Randomized, controlled pilot study of nicotinamide in polycystic kidney disease

描述（由申请人提供）：常染色体显性多囊肾病（PKD）是一种常见的遗传性疾病，可导致肾小管囊性扩张和进行性肾衰竭。目前尚无有效的治疗方法。Sirtuin 1在肾脏PKD小鼠模型中上调，并作为视网膜母细胞瘤蛋白（Rb，导致其磷酸化）和p53的去乙酰化酶，共同驱动不受控制的上皮增殖和膀胱形成。用烟酰胺（维生素B3的一种成分）抑制SIRT1可以延缓小鼠PKD的进展。该建议的总体假设是烟酰胺可以抑制SIRT1去乙酰化酶活性，安全有效地延缓PKD患者的囊肿扩大和疾病进展。烟酰胺是治疗PKD的一个特别有吸引力的候选药物，因为它具有良好的安全性，而且作为一种营养补充剂，它不需要FDA的批准。因此，如果它能被证明是有效的，PKD患者将立即获得使用它。这项初步研究的目的是为烟酰胺治疗PKD患者的生物学和临床疗效提供初步估计。这个

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.