Defatting of donor transplant livers Surgery
Conditions
Interventions
bile composition
vascular flows
perfusate pH
glucose metabolism
In the proposed multi-centre pilot clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim t
transaminase levels.
Clinical secondary endpoints will include: proportion of livers transplanted in the 2 arms, graft function
cell-free DNA (cfDNA) at follow-up visits (cfDNA has been correlated with allograft injury, rejection and formation of de novo donor specific antibodies)
patient and graft survival
hospital and ITU stay
evidence of ischemia-reperfusion injury (IRI)
ischaemic cholangiopathy
recurrence of steatosis (determined on MRI at 6 months).
Mechanistic secondary endpoints will include histological quantification of steatosis sequentially during perfusion and following reperfusion
Sponsors
University of Oxford
Eligibility
Sex/Gender
All
Age
18 Years to 110 Years
Inclusion criteria
Inclusion criteria: Donor Livers: 1. Donors aged 18 years or over 2. Offered through the national offering scheme and accepted by participating liver transplant centre 3. Moderate-severe steatosis: macroscopic characteristics based on colour, texture, rounded edges, size and weight at point of inspection at the transplant hospital to confirm suitability for randomisation. Where available, the results of clinical biopsies demonstrating moderate-severe steatosis (> 30%) will also be taken into account to assess suitability for randomisation. Liver transplant recipients: 1. Recipients 18 years of age or above 2. Elective waiting list at a participating centre 3. Willing to consent for inclusion into the study and collection and use of their data
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 17/10/2023: Donor Livers: 1. Donors from outside of the UK 2. Donor is HIV, hepatitis B or C positive 3. Cold ischaemia time (CIT) expected to exceed > 10 hours 4. Macroscopic evidence of fibrosis 5. Livers undergoing any other form of ex-situ machine preservation 6. Participating centre cannot offer NMP due to device, logistical or staffing reasons Liver transplant recipients: 1. Receipt of a liver that has not undergone randomisation 2. Receipt of super urgent transplant for acute liver failure 3. Receipt of a split liver transplant 4. Receipt of a multi-organ transplant 5. Transplanted outside of the participating centres 6. Contra-indication to MRI e.g. pacemaker _____ Previous exclusion criteria: Donor Livers: 1. Donors from outside of the UK 2. Donor is HIV, hepatitis B or C positive 3. Cold ischaemia time (CIT) expected to exceed > 10 hours 4. Macroscopic evidence of fibrosis 5. Livers undergoing normothermic regional perfusion (NRP) 6. Livers undergoing any other form of ex-situ machine preservation 7. Participating centre cannot offer NMP due to device, logistical or staffing reasons Liver transplant recipients: 8. Receipt of a liver that has not undergone randomisation 9. Receipt of super urgent transplant for acute liver failure 10. Receipt of a split liver transplant 11. Receipt of a multi-organ transplant 12. Transplanted outside of the participating centres 13. Contra-indication to MRI e.g. pacemaker
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary endpoint is the proportion of livers that achieve all of the following functional criteria at 6 hours of perfusion, as defined by: 1. Clearance of lactate to a level <2.5mmol/L 2. Perfusate pH =7.20 3. Evidence of glucose metabolism (spontaneous fall in perfusate glucose) 4. Minimum bile pH =7.5 (if bile produced) 5. Bile glucose concentration =3 mmol/L or =10 mmol less than perfusate glucose 6. Hepatic arterial flow =100ml/min; portal venous flow =500ml/min 7. Perfusate alanine aminotransferase (ALT) <6000U/L at 6 hours These objective criteria, reflecting hepatic metabolism and injury, have been derived by a process of consensus amongst current NMP users and are increasingly recognised as a way to discriminate livers with favourable post-transplant outcomes. These parameters are not intended as an instruction to the implanting surgeon, but rather as a consistent endpoint for the trial. The decision as to whether a liver is actually transplanted will remain with the implanting surgeon, who will base this on a number of criteria, including some that are recipient-related rather than donor organ-related (e.g. the urgency with which the patient needs a transplant may determine the decision). | — |
Secondary
| Measure | Time frame |
|---|---|
| Clinical secondary endpoints: 1. Proportion of livers transplanted in the 2 arms, graft function; 2. Cell-free DNA (cfDNA) at follow-up visits (cfDNA has been correlated with allograft injury, rejection and formation of de novo donor specific antibodies); 3. Patient and graft survival; 4. Hospital and ITU stay; 5. Evidence of ischemia-reperfusion injury (IRI); 6. Ischaemic cholangiopathy; 7. Recurrence of steatosis (determined on MRI at 6 months). Mechanistic secondary endpoints (analysed subsequent to the main clinical outcomes): Histological quantification of steatosis sequentially during perfusion and following reperfusion (in recipients). We will measure markers of hepatic lipid metabolism, allograft injury (cfDNA) and cytokines implicated in ischaemia-reperfusion injury (IRI) during ex-situ perfusion and peri-operatively (prior to and following reperfusion in the recipient). RNA sequencing, proteomic and glycomic analysis will investigate the effect of defatting on the expression of genes and proteins associated with post-transplant outcome, testing proposed viability markers for use in future studies and/or clinical practice. | — |
Countries
England, United Kingdom
Contacts
Public Contact- Study team
Outcome results
None listed