Randomized, controlled pilot study of nicotinamide in polycystic kidney disease

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DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (PKD) is a common genetic disorder that causes cystic dilatation of the renal tubules and progressive kidney failure. There is currently no effective treatment. Sirtuin 1 is upregulated in the kidney i murine models of PKD and acts as a deacetylase of retinoblastoma protein (Rb, leading to its phosphorylation) and p53, which together drive uncontrolled epithelial proliferation and cystogenesis. Inhibition of SIRT1 with nicotinamide, a component of vitamin B3, retards progression of PKD in mice. The overarching hypothesis of this proposal is that nicotinamide can inhibit SIRT1 deacetylase activity and safely and effectively retard cyst enlargement and disease progression in patients with PKD. Nicotinamide is a particularly attractive candidate for treatment of PKD because it has a well-established safety profile and, as a nutritional supplement, it does not require FDA approval. Thus, if it can be proven to be effective, PKD patients would have access to its use immediately. The goal of this pilot study is to provide initial estimates of the biological and clinical efficacy of nicotinamide in patients with PKD. The resulting estimates will provide critical information to determine if we can detect any hint of a beneficial clinical effect on cyst progression and provide a plausible range of effect sizes for th design of a subsequent, larger, confirmatory trial. We propose to enroll 30 adult subjects with PKD in a double blind, randomized, placebo-controlled clinical trial of nicotinamide, 30 mg/kg/d orally. Our specific aims are to estimate the effect of nicotinamide on: 1) SIRT1 deacetylase activity, and 2) biomarkers of PKD progression. To measure SIRT1 activity, peripheral blood mononuclear cells will be isolated and acetylated and total p53, and phosphorylated and total Rb will be measured by ELISA. To monitor PKD progression, MRI of the kidneys will be performed to determine total kidney volume, kidney pain will be measured with a questionnaire, and urine MCP1, KIM1, NGAL and other biomarkers will be measured. Positive outcomes in this pilot study would lay the groundwork for a larger confirmatory trial that could definitively tst whether nicotinamide ameliorates disease progression in individuals with PKD.