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. An increase in total kidney volume (TKV) precedes the decline in kidney function, thus rate of TKV, as measured by magnetic resonance imaging (MRI) is an important indicator of progression early in the course of ADPKD. As there are currently no FDA-approved medications specifically for the treatment of cyst growth in ADPKD, interventions that may slow progression of ADPKD are of considerable clinical importance. Similar to the general population, the prevalence of overweigh and obesity have been rising in ADPKD. Surprisingly, the role of obesity in ADPKD progression is currently unknown. We 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 AMP-activated kinase (AMPK) pathway activation and suppression of mammalian target of rapamycin (mTOR)/S6 kinase (S6K) signaling and insulin-like growth factor-1 (IGF-1) levels. Collectively, these data suggest that dietary restriction regimens may slow ADPKD progression. The current standard of care dietary approach for treatment of obesity is daily caloric restriction (DCR). An alternate approach to traditional DCR is intermittent fasting (IMF), which consist of reducing caloric intake 1-3 days per week. Notably, the periods of fasting implemented with the latter approach may have profound effects upon pathways implicated in ADPKD progression, including AMPK activation, suppression of the mTOR-S6K signaling, and reduced IGF-1 signaling. Accordingly, the primary aim is to determine the feasibility of delivering a behavioral weight loss intervention (based on either DCR or IMF; 3 month intensive phase; 9 month maintenance phase) in 30 adults with ADPKD and overweight/obesity and normal renal function, based on either DCR or IMF, with a similar (~30%) targeted weekly energy deficit. A key secondary goal is to evaluate safety, acceptability, and tolerability of IMF in ADPKD versus DCR. Last, a third exploratory aim is to a) obtain mechanistic insight into biological pathways that may be altered (including IGF-1/IGF binding protein-1 levels, peripheral blood mononuclear cell expression of p-AMPK and p-S6K, and serum ?-hydroxybutyrate (ketone) levels after 3 and 12 months; b) provide initial insight regarding any changes in TKV at 12 months with IMF and/or DCR. These aims will be tested in a randomized, two-active arm, pilot clinical trial. Although weight loss is recommended for individuals with overweight/obesity in the general population, clinical studies evaluating the feasibility and efficacy of this recommendation in ADPKD patients, surprisingly, have not been performed. The proposed aims will provide the necessary foundation for a subsequent long-term trial assessing the efficacy of dietary restriction for slowing ADPKD progression.

R03DK118215

2018-09-15

2020-07-31