitigate ischemia-reperfusion injury, thereby potentially improving graft viability and expanding the utilization of marginal organs.

In this study, liver grafts from deceased donors will be allocated to either hypothermic machine perfusion or conventional static cold storage. Following procurement, grafts assigned to the intervention group will undergo ex situ hypothermic perfusion using an oxygenated preservation solution under controlled conditions, while the control group will follow standard institutional preservation protocols.

All transplant procedures and perioperative management will be conducted according to institutional standards. Post-transplant follow-up will include clinical and laboratory monitoring to assess graft function and detect complications.

Interventions

• Device Hypothermic Machine Perfusion
  Hypothermic machine perfusion of the liver graft is performed prior to transplantation using an ex situ perfusion system under controlled conditions, in which an oxygenated perfusate is circulated through the liver graft vasculature.
• Procedure Static Cold Storage
  Liver graft preservation using conventional static cold storage under hypothermic conditions until transplantation.

Primary outcome measures

• Incidence of Early Allograft Dysfunction (EAD) [Time frame: Within 7 days after transplantation]

Secondary outcome measures (8)

• Change in Liver Function Tests (AST, ALT, Total Bilirubin) [Time frame: At 7 days, 30 days, 6 months, and 1 year after transplantation]
• Incidence of Acute Kidney Injury (AKI) [Time frame: Within 7 days and up to 30 days after transplantation]
• Incidence of Post-Reperfusion Syndrome (PRS) [Time frame: During transplantation procedure]
• Incidence of Post-Transplant Complications [Time frame: Up to 1 year after transplantation]
• Graft Survival [Time frame: Up to 1 year after transplantation]
• Patient Survival [Time frame: Up to 1 year after transplantation]
• Length of Intensive Care Unit Stay [Time frame: From liver transplantation until intensive care unit discharge, up to 30 days]
• Length of Hospital Stay [Time frame: From liver transplantation until hospital discharge, up to 30 days]

Eligibility criteria

Donor-related inclusion criteria:

• Liver donors with confirmed diagnosis of brain death.
• Extended criteria donors (ECD).
• Age ≥18 years.
• Family consent for organ donation obtained.
• Negative serology for HTLV, HIV, Chagas disease, and hepatitis B and C.

Recipient-related inclusion criteria:

• Adult patients (≥18 years) undergoing liver transplantation.
• Diagnosis of end-stage liver disease or indication for liver transplantation.
• Candidates for primary liver transplantation.
• Ability to understand and provide written informed consen

Donor-related exclusion criteria:

• Presence of moderate or severe hepatic steatosis.
• Pediatric donors.
• Donors classified as ideal, defined by the simultaneous presence of all of the following criteria: Age <35 years, Body mass index (BMI) <28 kg/m², No history of cardiopulmonary resuscitation, Norepinephrine requirement <0.5 µg/kg/min, Liver enzymes (AST or ALT) ≥2 times the upper limit of normal, Intensive care unit stay ≤7 days

Recipient-related exclusion criteria:

• Complex portal vein thrombosis (grade III or IV).
• Combined or dual organ transplantation.
• Retransplantation.
• Acute liver failure.
• MELD score >30.
• History of multiple prior liver or biliary surgeries.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP) — São Paulo

Publications

• Czigany Z, Lurje I, Schmelzle M, Schoning W, Ollinger R, Raschzok N, Sauer IM, Tacke F, Strnad P, Trautwein C, Neumann UP, Fronek J, Mehrabi A, Pratschke J, Schlegel A, Lurje G. Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications. J Clin Med. 2020 Mar 20;9(3):846. doi: 10.3390/jcm9030846. PMID 32244972
• Patrono D, Surra A, Catalano G, Rizza G, Berchialla P, Martini S, Tandoi F, Lupo F, Mirabella S, Stratta C, Salizzoni M, Romagnoli R. Hypothermic Oxygenated Machine Perfusion of Liver Grafts from Brain-Dead Donors. Sci Rep. 2019 Jun 27;9(1):9337. doi: 10.1038/s41598-019-45843-3. PMID 31249370

Identifiers

NCT: NCT07595627 · 7.497.991 · 2025/08106-0

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗