Alport syndrome is a genetic kidney disease that results from mutations in type IV collagen, an integral component of tissue structures known as basement membranes. These mutations result in defects in type IV collagen in the glomerular basement membrane (GBM), a structure that plays a critical role in preventing the leakage of blood proteins into the urine. Proteinuria (the leakage of proteins into the urine) is an important feature of Alport syndrome. The goals of this proposal are (1) to understand how proteinuria develops in Alport syndrome and (2) to test whether cyclosporine can reduce protienuria and prevent renal failure in Alport syndrome. Kidney disease that is indistinguishable genetically, biochemically and pathologically from Alport syndrome occurs spontaneously in dogs. We propose to perform three sets of studies on these dogs. (1) We will obtain glomeruli from affected dogs and their normal littermates by serial kidney biopsies, and we will compare the permeability of affected and normal glomeruli to protein. Our hypothesis is that glomerular permeability to protein is normal early in the course of Alport syndrome, but increases as certain collagens accumulate abnormally in the GBM. (2) We will isolate GBM from affected and normal glomeruli to test whether the abnormal composition of the Alport GBM interferes with the ability of glomerular epithelial cells (GEC) to attach to it. GEC also play a role in preventing protein leakage into the urine. Our hypothesis is that GEC do not attach normally to Alport GBM, and that abnormal attachment is associated with proteinuria, and results in changes in the activity of certain genes in these cells (3) There is currently no treatment for Alport kidney disease, other than renal transplantation. A recent report described suppression of proteinuria and stabilization of renal function in Alport patients by long-term treatment with cyclosporine. This study was uncontrolled and included only 8 patients. In addition, cyclosporine itself can cause kidney damage. For these reasons we propose to conduct a controlled trial of cyclosporine therapy in dogs with Alport syndrome. This trial will compare urinary protein levels, kidney function, and renal structural changes in treated and untreated dogs.
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