Fabry disease, due to an inherited defect in the enzyme enzyme alpha galactosidase A, causes kidney failure in most males and about 1 in 6 females with this disease by resulting in the accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysozymes of kidney cells. Once kidney disease is clinically manfest with substantial increases in urinary protein, treatment using enzyme replacement therapy (ERT) frequently cannot stop progression towards kidney failure. Some cells in the filters of the kidney (glomeruli) clear quickly including endothelial and mesangial cells. The podocytes (PC), on the outside of the glomerular filter, are crucial for maintaining the filter's barrier to protein leakage into the urine and loss of PC leads to scarring of glomeruli with resultant loss of filtering function and kidney failure. Unfortunately the poorly replicating PC clear poorly of their GL-3 content with ERT. There are data supporting that earlier ERT initiation may result in better PC GL-3 clearance with ERT. Delayed or inadequate (low ERT dose) treatment, we posit, leads to PC injury and death, and when PC loss becomes critical, glomecular scarring.
Our aims are to 1) determine the effect of age on PC GL-3 content and PC numbers in males and females with Fabry disease. 2) study the effects of age of ERT initiation, gender, duration of treatment and ERT dose on PC and other renal cell GL-3 clearance in children and adults with Fabry disease. 3) evaluate the effects age of initiation, gender duration and dose of ERT on PC foot process width, an important indicator of PC injury and correlate of proteinura. 4) evaluate the effects of age of ERT initiation of ERT on PC number in Fabry disease males. We will have access to the world's largest collection of kidney biopsies performed before and at various times after ERT initiation in Fabry disease male and female adult and pediatric patients with ERT given at variable dose and for variable duration. We have a world class renal morphometry laboratory and will use quantitative electron microscopic measurement tools that we have developed to accurately estimate the kidney structural variables mentioned above.
Our studies will strongly contribute to new standards of care regarding age of institution and dose of ERT in persons with Fabry disease. Moreover our data from will help in the design of and power analyses for clinical trials testing new Fabry disease treatments. This is especially true for add on therapies to ERT where residual PC GL-3 will be the treatment target, since other renal cells will have cleared with ERT alone.
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