PROTECTING KIDNEYS FROM ISCHEMIC INJURY

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Currently the major cause of acute renal failure in man is ischemic insult to the kidneys. In the proposed studies we will evaluate and develop new protective solutions, drugs, and techniques which have the potential of significantly reducing or eliminating the acute renal failure associated with warm or cold renal ischemia. Based in part on principles which were outlined in our previously revised proposal, we have recently developed an in situ flushing solution which will completely prevent the acute renal failure associated with one hour of warm ischemia to the kidneys. In the proposed studies, we will further test the potential of this warm flushing solution and attempt to improve it through the use of other potentially more effective osmotic agents and drugs. Pilot investigations have suggested that simple intravenous administration of certain drugs or osmotic agents can also effectively reduce postischemic acute renal failure better than other currently available pretreatments. We will therefore test these compounds both alone and in specific combinations to study their ability to reduce renal damage resulting from warm ischemia to kidneys. The most effective of the foregoing drugs and/or osmotic agents will also be used in combination with ATP-MgCl2, a compound which will accelerate recovery of renal cells from ischemic injury. Pilot transplantation studies, extensive morphological studies, and the success of our warm flushing solution all suggest that our recently developed cold flushing and storage PBSucrose solutions are probably superior to other cold storage solutions which are currently used to preserve kidneys prior to their transplantation. In the proposed studies, we have therefore outlined studies to evaluate the post-transplantation function of kidneys stored in this new solution. In addition, it appears not unlikely that we may be able to further improve this cold storage solution through the use of (1) more effective osmotic agents, (2) drugs which also prevent cell swelling, and (3) the addition of ATP-MgCl2 which may be able to ameliorate the effects of cold as well as warm ischemic damage. All the foregoing proposed techniques, solutions, and compounds to be tested are supported by prior published investigations and pilot studies. Together, it is believed that these studies will result in the development of new and very effective ways to reduce the acute renal failure associated with either warm or cold iscemia.