We propose to explore predisposition of insulin-dependent diabetic (IDDM) patients to diabetic nephropathy (DN) by studying a unique cohort of patients at the University of Minnesota. The rate at which the critical lesions of DN recur in kidneys transplanted (TX) into IDDM patients with DN is highly variable and ranges, 10 to 15 years post-kidney TX, from barely detectable to advanced changes associated with overt DN. These variations in rate, only loosely associated with glycemia and unrelated to the duration of IDDM prior to end-stage renal disease in the patients' native kidneys, suggest that there may be factors within the kidney itself which determine susceptibility to or protection from DN. Recently, strong familial tendencies to DN risk have been described. Also, the sodium hydrogen (Na+/H+) antiport activity and DNA synthesis rates in cultured skin fibroblasts (CSF) from patients with DN have been found to be elevated compared to CSF from patients without this complication. We propose to test the hypotheses that the Na+/H+ antiport activity in skin fibroblasts of the kidney transplant donor can predict the risk of redevelopment of DN in the IDDM kidney TX recipient. We will also test the hypothesis that there is a correlation between the activity of the Na+/H+ antiporter in renal interstitial and skin fibroblasts. Our objective is to provide a large cohort of IDDM with a functioning renal graft from a living donor at least 10 years ago. From an allograft renal biopsy the degree of DN recurrence will be quantified using electron microscopic morphometric techniques. Also, renal and skin fibroblast Na+/H+ antiport activity will be measured in the recipient. The living donors of the patients shall undergo skin biopsy for measure of Na+/H+ antiport activity. In addition, the relationship between the activity of skin and renal fibroblast Na+/H+ antiport activity will be studied in normals who will have skin and renal biopsies taken at the time of kidney donation. Growth patterns will also be studies in cultured skin and renal fibroblasts in diabetics with and without recurrent nephropathy and their donors with measures of cell size and number and 3H thymidine incorporation. Patients will also be characterized as to their degree of post-kidney transplant glycemic and blood pressure control. These studies will allow us to determine if the Na+/H+ activity and cell growth pattern of CFS of the donor is independently predictive of DN risk in the recipient, if Na+/H+ activity of skin and kidney fibroblast are interrelated and, if so, if the transplant kidney fibroblasts reflect more closely donor or recipient skin cell characteristics. These studies may provide evidence of tissue specific (perhaps genetically determined) risk factors for the development of DN.
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