Daily Caloric Restriction in Overweight and Obese Adults with ADPKD
Project Number5R01DK129259-04
Contact PI/Project LeaderNOWAK, KRISTEN LYNN
Awardee OrganizationUNIVERSITY OF COLORADO DENVER
Description
Abstract Text
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.
Public Health Relevance Statement
Project Narrative
The proposed clinical trial will determine whether a daily-caloric restriction-based weight loss intervention can
slow kidney growth in adults with autosomal dominant polycystic kidney disease who are overweight or obese.
The study will also evaluate changes in abdominal fat by magnetic resonance imaging. Blood and fat samples
will provide insight into biological changes that may contribute to any observed benefits of the intervention.
National Institute of Diabetes and Digestive and Kidney Diseases
CFDA Code
847
DUNS Number
041096314
UEI
MW8JHK6ZYEX8
Project Start Date
01-July-2021
Project End Date
31-May-2026
Budget Start Date
01-June-2024
Budget End Date
31-May-2025
Project Funding Information for 2024
Total Funding
$494,915
Direct Costs
$336,442
Indirect Costs
$158,473
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Diabetes and Digestive and Kidney Diseases
$494,915
Year
Funding IC
FY Total Cost by IC
Sub Projects
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Outcomes
The Project Outcomes shown here are displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed are those of the PI and do not necessarily reflect the views of the National Institutes of Health. NIH has not endorsed the content below.
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