HOPE for ECD liver allografts

The first human orthotopic liver transplantation (OLT) was performed by Starzl et al. in 1963 and has evolved as the standard treatment approach for end-stage liver disease [1]. In 2015, approximately 1500 patients were listed for liver transplantation in Germany, however only 894 transplants were performed due to organ shortage [2]. To increase the availability of organs and reduce waiting list mortality, graft acceptance criteria were extended increasingly over the decades which has also led to an increased incidence in graft related complications, such as ischemic cholangiopathy [2].

As such, several strategies have been developed aiming at “reconditioning” poor quality extended criteria grafts [3-9]. Hypothermic oxygenated machine perfusion (HOPE) has been tested intensively in pre-clinical animal experiments [3]. The positive effects of HOPE in this setting have been demonstrated among others to reduce incidence of biliary complications, mitochondrial damage and level of cellular energy- status [3]. In the HOPE setting, organ perfusion is performed in the transplant center shortly before the actual implantation using an extra corporal organ perfusion system with full oxygen saturation over the portal vein [3]. The first clinical study with this promising technique was published recently in a Swiss cohort of patients who received organs from donation after cardiac death (DCD) [10]. In organ donation after brain death (DBD), the only legally accepted approach for organ donation in Germany and many other European countries, HOPE and its effect on early graft function and postoperative complications has not been reported yet [2].

The purpose of this study is to test the effects of the novel HOPE technique in a prospective randomized clinical trial (RCT) on ECD liver grafts in DBD liver- transplantation (HOPE-ECD-DBD). Twenty-three human whole organ liver grafts will be submitted to 1 hour of HOPE directly before implantation and going to be compared to a Control-group of patients (n=23), transplanted after conventional cold storage. Inclusion criteria are: adult whole liver graft transplantation. Primary (early graft function) and secondary (e.g. postoperative complications, hospital stay, survival) objectives are going to be analysed. Alterations in various cellular markers will be assessed using routinely harvested liver tissue samples. Follow-up is determined in 12 months.

DCD has been introduced to ease organ shortage. In general, DCD transplantation has an inferior outcome and it is not accepted legally and ethically in several countries, among others in Germany. Despite its benefits demonstrated in pre- clinical studies, HOPE is still not generally recognized within the transplant community, due to the lack of clinical data in DBD. HOPE ECD-DBD will deliver the first prospective clinical data on HOPE machine perfusion in DBD liver-transplantation.

References:

1. Starzl, T.E. and J.J. Fung, Themes of liver transplantation. Hepatology, 2010. 51(6)

2. Tacke, F., et al., Liver transplantation in Germany. Liver Transpl, 2016.

3. Schlegel, A., P. Kron, and P. Dutkowski, Hypothermic machine perfusion in liver transplantation. Curr Opin Organ Transplant, 2016. 21(3): p. 308-14

4. Marecki, H., et al., Liver ex-vivo machine perfusion preservation: A review of the methodology and results of large animal studies and clinical trials. Liver Transpl, 2017.

5. Gurusamy, K.S., H.D. Gonzalez, and B.R. Davidson, Current protective strategies inliver surgery. World J Gastroenterol, 2010. 16(48): p. 6098-103.

6. Burlage, L.C., et al., Oxygenated hypothermic machine perfusion after static cold storage improves endothelial function of extended criteria donor livers. HPB (Oxford), 2017.

7. Minor, T. and A. Paul, Hypothermic reconditioning in organ transplantation. Curr Opin Organ Transplant, 2013. 18(2): p. 161-7.

8. Compagnon, P., et al., An Oxygenated and Transportable Machine Perfusion System Fully Rescues Liver Grafts Exposed to Lethal Ischemic Damage in a Pig Model of DCD Liver Transplantation. Transplantation, 2017.

9. Ceresa, C.D.L., et al., Cold storage or normothermic perfusion for liver transplantation: probable application and indications. Curr Opin Organ Transplant, 2017. 22(3): p.300-305.

10. Dutkowski, P., et al., First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An international-matched Case Analysis. Ann Surg, 2015. 262(5): p. 764-70; discussion 770-1.