Autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal monogenetic disease, affecting 1/500 to 1/1000 of the US population. 50% of those affected with ADPKD will develop end-stage renal disease by the 6th decade of life. There are no proven therapies to slow the inexorable loss of kidney function in those with progressive disease. Interruption of the renin-angiotensin-aldosterone system (RAAS) has been shown to reduce the progressive decline in renal function in both diabetic and non-diabetic kidney diseases, but it is unknown whether these results extend to ADPKD. Abundant evidence implicates angiotensin II in the pathogenesis of hypertension, but small single-center studies of limited duration have reported inconsistent results of ACE inhibitor (ACE-I) therapy on disease progression. This application is submitted in response to RFA DK-01-029 to establish a PKD Clinical Trials Network of clinical centers that will each enroll 500 ADPKD patients and conduct a clinical trial to assess the efficacy of therapeutic interruption of the RAAS on renal progression. We have proposed a randomized, double-blinded trial to compare ACE-I vs. active control in hypertensive ADPKD patients with renal insufficiency (GFR 30-65 ml/min/1.73 m2) on the time to reach a composite outcome of doubling of serum creatinine, ESRD, or death. The Clinical Center will be based at the New England Medical Center and Beth Israel Deaconess Medical Center. The Principal and Co-Principal Investigators have had career-long interests in ADPKD and personally care for large numbers of ADPKD patients. We have identified 107 potentially eligible patients within our clinical sites. Additional strategies will be used to target patients locally and within contiguous New England States. Strong institutional support is available at the highest levels, including the General Clinical Research Centers at NEMC and BIDMC. As part of this RFA, we have proposed a pilot study to assess the safety of cyclooxygenase-2 inhibition, which has been implicated in angiogenesis and cyst development in animal models of ADPKD. Thirty ADPKD patients with GFR >70 ml/min/1.73 m2 will be randomized to treatment with celecoxib vs. placebo and followed for 16 weeks. Change in GFR is the primary outcome measure and incidence of hyperkalemia, fluid retention, and elevated blood pressure will be assessed.
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