Studies of Organ Transplantation in Animals and Man

A. To study the effects of pancreas transplantation (PT) on the structural abnormalities of diabetic nephropathy (DN) in patients with type 1 (insulin-dependent) diabetes mellitus (type 1 D). These studies will address the influence of long-term normoglycemia on two stages of diabetic renal disease. Due to the difficulties encountered for recruitment of patients to agree to undergo a GFR and a native kidney biopsy in conjunction with their clinical evaluation visit for transplant, we are now focusing efforts on obtaining skin biopsies previous to transplant, and then at regular intervals (3, 6, and 9 months, and yearly) following a successful transplantation. * Pancreas Transplantation Alone (PTA). To determine, at 5, 10, and 15 years after PTA, the effects of normoglycemia on the established lesions of DN in the long-term type 1 D patients' own kidneys. * Islet Transplantation Alone (ITA). To determine, at 5 years after ITA, the effects of normoglycemia on the early lesions of DN in type 1 D patients' own kidneys. * Pancreas Transplantation after Kidney Transplantation (PAK). To determine at 5-10 years the effects of normoglycemia on the early structural lesions of DN in kidneys transplanted some years earlier into type 1 D recipients. Hypothesis: The benefits of PT on the early glomerular lesions of DN will be demonstrable after 5 years in kidneys exposed to diabetes for a short duration, while in patients with long-standing type 1 D and more advanced glomerular DN lesions, longer exposure to euglycemia is necessary to demonstrate arrest or regression of the lesions.

These continuation studies focus on large pancreas (PTx) and kidney (KTx) transplant populations of type 1 diabetic (D) patients (pts) in order to better understand diabetic nephropathy (DN), the leading cause of renal failure. Objectives are: (a) to determine whether PTx can more readily arrest or reverse the early vs. the more established lesions of DN; (b) to continue studies of renal structural-functional relationships in DN, with emphasis on the multifaceted pathologic DN lesions, including glomerular, vascular, interstitial lesions and glomerular-tubular connections; (c) to continue studies of DN natural history and the role of renal biopsy in predicting outcome; (d) to quantitate and understand the basis of atubular glomeruli (AG) in DN; (e) to elucidate glomerular (glom) epithelial cell abnormalities in DN; (f) to study the glom extracellular matrix abnormalities of DN; (g) to study the recurrence of DN in the KTx; (h) to study the molecular/genetic basis of DN and develop cellular markers of DN risk; (i) to determine the long-term (10-15 yr) structural consequences of cyclosporine (CSA) on the native kidneys of PTx recipients; and (j) to determine the shorter-term (5 yr) consequences of Prograf on the native kidneys of PTx recipients and compare these with those seen after 5 years of CSA treatment. Together, these studies will help to elucidate the pathogenesis and natural history of DN, unravel some of the molecular and genetic aspects of this disease, describe the dynamics of DN reversal in PTx pts, and recurrence in KTx pts and expand our knowledge of the nephrotoxic effects of calcinosis inhibitors.