Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD

Abstract

ABSTRACT Background Dysregulated energy metabolism is a recently discovered key feature of autosomal dominant polycystic kidney disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate (BHB) concentrations are associated with reduced disease progression in patients with ADPKD. Methods We analyzed data from 670 patients with ADPKD participating in the Developing Intervention Strategies to Halt Progression of ADPKD (DIPAK) cohort, a multi-center prospective observational cohort study. BHB was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting or had missing BHB levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. Results Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 [interquartile range (IQR) 495–1327] mL/m and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73 m2. The median concentration of BHB was 94 (IQR 68–147) µmol/L. Cross-sectionally, BHB was associated neither with eGFR nor with htTKV. Longitudinally, BHB was positively associated with eGFR slope {B = 0.35 mL/min/1.73 m2 [95% confidence interval (CI) 0.09 to 0.61], P = .007}, but not with kidney growth. After adjustment for potential confounders, every doubling in BHB concentration was associated with an improvement in the annual rate of eGFR by 0.33 mL/min/1.73 m2 (95% CI 0.09 to 0.57, P = .008). Conclusion These observational analyses support the hypothesis that interventions that raise BHB concentration could reduce the rate of kidney function decline in patients with ADPKD.