Randomized, controlled pilot study of nicotinamide in polycystic kidney disease

描述（由申请方提供）：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。目前没有有效的治疗方法。Sirtuin 1在PKD的鼠模型中的肾脏中上调，并且充当视网膜母细胞瘤蛋白（Rb，导致其磷酸化）和p53的脱乙酰酶，其一起驱动不受控制的上皮增殖和囊形成。用烟酰胺（维生素B3的一种成分）抑制SIRT 1可延缓小鼠PKD的进展。该建议的首要假设是，烟酰胺可以抑制SIRT 1脱乙酰酶活性，并安全有效地延缓PKD患者的囊肿扩大和疾病进展。烟酰胺是治疗PKD的特别有吸引力的候选药物，因为它具有良好的安全性，并且作为营养补充剂，它不需要FDA批准。因此，如果它可以被证明是有效的，PKD患者将可以立即使用它。 本初步研究的目的是提供烟酰胺在PKD患者中的生物学和临床疗效的初步估计。的 结果估计将提供关键信息，以确定我们是否可以检测到对囊肿进展有益的临床效果的任何暗示，并为后续更大的验证性试验的设计提供合理的效应量范围。我们计划入组30例PKD成人受试者，进行烟酰胺30 mg/kg/d口服给药的双盲、随机、安慰剂对照临床试验。我们的具体目标是评估烟酰胺对以下方面的影响：1）SIRT 1脱乙酰酶活性，和2）PKD进展的生物标志物。为了测量SIRT 1活性，将分离外周血单核细胞并通过ELISA测量乙酰化和总p53、磷酸化和总Rb。为了监测PKD进展，将进行肾脏MRI以确定肾脏总体积，将使用问卷测量肾脏疼痛，并测量尿液MCP 1、KIM 1、NGAL和其他生物标志物。 这项试点研究的积极结果将为更大规模的验证性试验奠定基础，该试验可以明确测试烟酰胺是否改善PKD患者的疾病进展。

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.