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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046190-25
Application #
2749488
Study Section
Special Emphasis Panel (ZRG7-SSS-X (79))
Project Start
1982-08-01
Project End
2000-07-31
Budget Start
1998-08-25
Budget End
1999-07-31
Support Year
25
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Harvard University
Department
Surgery
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Gasser, Martin; Waaga-Gasser, Ana Maria; Grimm, Michael W et al. (2005) Selectin blockade plus therapy with low-dose sirolimus and cyclosporin a prevent brain death-induced renal allograft dysfunction. Am J Transplant 5:662-70
Pratschke, Johann; Paz, Dustin; Wilhelm, Markus J et al. (2004) Donor hypertension increases graft immunogenicity and intensifies chronic changes in long-surviving renal allografts. Transplantation 77:43-8
Gasser, Martin; Waaga, Ana Maria; Kist-Van Holthe, Joana E et al. (2002) Normalization of brain death-induced injury to rat renal allografts by recombinant soluble P-selectin glycoprotein ligand. J Am Soc Nephrol 13:1937-45
Laskowski, Igor A; Pratschke, Johann; Wilhelm, Markus J et al. (2002) Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats. J Am Soc Nephrol 13:519-27
Wilhelm, M J; Pratschke, J; Beato, F et al. (2002) Activation of proinflammatory mediators in heart transplants from brain-dead donors: evidence from a model of chronic rat cardiac allograft rejection. Transplant Proc 34:2359-60
Laskowski, Igor A; Pratschke, Johann; Wilhelm, Marcus M et al. (2002) Early and late injury to renal transplants from non-heart-beating donors. Transplantation 73:1468-73
Tilney, N L; Paz, D; Ames, J et al. (2001) Ischemia-reperfusion injury. Transplant Proc 33:843-4
Laskowski, I A; Pratschke, J; Wilhelm, M J et al. (2001) Prolongation of survival and preservation of allograft structure and function by a signaling CD28 mAB in a rat model of chronic kidney rejection. Transplant Proc 33:567-8
Laskowski, I A; Hancock, W W; Pratchke, J et al. (2001) Accelerated graft dysfunction in renal isografts from non-heart-beating donors. Transplant Proc 33:909-10
Pratschke, J; Wilhelm, M J; Laskowski, I et al. (2001) Influence of donor brain death on chronic rejection of renal transplants in rats. J Am Soc Nephrol 12:2474-81

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