Daily Caloric Restriction and Intermittent Fasting in Overweight and Obese Adults With Autosomal Dominant Polycystic Kidney Disease

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. Surprisingly, the
role of obesity in ADPKD progression is currently unknown. The investigators have novel
preliminary data that overweight and obesity are independently associated with substantially
faster kidney growth in ADPKD patients. Furthermore, in rodent models of ADPKD,
mild-to-moderate food restriction profoundly slows cyst growth and maintains renal function
via mechanisms including AMPK-activated kinase pathway activation and suppression of
mammalian target of rapamycin/S6 kinase signaling and insulin-like growth factor-1 levels.
Collectively, these data suggest that dietary restriction regimens may slow ADPKD
progression. Accordingly, the primary aim is to determine the feasibility of delivering a 1
year behavioral weight loss intervention program in 30 overweight/obese adults with ADPKD,
based on either daily caloric restriction (DCR) or intermittent fasting (IMF), with a similar
(~34%) targeted weekly energy deficit. A key secondary goal is to evaluate safety,
acceptability, and tolerability of IMF in ADPKD versus DCR. Last, the third exploratory aim
is to a) obtain mechanistic insight into biological pathways that may be altered and b)
provide initial insight into any changes in total kidney volume by magnetic resonance imaging
with IMF and/or DCR.

Inclusion Criteria:

1. Aged 18-65 years

2. ADPKD diagnosis based on the modified Pei-Ravine criteria

3. BMI 25-45 kg/m^2

4. Normal to mildly declined renal function with an estimated glomerular filtration rate
(eGFR) ≥30 mL/min/1.73 by the CKD-EPI equation

5. Access to the internet with video chat capabilities

6. No plans for extended travel (>2 weeks) during the 3 month intesive period

7. Not currently participating in another interventional study or weight loss program

8. Ability to provide informed consent

Exclusion Criteria:

1. Diabetes mellitus (diagnosis or fasting glucose >126 mg/dL or Hemoglobin A1C >6.5%)

2. Current nicotine use or history of use in the past 12 months

3. Alcohol or substance abuse (self-report or undergoing treatment)

4. History of hospitalization or major surgery within the last 3 months

5. Untreated dyslipidemia (low density lipoprotein cholesterol > 190 mg/dL or
triglycerides >400 mg/dL)

6. Uncontrolled hypertension (systolic blood pressure > 160 or diastolic blood pressure
>100 mm Hg)

7. Pregnancy, lactation, or unwillingness to use adequate birth control

8. Cardiovascular disease, peripheral vascular disease, cerebrovascular disease,
significant pulmonary or gastrointestinal disease (described below), cancer (within
the last 5 years, except skin cancer or other cancers considered cured with excellent
prognosis)

9. Abnormal resting electrocardiogram (ECG): serious arrhythmias, including multifocal
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

10. Significant gastrointestinal disorders including: chronic malabsorptive conditions,
peptic ulcer disease, Crohn's disease, ulcerative colitis, chronic diarrhea, or active
gallbladder disease

11. Significant pulmonary disorders including: chronic obstructive pulmonary disease,
interstitial lung disease, cystic fibrosis, or uncontrolled asthma

12. Regular use of prescription or over-the-counter medications that may affect weight,
appetite, food intake, or energy metabolism (e.g. appetite suppressants, lithium,
stimulants, anti-psychotics, tricyclic antidepressants; Study M.D. will be consulted
as needed; antibiotics started during the intervention period are not an exclusion);
regular use of obesity pharmacotherapeutic agents within the last 6 month

13. History of clinically diagnosed eating disorder including anorexia nervosa, bulimia,
binge eating disorder

14. Weight loss >5% in past 3 months for any reason except post-partum weight loss; weight
gain >5% in past 3 months requires assessment by PI to determine reason for weight
gain and if it is appropriate for the subject to participate in the study.

15. Untreated hyper- or hyperthyroidism (TSH outside of normal range for laboratory or
history of uncontrolled thyroid disorder). History of thyroid disorder or current
thyroid disease treated with stable medication regimen for at least 6 months in
acceptable.

16. Current severe depression or history of severe depression within the previous year,
based on DSM-IV-TR criteria for Major Depressive Episode.

17. History of other significant psychiatric illness (e.g. psychosis, schizophrenia,
mania, bipolar disorder) which in the opinion of the Study MD would interfere with
ability to adhere to dietary interventions.

18. Inability to cooperate with/clinical contraindication for MRI including severe
claustrophobia, implants, devices, or non-removable body piercings