title: The use of pre-implantation perfusion techniques of kidney grafts to increase organ utilisation and the investigation of regenerative cell therapy
Creators: name: Pearson, Robert
Publisher: name: University of Glasgow
Year: 2024

description: Despite the advancements in solid organ transplantation, including an ever-increasing living donation programme, there remains a significant shortfall of utilisable grafts to meet the demand. In the United Kingdom, NHS Blood and Transplant released a mission statement entitled “2030: Meeting the Need," highlighting key areas to focus efforts on and tailor technologies. Within this statement, organ utilisation was highlighted as a critical area for improvement and development.

There have been significant developments in recent years with regard to deceased donation in how organs are assessed, transported and prepared for transplantation with organ utilisation in mind. Despite these advancements, the rate of organ decline remains high, and tools and technologies that allow clinicians to assess organs, providing more confidence to accept and utilise offered organs, are vital to improving our utilisation rates. Furthermore, pre-implantation therapeutics may improve grafts from those deemed unsuitable for transplantation to those considered utilisable in certain circumstances.

Ex-vivo normothermic perfusion (EVNP) is one such technology that delivers warmed, oxygenated blood with added nutrients to a kidney graft before implantation, allowing for a period of assessment, and potentially mitigates against some of the critical issues within deceased donation, such as ischaemic reperfusion injury.

The implementation of a clinical EVNP service is then described. Herein we describe the mechanisms by which the technology was introduced as a clinical service to assess the viability of marginal grafts, including the requisite training and trust approval. Obstacles and pitfalls are also discussed, including the sourcing of blood products, staffing considerations and the perfusion of grafts with variant anatomy.

This thesis first outlines the risks evident when high-risk donor kidneys and recipients combine. Retrospective analysis demonstrated that although graft survival and function are satisfactory, this high-risk combination is associated with delayed graft function, prolonged length of stay in hospital and increased use of secondary care within the first 90 days posttransplant.

This is followed by a report of the successful implantation of seven kidneys as a result of this novel assessment tool. This includes grafts in the deceased donor setting with severe acute kidney injury, poor perfusion and in the context of dual kidney transplantation. Furthermore, the use of this technology to assess arterial reconstruction in two cases of living donor nephrectomy for renal artery stenosis is detailed. To our knowledge, this series includes examples of world-firsts in the use of this technology to expand the donor pool of utilisable grafts.

A systematic review is then conducted which sets the scene for a study in which adiposederived regenerative cells (ADRC), harvested from donor peri-renal tissue, were delivered via EVNP technology to discarded human kidneys. Perfusion characteristics and urine output were unchanged with ADRC treatment, as were histological features of acute tubular injury. RNA sequencing, however, highlighted differential gene expression to guide further mechanistic evaluation. Of note, no adverse events were found with the delivery of this regenerative therapy.

In summary, EVNP is a valuable assessment tool in transplantation decision-making, with the potential to improve organ utilisation. Furthermore, it provides an opportunity to deliver therapeutic agents, such as regenerative cell populations, as described herein.