Ketogenic diet ameliorates diabetic kidney disease but promotes renal lipid and calcium deposition

Abstract The ketogenic diet (KD) is widely used for weight loss and the treatment of type 2 diabetes (T2D), yet its impact on diabetic kidney disease (DKD) remains unclear. Here, we show that KD induces weight loss, normalizes hyperglycemia, and promotes sustained ketosis, leading to improved structural and functional features of DKD in a mouse model of T2D, effects not fully recapitulated by exogenous ketone supplementation. Despite these improvements, KD promotes ectopic lipid accumulation and calcium deposition within the kidney. Mechanistically, KD lowers circulating lipids while increasing the circulating abundance of ApoB48-containing intestinal triglyceride-rich lipoproteins and enhancing renal lipid processing, fatty acid uptake, and triglyceride synthesis. In parallel, KD induces hypercalciuria and renal calcification through increased intestinal calcium absorption, driven by activation of the renal–intestinal vitamin D axis, but independent of bone resorption. Together, these findings demonstrate that KD confers renoprotective effects while inducing metabolic adaptations that may compromise renal health.