Pre-transplant normothermic liver perfusion
Research type
Research Study
Full title
Development of pre-transplant normothermic perfusion reconditioning for human livers donated after circulatory death
IRAS ID
143096
Contact name
Christopher JE Watson
Contact email
Sponsor organisation
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
Research summary
Summary of Research
Liver transplantation is the only life saving treatment for patients with irreversible liver failure. However, due to a chronic shortfall in organ donors and an annually increasing demand only selected patients can be listed for liver transplantation in the UK. Each year, 10-15% of wait-listed patients will either die or deteriorate to the extent they have to be removed from the waiting list before transplantation. To increase the donor pool, organs from donors who have died following
circulatory arrest are being increasingly used and such donors comprise up to 40% of all deceased organ donors in the UK. Livers procured in this manner suffer a long period without blood circulation before they can be cooled down causing depletion of the cellular energy stores and tissue injury. The latter is accentuated by the ensuing period of cold storage. These livers may not function following transplantation and have higher complication risk; consequently, only 30% are currently accepted for transplantation compared to 85% of livers donated after brain death.
The aim of the proposed study is to examine the potential of machine perfusion of deceased donor livers, using oxygenated blood at normal body temperature, to minimise the effects of tissue ischaemia and recondition the liver before transplantation. A series of experiments will be performed using livers procured for transplantation and then deemed unusable. The perfusion parameters, duration and perfusion fluid characteristics required for optimal liver reconditioning and the best molecular markers to enable assessment of liver suitability for transplantation will be determined. The research findings will form the basis for future clinical implementation of normothermic liver perfusion within the context of a clinical trial. Knowledge gained form this study may enable clinicians to utilise more deceased donor livers, especially from donors after circulatory death, and improve outcomes following liver transplantation.Summary of Results
The study placed livers turned down for transplantation onto a machine to restore a blood based circulation, thus trying to mimic the situation in the body had they been transplanted. When the study started normothermic (ie at normal body temperature) ex situ (out of the body) liver perfusion (NESLiP) was very new, and had only occurred clinically in two hospitals in the UK. Our study had several intended and unintended spinoffs
1. We were able to define criteria that were associated with a liver that was likely to work well post transplantation. This has enabled us to test and transplant more livers than we were previously able to, because we can now be confident they will function.
2. We showed the importance of measuring the chemistry of bile as a marker of the how well preserved the bile ducts are – these are the tubes taking bile from the liver to the gut.
3. We have shown that fibrin clots form in bile ducts of the liver while it is stored in ice, and that these can be flushed out with the help of alteplase (a clot busting drug)
4. We have been able to show that livers have a similar inflammatory profile during ex situ perfusion as kidneys and lungs, and that this is modified by use of filters which remove inflammatory messengers (cytokines) and cells (leucocytes) from the circulation.
5. We have shown which amino acids are preferentially consumed, and which are not, and now use that as the basis for our additives during clinical perfusion to feed the livers.
6. Some of our objectives were not able to be met. We could not get sufficient fresh human whole blood in a timely manner to simulate transplantation after a period or perfusion
7. The study has triggered several other studies, two of which we have running at present examining different treatments to transplanted livers, which are a less heterogeneous group than discarded livers.REC name
East of England - Cambridge East Research Ethics Committee
REC reference
14/EE/0137
Date of REC Opinion
25 Apr 2014
REC opinion
Favourable Opinion