β-Hydroxybutyrate: a renoprotective hormone in polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic form of chronic kidney disease characterized by highly variable rates of progression. This variability suggests that nutritional, lifestyle, and environmental factors may significantly influence disease course. Despite its prevalence, pharmacological treatment options for ADPKD remain very limited, underscoring the urgent need for safe and effective therapeutic strategies. Recent research has identified ADPKD as a metabolic disorder at the cellular level, marked by impaired mitochondrial function and a pathological reliance on glucose metabolism in affected cells. Ketogenic metabolic therapy (KMT) targets this metabolic vulnerability and has shown promising outcomes in both preclinical models and early clinical studies. KMT encompasses a range of interventions including ketogenic diets, intermittent fasting, time-restricted feeding, and supplementation with the ketone body β-hydroxybutyrate (BHB). Accumulating evidence suggests that BHB is the principal renoprotective mediator underlying the therapeutic benefits of KMT. Beyond serving as an alternative energy substrate, BHB exerts pleiotropic signaling effects that may synergistically contribute to reduced cyst proliferation, inflammation, oxidative stress, and fibrosis, while enhancing mitochondrial function. These attributes position BHB as a renoprotective signaling hormone. Importantly, chronic suppression of endogenous ketogenesis is common in modern societies because of dietary and lifestyle patterns and may deprive tissues of BHB's pleiotropic signaling functions. In this narrative review, we summarize the current understanding of KMT and BHB in the context of ADPKD and discuss their potential as safe, noninvasive, and disease-modifying interventions.