New immunosuppressive techniques continue to increase the long- term graft survival of clinical renal transplants. There has been little progress, however, in improving the quality or duration of renal preservation. The proposed research is a comprehensive study of the mechanism of renal injury in preserved kidneys. In particular, we will examine the roles of: a) Ca, b) O2 free radicals, and c) microcirculatory changes in the loss of renal function after transplantation. We will use 3- and 5-day preserved dog kidney models to study the mechanism of kidney injury. In earlier studies we were unable to detect major metabolic differences between 3-day (viable) and 5- day (marginally viable) preserved kidneys at the end of preservation; this suggests that functional differences become apparent only after reperfusion. The extent, type, and rate of onset of renal injury will be analyzed for periods of 15 minutes to 24 hours during kidney reperfusion, using perfusor dog or transplantation models. We will use several techniques to assess the extent and type of injury: a) biochemical techiques (mitochondria, microsomes, lipid metabolism, Ca metabolism, lipid peroxide formation, calmodulin, adenine nucleotides, cyclic AMP, and membrane permeability studies); b) physiological techniques (total renal blood flow, renal cortical microcirculation, glomerular filtration rate, percent Na reabsorption, urine/plasma protein ratio, and urine production); and c) morphological techniques (electron microscopy and microangiogram). Identifying the mechanism of kidney injury will allow the appropriate selection of specific drugs to test in the dog model. Drugs likely to be appropriate include Ca antagonists (plasma membrane-active, intracellular-active, or both), phospholipase inhibitors, calmodulin inhibitors, O2 free radical scavengers, and vasoactive agents. We will evaluate how these drugs affect the mechanism of renal damage and how they relate to improve renal function. Renal function and long-term survival in the transplantation model will be the final test of perfusate modification and drug therapy. The long-range of this research is the consistent, successful preservation of kidneys for at least 5 days.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37DK018624-17
Application #
3483264
Study Section
Special Emphasis Panel (NSS)
Project Start
1979-04-01
Project End
1995-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
17
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
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
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
Saunder, A; Southard, J H; Belzer, F O (1993) Beneficial effect of aspirin and heparin in three-day dog kidney preservation. Transplantation 56:1044-5
Saunder, A; Ametani, M S; Belzer, F O et al. (1993) Cytoprotective effect of glycine in cold stored canine renal tubules. Cryobiology 30:243-9

Showing the most recent 10 out of 27 publications