Multi-center Controlled Clinical Trials in Alport Syndrome-A Feasibility Study

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DESCRIPTION (provided by applicant): Over the past 30 years much has been learned about the molecular genetics and natural history of familial forms of hematuria. However, enhanced understanding of these conditions has yet to generate effective therapies for Alport syndrome, the form of familial hematuria associated with end-stage renal disease. Males with Alport syndrome inevitably develop end-stage kidney failure, with a 50% likelihood of dialysis or kidney transplantation by age 25 years. There is no proven treatment for Alport syndrome, although studies in animals have suggested several promising potential therapies. Pharmacological or biological treatments that might delay or prevent the development of kidney failure exist, but need to be evaluated through clinical trials. Researchers interested in implementing clinical trials in Alport syndrome will face several challenges, the foremost of which is the relative rarity of the disease, necessitating aggressive efforts to identify and recruit potential subjects for multi-center collaborative clinical trials. Funding for this feasibility study will enable the five regional recruitment centers in the United States, Canada, China, France and Germany to interrogate existing Alport syndrome registries and databases, and monitor accrual of new Alport cases over an 18-month period, in order to quantify subjects in the disease categories of interest. Funding will also allow us to examine the utility of urinary uromodulin excretion as a marker of kidney injury and potential trial endpoint in Alport syndrome clinical trials. The Alport Syndrome Research Collaborative (ARC) was established in 2009 as a partnership of the Alport Syndrome Treatments and Outcomes Registry (ASTOR), the European Alport Registry and centers of Alport syndrome research in Canada, China and France with the objective of testing potential treatments to delay or prevent terminal renal failure in people with Alport syndrome. This proposal seeks funding to (1) demonstrate that participating centers have access to sufficient numbers of males and females with Alport syndrome to populate adequately-powered clinical trials focused on two clinical targets, microalbuminuria and overt proteinuria, and (2) to test the hypothesis that in males with Alport syndrome urinary uromodulin excretion decreases as albuminuria and proteinuria increase and that uromodulin offers an independent and insightful measure of renal fibrosis and response to therapy.