Daily Caloric Restriction in Overweight and Obese Adults with ADPKD

项目摘要 常染色体显性遗传性多囊肾病（ADPKD）是一种常见的遗传性疾病，导致终末期肾病。 阶段性肾病到目前为止，托伐普坦是唯一批准的减缓肾脏疾病进展的干预措施 在ADPKD患者中。然而，托伐普坦受到高成本和常见副作用的限制， 坚持，仅适用于快速进展的ADPKD。因此，替代或并行干预措施 可能减缓ADPKD进展的药物具有相当大的临床意义。与将军相似 在人群中，ADPKD患者的体重指数一直在增加，大约70%的 患有ADPKD的成年人超重或肥胖。脂肪细胞不仅仅是一个脂肪储存库， 内分泌器官，因此可能是ADPKD管理的有希望的临床靶点。越来越多的证据 也表明ADPKD中存在代谢缺陷，这可能有助于囊性上皮增生 以及随后的囊肿生长。轻度至中度的食物限制大大减缓了囊肿的生长， 通过包括AMP活化激酶的活化在内的机制，在许多PKD啮齿动物模型中观察肾功能 以及抑制哺乳动物靶雷帕霉素-S6激酶信号传导和胰岛素样生长因子-1水平。 此外，我们已经表明，超重和肥胖是更快速的独立预测因子， 肾脏生长，通过肾脏总体积（TKV）测量。我们最近完成了一项R 03资助的试点研究， 支持通过每日热量限制（DCR）对ADPKD成人进行行为减肥干预 和超重或肥胖：1）是可行的和可接受的; 2）肾脏生长减慢（身高的年%增长率- 调整的TKV [htTKV]）; 3）减少腹部肥胖;和4）改变生物途径的标志物 与ADPKD进展和代谢有关。然而，我们的试点和可行性研究受到限制， 样本量小，持续时间相对较短，缺乏对照组。因此，要翻译这些有前途的 根据我们对临床实践的初步研究结果，我们提出了一个平行组，随机，对照的临床研究。 在126名患有ADPKD和超重或肥胖的成年人中进行的一项试验，直接比较行为体重的有效性 基于DCR与对照（ADPKD的标准临床建议）的损失干预，用于减缓肾脏生长超过 持续时间更长。腹部肥胖的变化将作为次要结局。减肥的效果 循环和脂肪生物途径的标志物将提供机制的见解。 具体目标1：确定基于DCR的行为减肥干预对肾脏生长的影响 （24个月内通过MRI测量的年度%TKV）与对照组（ADPKD的标准临床饮食建议）。 具体目标2：通过MRI量化每个患者的腹部肥胖（内脏、皮下和总体）变化 组及其与htTKV和生物途径标志物变化的相关性。 具体目标3：测量血液和脂肪组织中生物途径标记物的变化。 具体目的4：进一步评价DCR与对照相比在ADPKD中的安全性，以优化临床转化。

Project Summary Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to end- stage kidney disease. To date, tolvaptan is the only approved intervention to slow kidney disease progression in patients with ADPKD. However, tolvaptan is constrained by high cost and common side effects that limit adherence and is only indicated for rapidly progressing ADPKD. Thus, alternative or concurrent interventions that may slow progression of ADPKD are of considerable clinical importance. Similar to the general population, body-mass index has been increasing in patients with ADPKD, and approximately nearly 70% of adults with ADPKD are overweight or obese. Adipocytes do not simply act as a fat reservoir, but are active endocrine organs, and thus, may be a promising clinical target for ADPKD management. Mounting evidence also suggests that a metabolic defect exists in ADPKD, which likely contributes to cystic epithelial proliferation and subsequent cyst growth. Mild-to-moderate food restriction profoundly slows cyst growth and maintains renal function in numerous rodent models of PKD via mechanisms including activation of AMP-activated kinase and suppression of mammalian target of rapamycin-S6 kinase signaling and insulin-like growth factor-1 levels. Additionally, we have shown that overweight and obesity are strong independent predictors of more rapid kidney growth, measured by total kidney volume (TKV). We recently completed a R03-funded pilot study supporting that a behavioral weight loss intervention via daily caloric restriction (DCR) in adults with ADPKD and overweight or obesity: 1) is feasible and acceptable; 2) slowed kidney growth (annual %∆ in height- adjusted TKV [htTKV]); 3) reduced abdominal adiposity; and 4) altered markers of biological pathways implicated in ADPKD progression and metabolism. However, our pilot and feasibility study was limited by a small sample size, relatively short duration, and lack of a control group. Thus, to translate these promising results of our pilot study towards clinical practice, we propose a parallel-group, randomized, controlled clinical trial in 126 adults with ADPKD and overweight or obesity to directly compare the efficacy of behavioral weight loss intervention based on DCR vs. control (standard clinical advice for ADPKD) for slowing kidney growth over a longer duration. Changes in abdominal adiposity will serve as a secondary outcome. Effects of weight loss on circulating and adipose markers of biological pathways will provide mechanistic insight. Specific Aim 1: Determine the effect of a DCR-based behavioral weight loss intervention on kidney growth (annual %∆ htTKV by MRI over 24 months) vs. control (standard clinical dietary advice for ADPKD). Specific Aim 2: Quantify changes in abdominal adiposity (visceral, subcutaneous, and total) by MRI in each group and their association with changes in htTKV and markers of biological pathways. Specific Aim 3: Measure changes in makers of biological pathways in blood and adipose tissue. Specific Aim 4: Further evaluate the safety of DCR in ADPKD vs. control, to optimize clinical translation.