Diabetic nephropathy poses a major life-threatening consequence for the patient with either type I or type II diabetes mellitus. Although glycemic control has been implicated in preventing or reversing the functional and structural manifestations of diabetic nephropathy (especially in experimental animals), the long-term effects of near-normal glycemic control on preventing or reversing the progression of diabetic renal lesions in man have not been rigorously examined. Pancreas transplantation to patients with type I diabetes mellitus provides the opportunity to effect long-term euglycemia under several venues: simultaneous pancreas and kidney transplantation alone. Studies of renal biopsies and renal function occurring at the time of pancreas transplantation and at 2 and 5 years (and in some cases 10 years) later yield quantitative morphometric analyses of glomerular structure and measures of glomerular filtration rate and renal blood flow. The primary endpoint in all cases will be the expansion of the glomerular mesangium by measuring its volume fraction and total volume in the glomerulus. Secondary endpoints include glomerular basement membrane width, mesangial matrix volume and measures of renal function. Three different specific aims can be addressed: the prevention of renal lesions of diabetic nephropathy with euglycemia established by concurrent pancreas/kidney transplantation; the halting or reversal of the progression of early renal lesions present in the previously transplanted kidney with subsequent pancreas transplantation; and the amelioration of established renal lesions in patients with their own kidneys who received pancreas transplantation alone. Diabetic and non-diabetic recipients of renal transplants alone constitute control groups with which to compare the results from the renal transplant recipients who also received pancreatic transplants, as do untreated diabetic patients when compared to recipients of pancreas transplants alone. Since pancreas transplantation has become a more frequently applied procedure to manage the patient with type I diabetes mellitus, the studies proposed will address the potential efficacy of the procedure in altering the course of diabetic nephropathy. With the extended period of time necessary to follow the course of diabetic renal disease, an immediate application of techniques to study diabetic renal disease and pancreas transplantation has the potential to address its efficacy in the shortest period of time and to contribute broadly to understanding the stage(s) of diabetic nephropathy ultimately benefiting from the establishment of a continuous euglycemic state.
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