Stephen O'Neill

Project Title

The role of heat shock protein 90 inhibitors in modulating ischemia-reperfusion injury in kidney transplantation

Funding

The PhD is funded by:

Tenovus Scotland Small Research Grant, Royal College of Surgeons Edinburgh Small Research Support Grant and Royal College of Surgeons Edinburgh Maurice Wohl Research Fellowship

Mason Medical Research Trust Fellowship and MRC Clinical Research Training Fellowship

Supervisor

This is supervised by Mr Ewen Harrison, Professor Stephen Wigmore, Professor Jim Ross and Professor Jeremy Hughes

Summary

Kidney transplantation is the gold standard treatment for established renal failure; however, an increasing disparity between the number of patients awaiting transplantation and the availability of donor organs exists. One strategy to redress this balance is the use of donation-after-cardiac death (DCD) donors (now 30% of deceased kidney donors). DCD kidneys are an important resource but suffer greater ischemia-reperfusion injury (IRI) than standard brain dead donors as a result of the donation procedure. IRI contributes to a delay in graft function which is associated with poorer graft survival. Our group has shown a reduction in renal IRI using the Hsp90 inhibitor geldanamycin; however, this drug has significant toxicities. We have identified a novel, small molecule Hsp90 inhibitor with activity at nanomolar concentrations and a low toxicity profile in phase II studies. The mechanism of protection by Hsp90 inhibition is unknown and the efficacy of such protection in preclinical models remains to be tested. If administered to donors or directly to the kidney, this drug has the potential to significantly improve outcomes after kidney transplantation. There is currently no active pharmacological agent used at the time of organ donation to reduce IRI. The use of this agent in a clinical setting would therefore be unique.

Publications