The discrepancy between the supply of cadaver kidneys for transplantation and demand from potential recipients with renal failure is increasing steadily. As a result, new organ sources are being sought which include those from older or brain dead hypertensive individuals. There is also growing appreciation that the clinical results of grafted kidneys from such """"""""marginal"""""""" donors may be relatively unsatisfactory over both the short and long term. The importance of this concept has been reinforced by the observation that the survival rate of kidneys from living unrelated sources are similar to those of one haplotype matched living-related donors and significantly better than those of randomly matched cadaver transplants. The overall hypothesis of the proposed study is that kidneys from brain dead and marginal donors may be biologically """"""""activated"""""""", triggering inflammatory responses which, in turn, may amplify later host alloresponsibeness. The major focus of these investigations is to define the influence of these donor perturbations on later graft behavior, using an integrated, physiological, cellular and molecular approach. In the initial series of experiments, the effects of brain death, altered systemic hemodynamics and their correction by pressor on the expression of cell adhesion molecules and cytokines in the kidney will be examined. Circulating factors putatively responsible for such changes will be defined in vivo and in vitro. Secondly, mechanisms whereby kidneys from marginal donors may develop increased susceptibility to transplant associated injury will be determined; we hypothesize that the extent of activation of the kidney before removal from the donor will relate to the severity of ischemia/reperfusion injury and acute rejection after engraftment. Thirdly, specific interventions which target surface molecules, cytokines and T cell activation will be used to define their roles in injury mechanisms and to assess their potential usefulness in designing future therapies. By understand the determinants of these potentially altered kidneys as well as defining means to modulate them, it may be possible to improve success of grafts from brain dead and marginal donors and ultimately expand the existing donor pool.
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