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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：
10623248
负责人：
Kristen Lynn Nowak
金额：
$ 51.55万
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/10623248
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 Epithelium 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 Proliferating 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 acceptability and feasibility adipokines adiponectin adult obesity 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.

项目总结