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.

项目摘要常染色体显性多囊性肾脏疾病（ADPKD）是一种常见的遗传性疾病，导致终结肾脏疾病。迄今为止，Tolvaptan是唯一批准的肾脏疾病进展缓慢的干预措施 ADPKD患者。但是，Tolvaptan受到高成本和常见副作用的约束依从性，仅用于快速进步的ADPKD。那是替代或并发干预措施 ADPKD的进展可能会减慢临床重要性。类似于一般 ADPKD患者的人体质量指数一直在增加，约有近70％患有ADPKD的成年人超重或肥胖。脂肪细胞不仅仅是充当脂肪储层，而且活跃内分泌器官，因此可能是ADPKD管理的有希望的临床目标。越来越多的证据还表明ADPKD中存在代谢缺陷，这可能有助于囊性上皮增殖和随后的囊肿生长。轻度至中度的食物限制深刻减慢了囊肿的生长并保持 PKD的许多啮齿动物模型中的肾功能通过机制，包括激活AMP激活激酶以及抑制雷帕霉素-S6激酶信号传导和胰岛素样生长因子1水平的哺乳动物靶标。此外，我们已经表明超重和肥胖是更快的独立预测指标肾脏生长，通过总肾脏体积（TKV）衡量。我们最近完成了一项R03资助的试点研究支持ADPKD成人每日热量限制（DCR）的行为减肥干预超重或肥胖症：1）可行且可以接受； 2）肾脏生长速度放慢（高度的年％∆ 调整后的TKV [httkv]）; 3）减少腹部肥胖； 4）生物学途径的变化标记在ADPKD进展和代谢中实施。但是，我们的飞行员和可行性研究受到小样本量，相对短持续时间和缺乏对照组。那是为了翻译这些诺言我们针对临床实践的试点研究的结果，我们提出了一个平行组，随机，受控的临床在126名患有ADPKD和超重或肥胖的成年人中的试验直接比较行为重量的效率基于DCR与对照（ADPKD的标准临床建议）的损失干预，以减缓肾脏的生长持续时间更长。腹部肥胖的变化将是次要结果。减肥的影响关于生物途径的循环和脂肪标记，将提供机械洞察力。特定目标1：确定基于DCR的行为减肥干预对肾脏生长的影响（MRI在24个月内通过MRI的年度％∆ HTTKV）与对照（ADPKD的标准临床饮食建议）。特定目标2：通过MRI量化腹部肥胖的变化（内脏，皮下和总计）小组及其与HTTKV的变化和生物途径标记的关联。特定目标3：测量血液和脂肪组织生物途径制造商的变化。特定目标4：进一步评估DCR在ADPKD与控制中的安全性，以优化临床翻译。