Using minimal Factor H therapy and normothermic conditions to prepare kidneys for transplantation

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Kidney transplant is the gold-standard treatment for patients with renal failure. However, the supply of organs is limited in number and quality. This has necessitated the transplantation of kidneys from donation after the donors death or from non-optimal donors that are associated with increased risks. These kidneys are associated with prolonged times without adequate oxygen supply and increased cellular damage resulting in increased organ injury immediately after transplant. This can shorten the long-term survival of the kidney and result in patients requiring another transplant, compounding the organ shortage crisis.We have developed a novel anti-complement therapy based on a blood defence protein called factor H and one of its related proteins. Our drug is called HDM-FH (homodimeric minimal factor H). HDM-FH has been found to be highly effective in experimental rodent models of kidney disease. HDM-FH should have a clear use in transplantation. The complement system normally protects against invading pathogens and helps to clear cellular waste in our bodies. However, complement can become over active and it drives inflammation. In transplantation, the transplanted organ can be detected as non-self (like a pathogen) and activation of complement can lead to organ rejection. This rejection can be immediate or can take years due to complex processes that are triggered by the complement activation. Thus, preventing complement activation and associated cellular/organ injury during the first minutes of transplantation will significantly prolong the survival of transplanted organ and the well being of the transplant recipient. In Newcastle, we are working on methods to improve the function of kidney through a technique call ex vivo normothermic machine perfusion (EVNP for short), i.e. organs destined for transplant are warmed up with oxygenated blood flow in the lab and allowed to recover from the shock of being transported between hospitals (in cold liquids with no oxygen) prior to organ transplant. EVNP has shown promise in the re-conditioning of organs that might otherwise have been deemed unfit for transplant. Our plan is to try to further improve the outcome of transplanted organs after EVNP by using this system to introduce our anti-complement drug to the kidney, where it can bind and wait until the organ is transplanted into the recipient. Upon transplant, HDM-FH will then act as an organ defence against the recipients immune system. In this study, we will model exposure of human (discarded human kidneys - deemed unfit for transplant by transplant surgeons) and pig kidney (similar size etc to human, readily available from farm production) to the drug and assess how well it remains bound to the organ during EVNP. We will then model, by using whole blood in the EVNP system in the lab, whether we can show complement activation on the organ and that our drug can reverse that. After the successful completion of these experiments, we would use EVNP of pig kidney and transplantation into a small number of pigs (up to 12) to test our drugs in as robust a fashion as possible. These pig transplant experiments (in conjunction with existing data on pig kidney EVNP) would provide important evidence of the ability of our anti-complement drug to protect kidney in a whole animal system. We will be able to assess safety of the drug and any unexpected events with its use. These studies would guide us in the steps to testing these drugs in human transplant studies. Additionally, the success of these drugs in protecting kidneys from complement could lead to the use of the drugs in other situations where complement needs to be controlled, such as the rare kidney disease, C3G.Overall, this research is designed to lead to better organ transplant success, even from organs which are considered borderline for transplant. It will eventually be of significant benefit to the many thousands of people waiting on a renal transplant.