Daily Caloric Restriction in ADPKD

Daily Caloric Restriction in Overweight and Obese Adults With ADPKD

This 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.

Study Overview

• Status: Recruiting
• Conditions: Overweight and Obesity; Autosomal Dominant Polycystic Kidney
• Intervention / Treatment: Behavioral: Daily caloric restriction; Other: Standard advice control

Detailed Description

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by development and continued growth of numerous fluid-filled renal cysts that ultimately result in renal failure. Similar to the general population, the prevalence of overweight and obesity have been rising in ADPKD patients, effecting about two-thirds of individuals. Adipocytes do not simply act as a fat reservoir, but are active endocrine organs that promote release of pro-inflammatory cytokines, 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. Additionally, the investigators recently reported that overweight and obesity are strong independent predictors of more rapid kidney growth. Collectively, these data suggest that interventions to reduce abdominal adiposity may slow ADPKD progression.

Initial results from the investigators' R03-funded pilot and feasibility study support that a 12-month daily caloric restriction (DCR)-based behavioral weight loss intervention in adults with ADPKD and overweight or obesity: 1) is feasible and acceptable; 2) slowed kidney growth (annual %∆ in height-adjusted TKV [htTKV]), which was highly correlated with weight loss; 3) reduced abdominal adiposity; and 4) altered pathways implicated in ADPKD progression and metabolism. These initial results suggest that a DCR-based behavioral weight loss intervention offers a promising strategy to slow ADPKD progression. However, the 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 the pilot study towards clinical practice, the investigators are conducting a randomized, controlled clinical trial in a larger number of adults with ADPKD and overweight or obesity to directly compare the efficacy of a DCR-based behavioral weight loss intervention compared to control for slowing kidney growth (primary outcome) over a longer duration. Changes in abdominal adiposity will serve as a secondary outcome and effects of weight loss on circulating and adipose markers of biological pathways will provide mechanistic insight.

In a subset of participants recruited for this clinical trial, we will measure change in kidney oxidative metabolism, insulin sensitivity, plasma metabolomics, and gut microbiota. These additional measures will aim to compare kidney oxidative metabolism, insulin sensitivity, plasma metabolome and gut microbiota at baseline and 2 years. In addition, the investigators aim to define the relations among changes in kidney oxidative metabolism, insulin sensitivity, plasma metabolome, gut microbiota, total kidney volume, and body weight over 2 years. Currently, it is unknown if weight loss via DCR modifies renal energy expenditure, substrate utilization, plasma metabolomics, or the gut microbiome.

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Emily Andrews; Phone Number: 303-724-7790; Email: Emily.S.Andrews@cuanschutz.edu
• Study Contact Backup: Name: Kristen Nowak, PhD, MPH; Phone Number: 303-724-4842; Email: Kristen.Nowak@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado - Anschutz Medical Campus
      • Contact: Kristen Nowak, PhD, MPH; Phone Number: 303-724-4842; Email: Kristen.Nowak@cuanschutz.edu
      • Principal Investigator: Kristen Nowak, PhD, MPH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18-65 years of age
• ADPKD diagnosis based on the modified Pei-Ravine criteria
• Body-mass index of 25-45 kg/m^2
• Estimated glomerular filtration rate ≥ 30 mL/min/1.73m^2
• Total kidney volume (htTKV) > 600 mL, calculated from a previous kidney ultrasound or magnetic resonance imaging performed within the last 12 months
• Access to the internet with video chat capabilities
• No plans for extended travel (>2 weeks) without internet access during the 12-month intensive period
• Not currently participating in or planning to participate in any formal weight loss or physical activity program, or another interventional study
• Ability to provide informed consent

Exclusion Criteria:

• Diabetes mellitus
• Current smokers or history of smoking in the past 12 months
• Alcohol dependence or abuse
• History of hospitalization or major surgery within the last 3 months
• Untreated dyslipidemia
• Uncontrolled hypertension
• Pregnancy, lactation, or unwillingness to use adequate birth control
• Cardiovascular disease, peripheral vascular disease, or symptoms suggestive of cardiovascular disease: chest pain, shortness of breath at rest or with mild exertion, syncope
• Abnormal resting electrocardiogram (ECG): serious arrhythmias, including multifocal premature ventricular contractions (PVC's), frequent PVC's (defined as 10 or more per min), ventricular tachycardia (defined as runs of 3 or more successive PVC's), or sustained atrial tachyarrhythmia; 2nd or 3rd degree A-V block, QTc interval > 480 msec or other significant conduction defects
• Significant pulmonary disease including: chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, or uncontrolled asthma
• Regular use of prescription or over-the-counter medications that may affect weight, appetite, food intake, or energy metabolism
• History of clinically diagnosed eating disorder including: anorexia nervosa, bulimia, binge eating disorder
• Weight loss of >5% in the past 3 months for any reason except post-partum weight loss; weight gain >5% requires assessment by PI
• Major psychiatric disorder (e.g., psychosis, schizophrenia, mania, bipolar disorder) or current severe depression, based on DSM-IV-TR criteria for Major Depressive Episode, which in the opinion of the Study MD would interfere with ability to adhere to dietary interventions)
• Inability to cooperate with or clinical contraindication for magnetic resonance imaging, including: severe claustrophobia, implants, devices, or non-removable body piercings
• Previous obesity treatment with surgery or weight loss device, except: (1) liposuction and/or abdominoplasty if performed > 1 year before screening, (2) lap banding if the band has been removed > 1 year before screening, (3) intragastric balloon if the balloon has been removed > 1 year before screening (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year before screening or 5) AspireAssist or other endoscopically placed weight loss device if the device has been removed > 1 year before screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daily Caloric Restriction; The daily caloric restriction group will participate in a 2-year, group-based, behavioral weight loss intervention based on a 30% reduction in caloric intake and increased physical activity.	Behavioral: Daily caloric restriction; Weight loss based on daily caloric restriction and increased physical activity
Other: Standard Advice Control; The standard advice control group will receive an initial consultation with a registered dietician regarding current clinical recommendations for ADPKD without subsequent counseling sessions.	Other: Standard advice control; Initial nutrition consultation without subsequent counseling

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in height-Adjusted Total kidney volume	To assess kidney growth, we will measure height-adjusted total kidney volume by magnetic resonance imaging at baseline and 24 months to determine annual percent change.	Baseline, 24-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in abdominal adiposity	Abdominal adiposity (subcutaneous, visceral, and total) will be assessed by magnetic resonance imaging.	Baseline, 24-months
Change in the ratio of insulin-like growth factor-1 (IGF-1)/ to GF binding protein-1	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 12-months, 24-months
Change in adiponectin (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 12-months, 24-months
Change in leptin (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 12-months, 24-months
Change in intereukin-6 (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 12-months, 24-months
Change in tumor necrosis factor-alpha (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 12-months, 24-months
Change in C-reactive protein (circulating)	Venous blood samples will be analyzed for this mechanistic biomarker	Baseline, 12-months, 24-months
Change in peripheral blood mononuclear cell protein expression of pAMPK/AMPK	PBMCs will be isolated from whole blood to assess protein expression	Baseline, 12-months, 24-months
Change in peripheral blood mononuclear cell protein expression of pS6K/S6K	PBMCs will be isolated from whole blood to assess protein expression	Baseline, 12-months, 24-months
Change in adiponectin (adipose tissue)	A subcutaneous adipose tissue biopsy will be performed for assessment of this mechanistic biomarker.	Baseline, 24-months
Change in leptin (adipose tissue)	A subcutaneous adipose tissue biopsy will be performed for assessment of this mechanistic biomarker.	Baseline, 24-months
Change in interleukin-6 (adipose tissue)	A subcutaneous adipose tissue biopsy will be performed for assessment of this mechanistic biomarker.	Baseline, 24-months
Change in tumor necrosis factor-alpha (adipose tissue)	A subcutaneous adipose tissue biopsy will be performed for assessment of this mechanistic biomarker.	Baseline, 24-months
Change in renal oxygen consumption	Renal oxygen consumption will be assessed by a PET/CT scan using 11-C acetate in a sub-set of participants	Baseline, 24-months
Change in gut microbiota	16S rRNA gene sequencing will be used for taxonomic characterization of the gut microbiota in a subset of participants.	Baseline, 24-months
Change in plasma metabolome	Untargeted plasma metabolomics will be performed using high-performance liquid chromatography-tandem mass spectrometry in a subset of participants.	Baseline, 24-months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (adverse events)	Number of participants with treatment-related adverse events in each group as evaluated by the DSMB	24-months
Change in dietary Energy Intake	Multiple pass 24-hr dietary recalls will be analyzed to evaluate self-reported energy intake	Baseline, 1-, 6-, 12-, and 24-months
Adherence	Self-reported dietary adherence using a 1-10 likert scale (10 is highest adherence)	24 months
Tolerability (dropout due to adverse events)	Subject dropout due to treatment-emergent adverse events	24 months
Change in free-living physical activity	Estimated energy expenditure (METs) over a 7-day period will be quantified using the activPAL3 micro.	Baseline, 6-, 12- and 24-months
Change in percent body fat	Percent body fat will be assessed via DEXA scan in a sub-set of participants.	Baseline, 24-months
Change in plasma choline	Plasma choline will be analyzed by high-performance liquid chromatography-tandem mass spectrometry in a sub-set of participants.	Baseline, 24-months
Change in plasma trimethylamine	Plasma trimethylamine will be analyzed by high-performance liquid chromatography-tandem mass spectrometry in a sub-set of participants.	Baseline, 24-months
Change in plasma trimethylamine-N-oxide	Plasma trimethylamine-N-oxide will be analyzed by high-performance liquid chromatography-tandem mass spectrometry in a sub-set of participants.	Baseline, 24-months

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Mayo Clinic; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Kristen Nowak, PhD, MPH, University of Colorado - Anschutz Medical Campus

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2021
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: May 25, 2021
• First Submitted That Met QC Criteria: May 27, 2021
• First Posted (Actual): June 1, 2021

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Overnutrition; Nutrition Disorders; Body Weight; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Overweight; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
• Other Study ID Numbers: 21-2999; R01DK129259 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data obtained through this study may be provided to qualified researchers with academic interest in ADPKD. Data shared will be coded, with no PHI included. Approval of the request and execution of all applicable agreements (i.e. data use agreement) are prerequisites to the sharing of data with the requesting party.
• IPD Sharing Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• IPD Sharing Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No