Our objective is to better understand factors which lead to reversal, arrest, or progression of the lesions of diabetic nephropathy (DN) in the native kidneys of Type I diabetic patients undergoing successful pancreas transplantation (PTx). A key endpoint of these studies is change in the volume fraction of the mesangium comparing baseline biopsies with those taken at 2.5, 5 and 10 years after PTx. Multiple sources of evidence confirm the central role of renal extracellular matrix (ECM) accumulation in the development of the lesions of DN. We hypothesize that changes in renal ECM may be critical in determining the response of established lesions of diabetic nephropathy to long term normoglycemia induced by pancreas transplantation. We will study at baseline and 5 years post-PTx, renal collagens (especially various chains of Type IV and Types II and VI), noncollagenous glycoproteins (especially laminin, entactin, fibronectin and TN antigen) and heparin and chondroitin sulfate proteoglycans and perlican. We will use semiquantitative [immunofluorescence (IF) microscopy] and quantitative methods (image analysis IF and immunogold electron microscopy) to characterize the site specific pattern alterations and relative amounts of ECM components in relationship to the structural and clinical variables of DN. We will relate these ECM changes to severity of morphometric lesions and renal function in patients who do and do not receive pancreas transplants. We will determine whether alterations in ECM predict effects of normoglycemia on established lesions and which predict progression in patients with or without successful PTx. A second objective is to document the effects of long-term cyclosporine (CSA) administration in patients with pre-existing diabetes and a range of DN lesions. CSA in usual treatment doses induces a decline in glomerular filtration rate (GFR) and has been associated with a variety of renal structural changes including glomerular and interstitial scarring and arterial and arteriolar pathology. We will examine the baseline renal structural and functional status, CSA dose and CSA blood levels which may be associated with progressive renal injury in Type I diabetic patients using nontransplanted patients as controls. In this way, the risk benefit ratio of PTx for patients with native kidneys can be better defined.
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