Daily Caloric Restriction in Overweight and Obese Adults with ADPKD

患有 ADPKD 的超重和肥胖成人的每日热量限制

基本信息

批准号：
10676347
负责人：
Kristen Lynn Nowak
金额：
$ 11.66万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676347
关键词：
5&apos -AMP-activated protein kinase Abdomen Adherence Adipocytes Adipose tissue Adult Affect Anti-Inflammatory Agents Autosomal Dominant Polycystic Kidney Behavioral Biological Biological Markers Blood Body Weight decreased Body fat Body mass index C-reactive protein Caloric Restriction Chronic Clinical Clinical Research Clinical Trials Control Groups Cyst Cystic kidney Data Defect Development Disease Disease Management Disease Progression End stage renal failure Endocrine Glands Epithelial FRAP1 gene Fatty acid glycerol esters Feasibility Studies Funding General Population Genetic Diseases Growth Height Hereditary Disease IGFBP1 gene Individual Inflammatory Insulin-Like Growth Factor I Interleukin-6 Intervention Kidney Kidney Diseases Leptin Life Link Liquid substance Magnetic Resonance Imaging Malignant Neoplasms Measures Mediating Metabolic Metabolism Obesity Overweight Pathway interactions Patients Peripheral Blood Mononuclear Cell Pilot Projects Randomized Controlled Clinical Trials Recommendation Renal function Reporting Ribosomal Protein S6 Kinase Rodent Model STAT3 gene Safety Sample Size Sampling Serum Signal Pathway Signal Transduction Tissues Translating Visceral Visceral fat abdominal fat adipokines adiponectin adult obesity base clinical practice clinical translation comparative efficacy cost cytokine dietary efficacy evaluation food restriction functional decline improved outcome inflammatory marker insight lifestyle intervention novel primary outcome secondary outcome side effect subcutaneous systemic inflammatory response tolvaptan tumorigenic weight loss intervention

项目摘要

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.

项目概要常染色体显性多囊肾病 (ADPKD) 是一种常见的遗传性疾病，可导致最终迄今为止，托伐普坦是唯一被批准减缓肾脏疾病进展的干预措施。然而，托伐普坦受到高成本和常见副作用的限制。依从性，仅适用于快速进展的 ADPKD，因此，需要替代或同时进行干预。与一般情况相似，这可能会减缓 ADPKD 的进展，具有相当大的临床重要性。 ADPKD 患者的体重指数一直在增加，并且大约有近 70% 患有 ADPKD 的成年人超重或肥胖，脂肪细胞不仅充当脂肪储存库，而且还很活跃。内分泌器官，因此可能是 ADPKD 治疗的一个有前景的临床目标。还表明 ADPKD 存在代谢缺陷，这可能导致囊性上皮增殖以及随后的囊肿生长。轻度至中度的食物限制会极大地减缓囊肿的生长并维持囊肿的生长。通过激活 AMP 激活激酶等机制，研究众多 PKD 啮齿动物模型中的肾功能抑制哺乳动物雷帕霉素-S6 激酶信号传导靶标和胰岛素样生长因子-1 水平。此外，我们已经证明，超重和肥胖是加速肥胖的强有力的独立预测因素。肾脏生长，通过肾脏总体积 (TKV) 来衡量我们最近完成了一项由 R03 资助的试点研究。支持通过每日热量限制 (DCR) 对患有 ADPKD 的成人进行行为减肥干预和超重或肥胖：1) 可行且可接受；2) 肾脏生长减慢（每年身高 %Δ） TKV [htTKV] 调整）；3）减少腹部肥胖；4）改变生物途径标志物；然而，我们的试点和可行性研究受到以下因素的限制。样本量小，持续时间相对较短，并且缺乏对照组，因此，转化这些有希望的。根据我们针对临床实践的试点研究的结果，我们提出了平行组、随机、对照的临床实践在 126 名患有 ADPKD 且超重或肥胖的成年人中进行的试验，直接比较行为体重的功效基于 DCR 与对照（ADPKD 的标准临床建议）的损失干预可减缓肾脏生长腹部肥胖的持续时间较长将作为减肥的影响。对生物途径的循环和脂肪标记的研究将提供机制上的见解。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 测得的每年 %Δ htTKV）与对照（ADPKD 的标准临床饮食建议）。具体目标 2：通过 MRI 量化腹部肥胖（内脏、皮下和总体）的变化组及其与 htTKV 和生物途径标记物变化的关联。具体目标 3：测量血液和脂肪组织中生物途径制造者的变化。具体目标 4：进一步评估 ADPKD 与对照中 DCR 的安全性，以优化临床转化。