The first aim addresses the effects of normoglycemia by pancreas transplantation on the structural and functional manifestations of diabetic nephropathy (DN) in type 1 (insulin dependent) diabetes mellitus (IDDM). IDDM patients not receiving pancreas transplantation or suffering early graft failure will be untreated control subjects. These studies will encompass three broad stages in the development of DN: 1) Inception: the effects of simultaneous kidney and pancreas transplantation vs. kidney transplant alone in IDDM patients on the development of the earliest lesions of DN, with measures of kidney structure (biopsy) and renal function at baseline and 5 and 10 years later; 2) Early Diabetic Nephropathy. the effects of pancreas transplantation performed a few years after kidney transplant in IDDM (vs. kidney transplant alone) on the possibility of arresting or reversing the mild and early lesions of DN. Measures of kidney structure and function are done at baseline (pancreas transplantation) and at 5, 10 and 15 years later; 3) Established Diabetic Nephropathy: the effects of pancreas transplantation alone on the structure and function of native kidneys in patients with long-standing (10-40 yrs) IDDM vs. matched IDDM patients remaining diabetic. Kidney function and structure will be measured at baseline, 5, 10 and 15 years after pancreas transplantation and at parallel times in the matched patients.
The second aim continues studies of the natural history and structural/functional relationships in DN. The nonpancreas transplant patients will provide data regarding the following issues; 1) risk factors (glycemia, blood pressure, etc.); 2) the question of whether DN lesions develop at a linear rate over time (important in designing intervention studies); 3) the question of whether DN lesions develop in parallel (important in determining the primacy of the various structural parameters in relation to functional manifestations of DN).
The third aim determines the changes in extracellular matrix composition and matrix-related molecules in DN with specific emphasis on collagens, laminins, proteoglycans and integrins. These immunohistochemical studies will define whether certain ECM or integrin abnormalities predict reversibility of DN lesions with successful pancreas transplantation. They also will examine which patterns of abnormalities in renal expression of ECM or integrin molecules are most closely related to disease progression. Measures of kidney function include glomerular filtration rate (lothalamate clearance), renal blood flow (PAH clearance) urinary albumin excretion rate and blood pressure. Renal structure will be measured by morphometry: Light microscopy; glomerular volume, % sclerotic glomeruli, % tubular glomeruli, interstitial volume. Electron microscopy; GBM width, volume fraction of total mesangium, mesangial cells and mesangial matrix and filtration surface. Immunohistochemistry will include immunofluorescence microscopy and quantitative immunogold electron microscopy. Altogether, these studies will offer new insights into the pathogenic mechanisms of DN and provide information important in the development of new intervention strategies.
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