Autosomal dominant polycystic kidney disease (ADPKD) affects one in 500-1000 Americans and leads to end-stage renal disease (ESRD) in 50% of patients by age 60 years. Moreover, the life expectancy of ADPKD patients is significantly reduced compared with the general population, despite the availability of dialysis and transplantation, due to premature cardiovascular mortality. Recent advances have lead to greater understanding of the mechanisms of ADPKD, and several agents have been found to slow cyst growth in animal models. However, clinical interventions to ameliorate the course of ADPKD in humans are lacking. Therefore, the National Institute of Diabetes and Digestive and Kidney Diseases has proposed a PKD Clinical Trials Network to design and implement clinical trials to slow the progressive loss of renal function in PKD, including a large trial on blockade of the renin-angiotensin-aldosterone system (RAAS). The PKD Research Center at the University of Colorado Health Sciences Center maintains a database of nearly 800 families with ADPKD, and over 1000 family members have participated in previous clinical studies at our Center. Additional patients with ADPKD are available for recruitment from the Polycystic Kidney Research Foundation and from agreements with local health care providers. Thus, we are confident we can identify 500 patients with ADPKD who are eager and eligible to participate in a clinical trial. We propose both a large randomized controlled clinical trial featuring blockade of the RAAS and a pilot study to determine if treatment with an antiangiogenic agent slows the rate of renal growth in patients with ADPKD. Working in collaboration with the PKD Clinical Trials Network, our goal is to identify interventions that not only slow but prevent progression of ADPKD to ESRD, and interventions that ameliorate the cardiovascular complications in ADPKD. A 2 X 2 factorial design is proposed to examine the hypothesis that RAAS inhibition and rigorous blood pressure control will slow progression in advanced ADPKD and prevent progression of renal and cardiovascular disease in early ADPKD.
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