Ketone bodies for kidney injury and disease

Ketone bodies are metabolic fuels and endogenous signaling molecules with multi-systemic benefits. β-Hydroxybutyrate, the main circulating one during fasting, calorie restriction, and physical exercise, improves neurological and cardiovascular function and extends lifespan when administered exogenously. It is now clear that there exists bidirectional crosstalk between ketone bodies and the kidney. Ketones serve important energetic roles in the kidney, whereas the kidney contributes to maintaining ketone homeostasis through renal tubular reabsorption. Ketones are also beneficial for the kidney in distinct pathological conditions, including drug-induced nephrotoxicity, renal ischemia and reperfusion injury, nephrocalcinosis, polycystic kidney disease, diabetic nephropathy, hypertension, and renal aging. The underlying mechanisms involve regulating gene expression and modulation of several signal transduction pathways that lead to oxidative stress reduction, suppression of inflammation, prevention of interstitial fibrosis development, and protection of renal cells from apoptosis and pyroptosis. This brief review summarizes all the recent findings in cellular and animal models pointing to the renoprotective effect of ketones. It also considers potential therapeutic limitations and discusses the adverse impact of ketones when out of the physiological range. Finally, we suggest that dietary interventions, lifestyle changes, and pharmacological approaches that increase circulating ketones may be helpful to promote kidney resilience to both stress and disease in the clinical setting