Chronic renal failure is a major debilitating and life-threatening complication of Fabry disease known to account for 0.01% of end-stage renal disease in western countries. Enzyme screening studies in male dialysis patients suggest that this might be an underestimate of the true prevalence of the disease by 10- to 100-fold. Furthermore, the natural history of heterozygous females is even more unclear. Primary prevention, before the disease is clinically manifest, could be important to maximize the potential benefits of enzyme replacement therapy, but it will be important to evaluate such early intervention before consigning every child to life-long therapy. Understanding the cellular pathology, and the tempo of progression, will be crucial. However, the structural changes of Fabry renal disease responsible for glomular filtration rate (GFR) loss have not been systematically studied. Using quantitative morphometric stereologic methods we have recently demonstrated that podocyte GL-3 accumulation is progressive with age (time) while mesangial and endothelial cell accumulation is not. We will apply these systematic quantitative methods to 50-60 Fabry patients with a wide range of GFR with kidney biopsies performed prior to beginning enzyme replacement therapy. We will then develop a model of structural functional relationships which most closely predicts GFR loss. These data will be used for the power calculations needed to design early intervention trials based on those structural endpoints which are most closely related to important functional outcomes in Fabry disease.
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