THE ASSOCIATION OF BETA-HYDROXYBUTYRATE AND KIDNEY FUNCTION DECLINE IN THE GENERAL POPULATION-RESULTS FROM THE PREVEND STUDY

Abstract BACKGROUND AND AIMS Beta-hydroxybutyrate (BHB), a ketone body, has shown to be renoprotective in various disease-specific preclinical studies. The underlying mechanism of this renoprotective effect might be via the reduction of inflammation, apoptosis, oxidative stress, and fibrosis. Interest in the effects of this metabolite is rising because supplementation is possible as an intervention. We hypothesized that endogenous BHB is associated with better kidney function outcomes in the general population. The aim of this study is to assess the association between BHB and kidney function. METHOD We included 6127 participants with available plasma BHB data from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women. BHB was measured in fasting participants using nuclear magnetic resonance (NMR) spectroscopy. The association of BHB with estimated glomerular filtration rate (eGFR), calculated with the CKD-EPI creatinine cystatin C equation, was tested using multivariable linear regression for cross-sectional analyses and linear mixed modeling for longitudinal analyses. The analyses were adjusted for sex, age, BMI, smoking, diabetes type 2, hypertension and hyperlipidemia. RESULTS Overall, 50.6% of the included subjects were female, mean age was 53.6 ± 12.1 years. At baseline, the median BHB concentration was 121.5 μmol/L [inter quartile range (IQR) 92.8–169.2] and the mean eGFR was 92 ± 17 mL/min/1.73m2. In cross-sectional analyses, a higher BHB was associated with a lower eGFR, after adjustment for covariates (st.β= −0.041, P < 0.001). During a median follow-up of 7.5 years (IQR 7.2–8.0), the mean annual change in eGFR was −0.96 ± 0.52 mL/min/1.73m2/year. In longitudinal analyses, a higher BHB was associated with less eGFR decline in the fully adjusted model [0.17 (95% confidence interval, CI 0.01–0.33); P = 0.04]. After exclusion of participants with diabetes type 2, the association of BHB and eGFR decline became stronger [0.22 (95% CI 0.06–0.38); P = 0.01]. CONCLUSION Higher BHB levels were associated with less eGFR decline in this general population cohort. In combination with previous preclinical data, this data supports the hypothesis that BHB is renoprotective and forms a rationale to study whether supplementation with BHB attenuates kidney function decline in patients with chronic kidney disease.