The shortage of kidneys is limitation for an effective national renal transplant program. One solution is to use kidneys not now suitable for transplantation, i.e. those exposed to warm ischemia (WI) in the donor. This could increase renal transplants by 20 percent/year. To utilize these kidneys requires new preservation methods specific for WI kidneys. In this study we will develop methods to preserve the WI kidney. We will use a donor model (brain dead dog) to mimic the clinical situation.
Specific Aim 1 will determine the relationship between brain death (BD) and transplant viability, including variables such as time of BD, preservation method, and length of preservation.
Specific Aim 2 will determine if, in a renal transplant model, BD and WI cause greater injury to the kidney than WI by itself. These studies will define clearly the model necessary for the completion of this study.
Specific Aim 3 will define the mechanisms of BD, WI, and preservation injury on the renal vascular (endothelial and smooth muscle cells) and parenchymal cell metabolism. Our hypothesis is that BD and WI, combined with cold preservation 2causes a Ca-dependent disruption of cell metabolism in both endothelial and parenchymal cells leading to increased reactive oxygen metabolite (ROM) generation, and cytoskeletal changes leading to loss of cell viability. We will test this hypothesis in vitro using vascular and parenchymal cell models. We will study how agents that modify Ca metabolism, ROM generation, and cytoskeleton changes affect viability and functions of vascular and parenchymal cells from kidneys exposed to BD, WI, and preservation. We propose that continuous hypothermic machine perfusion of kidneys will reverse some of the consequences of BD and WI that cause irreversible injury, better than simple cold storage.
In Specific Aim 4, we will use the renal transplant model to develop an improved method to preserve the kidney from the BD donor after WI. Our method will be based upon perfusate modifications developed in Specific Aim 3 that are shown to improve preservation of the kidney in our in vitro models. Our goal will be to develop a new method of renal preservation, appropriate for not only the WI kidney, but also kidneys from hypotensive or older donors. This will increase the number of kidneys available for transplantation, and reduce the incidence of delayed graft function and primary nonfunction in both healthy and less-than-ideal donor kidneys.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK018624-28
Application #
6634847
Study Section
Special Emphasis Panel (ZRG1-SAT (02))
Program Officer
Eggers, Paul Wayne
Project Start
1979-04-01
Project End
2004-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
28
Fiscal Year
2003
Total Cost
$431,270
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Knes, Jane M; Hansen, Thomas N; Gilligan, Barbara et al. (2005) Loss of endothelium-dependent relaxation in abdominal aorta preserved in a co-storage system. Transpl Int 17:699-706
Gilligan, Barbara J; Woo, Heung M; Kosieradzki, Maciej et al. (2004) Prolonged hypothermia causes primary nonfunction in preserved canine renal allografts due to humoral rejection. Am J Transplant 4:1266-73
Mangino, Martin J; Ametani, Mary; Szabo, Csaba et al. (2004) Poly(ADP-ribose) polymerase and renal hypothermic preservation injury. Am J Physiol Renal Physiol 286:F838-47
Southard, J H; Knes, J M; Wang, H et al. (2001) Loss of No-induced relaxation in abdominal aorta preserved in a Co-culture system. Transplant Proc 33:855-6
Lindell, S; Nobel, M; Rankin, M et al. (1998) Optimal pH for simple cold storage or machine perfusion of dog kidneys with UW solution. Transpl Int 11:208-11
Hansen, T N; D'Alessandro, A; Southard, J H (1997) Reduced renal vascular injury following warm ischemia and preservation by hypothermic machine perfusion. Transplant Proc 29:3577-9
Hansen, T N; D'Alessandro, A; Southard, J H (1997) Long-term cold ischemia reduces nitric oxide metabolism in reperfused rabbit kidneys. Transplant Proc 29:3417-9
Southard, J H (1997) Improving early graft function: role of preservation. Transplant Proc 29:3510-1
Ametani, M S; D'Alessandro, A M; Southard, J H (1997) The effect of calcium in the UW solution on preservation of the rat liver. Ann Transplant 2:34-8
Stubenitsky, B M; Ametani, M; Danielewicz, R et al. (1995) Regeneration of ATP in kidney slices after warm ischemia and hypothermic preservation. Transpl Int 8:293-7

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