The role of heat shock protein 90 inhibition as a novel means of modulating ischemia/reperfusion injury in the kidney

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BACKGROUND The kidneys are a pair of organs in the abdomen that are essential to life. They function to excrete waste products, as well as maintaining salt water balance and blood pressure. Progressive and irreversible reduction in kidney function over time is termed chronic kidney disease (CKD).While conservative management of CKD is successful in the early stages of the disease, some patients will unfortunately progress to end-stage (or established) renal disease (ESRD), which is the most severe form of CKD and is defined as an irreversible decline in kidney function that is severe enough to be fatal in the absence of either dialysis or transplantation. Dialysis is a process that substitutes for the kidneys in the tasks of filtering blood and removing waste products while kidney transplantation is an operative procedure to transfer a healthy kidney from a donor to a recipient who has kidney failure. Collectively these two treatments are known as renal replacement therapy (RRT).In the UK the number of patients on RRT is rising rapidly and between 2000 and 2006 increased by 35%. By 2009 the rate of persons commencing RRT in the UK was 109 per million of the population. For many of these patients kidney transplantation is the treatment of choice as it not only offers freedom from daily or alternate day dialysis, but leads to increased survival, quality of life and is cheaper for the health service. However, kidney transplantation is a victim of its own success and currently the number of patients awaiting a kidney transplant far outweighs the availability of donor organs. This problem is compounded by the fact that due to the technical process of transplantation 10% of kidneys never work and 40% have delayed function. This leads to patients either dying or being forced back onto dialysis, which is devastating for those who have waited many years to receive their transplant in the first place. Even for patients whose transplanted kidneys recover from a delay in graft function there is an adverse impact on the long term outcome of their transplanted kidney.Our research group seeks to identify drugs that may reduce organ injury caused by the transplantation procedure. We have identified a promising candidate drug that reduces damage in both kidney cells and mouse kidneys in experiments simulating the injury sustained during transplantation. We wish to study this drug in human transplant patients, but prior to this wish to establish exactly how it works.METHODSThe research will be conducted in the University of Edinburgh by a medical doctor with a research background who is training to be a Transplant Surgeon. He will be supervised by a Professor in Transplant Surgery, a Professor in Renal Medicine and a Professor of Cell Biology. Work will begin in a mouse model, where protective drug treatment will precede the clamping of the blood supply to one kidney and the removal of the other kidney, after which the mouse will recover. This is analogous to the injury caused to the organ during the transplantation procedure. The kidneys and blood from these mice will be analysed using various investigative techniques to determine the mechanism by which the drug protects the kidney. Work will then be extended to kidney cells in the laboratory. The effect of the drug on cellular behaviour of white blood cells, immune cells and kidney cells will be examined as well as the interaction between these cells. We will also evaluate cellular pathways causing inflammation as it is likely that one or more of these pathways is blocked by this drug. Cells will also be subjected to stresses similar to that of an organ being transplanted and the effects of the drug on inflammation pathways measured.