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，会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 PKD 小鼠肾脏模型中表达上调，并作为视网膜母细胞瘤蛋白（Rb，导致其磷酸化）和 p53 的脱乙酰酶，共同驱动不受控制的上皮增殖和囊肿发生。用烟酰胺（维生素 B3 的一种成分）抑制 SIRT1 可延缓小鼠 PKD 的进展。该提案的总体假设是烟酰胺可以抑制 SIRT1 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，因为它具有完善的安全性，并且作为营养补充剂，不需要 FDA 批准。因此，如果它被证明是有效的，多囊肾患者将可以立即使用它。 这项试点研究的目的是提供烟酰胺对 PKD 患者的生物学和临床疗效的初步估计。的 由此产生的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应的任何暗示，并为后续更大规模的验证性试验的设计提供合理的效应大小范围。我们建议招募 30 名患有 PKD 的成年受试者参加一项口服烟酰胺 30 mg/kg/d 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) SIRT1 脱乙酰酶活性，2) PKD 进展的生物标志物。为了测量 SIRT1 活性，将分离外周血单核细胞并乙酰化，并通过 ELISA 测量总 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，通过问卷测量肾脏疼痛，并测量尿液 MCP1、KIM1、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，该试验可以明确检验烟酰胺是否能改善多囊肾患者的疾病进展。

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.