Mild reduction in food intake was recently shown to slow polycystic kidney disease (PKD) progression in mouse models, but whether the effect was due to solely reduced calories or some other aspect of the diet has been unclear. We now show that the benefit is due to the induction of ketosis. Time-restricted feeding, without caloric reduction, strongly inhibits mTOR signaling, proliferation, and fibrosis in the affected kidneys in a PKD rat model. A ketogenic diet had a similar effect and led to regression of renal cystic burden. Acute fasting in rat, mouse, and feline models of PKD results in rapid reduction of cyst volume, while oral administration of the ketone β-hydroxybutyrate (BHB) in rats strongly inhibits PKD progression. These results suggest that cystic cells in PKD are metabolically inflexible, which could be exploited by dietary interventions or supplementation with BHB, representing a new therapeutic avenue to treat PKD.
Keywords: beta-hydroxybutyrate; ketogenic diet; ketosis; metabolic inflexibility; polycystic kidney disease.
Copyright © 2019 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests
JT and TW are listed inventors on a provisional patent application filed by UCSB related to discoveries reported in this paper. TW is an inventor on a patent application by UCSB on a discovery unrelated to this paper. MM reports grants and consulting fees outside the submitted work from Otsuka Pharmaceuticals,Sanofi, and Chinook Therapeutics.
[Effect of a Modified Low Protein and Low Fat Diet on Histologic Changes and Metabolism in Kidneys in an Experimental Model of Polycystic Kidney Disease]N Banković-Calić et al. Srp Arh Celok Lek 130 (7-8), 251-7. PMID 12585002.Effect on histology: Low casein and soy feeding ameliorates Han: SPRD-cy rat polycystic kidney disease reducing both tubular remodeling and interstitial inflammation and …
Dietary n-3 Polyunsaturated Fatty Acids or Soy Protein Isolate Did Not Attenuate Disease Progression in a Female Rat Model of Autosomal Recessive Polycystic Kidney DiseaseKH Maditz et al. Nutr Res 34 (6), 526-34. PMID 25026920.Polycystic kidney disease (PKD) is an incurable genetic disorder that is characterized by multiple benign cysts. As PKD advances, cyst growth increases kidney volume, dec …
Periostin Overexpression in Collecting Ducts Accelerates Renal Cyst Growth and Fibrosis in Polycystic Kidney DiseaseA Raman et al. Am J Physiol Renal Physiol 315 (6), F1695-F1707. PMID 30332313.In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth and fibrosis, leading to progressive dete …
Recent Advances in Understanding the Pathogenesis of Polycystic Kidney Disease: Therapeutic ImplicationsBD Cowley Jr. Drugs 64 (12), 1285-94. PMID 15200344. - ReviewHereditary polycystic kidney disease (PKD) is a common cause of renal failure. Increasing knowledge is available regarding mechanisms of cyst development and progression, …
Inflammation and Fibrosis in Polycystic Kidney DiseaseCJ Song et al. Results Probl Cell Differ 60, 323-344. PMID 28409351. - ReviewPolycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151-164, 2004) and is caused by mu …