Ketone body metabolism in kidney disease: mechanisms, therapeutic opportunities, and translational challenges

The kidneys are central to systemic homeostasis, and the rising global burden of acute and chronic kidney disease has intensified the search for new therapeutic targets. Metabolic reprogramming is increasingly recognized as an important contributor to renal injury, highlighting metabolic and nutritional modulation as an area of growing interest. Ketone bodies, most notably β-hydroxybutyrate (BHB), function not only as alternative energy substrates but also as signaling molecules and epigenetic modifiers. Emerging evidence suggests that BHB may modulate oxidative stress, inflammation, and cellular stress responses through interconnected mechanisms involving histone deacetylase regulation, nuclear factor erythroid 2-related factor 2 (NRF2) signaling, and lysine β-hydroxybutyrylation (Kbhb). Preclinical evidence suggests that renal HMGCS2 can be induced under specific metabolic conditions, although the significance of renal ketone production in humans remains uncertain. In this review, we summarize renal ketone metabolism and examine the molecular mechanisms through which ketone bodies may influence renal physiology and disease. We specifically consider how nutritional strategies such as ketogenic diets, fasting-mimicking protocols, and exogenous ketone supplementation may affect mitochondrial function and epigenetic regulation in diseases such as diabetic kidney disease and obesity-related glomerulopathy. Finally, we evaluate the therapeutic potential, safety considerations, and translational challenges associated with ketone-based interventions in kidney disease.