Alpelisib

Inhibiting p110-alpha blocks insulin's own PI3K-dependent signaling, producing on-target insulin resistance with hyperglycemia and a compensatory hyperinsulinemic state (the hyperglycemia paradoxically reactivates tumor PI3K, the rationale for SGLT2 inhibitors as adjuncts). Marked hyperglycemia causes a glucose osmotic diuresis with renal sodium and water loss, volume contraction and prerenal azotemia; severe cases progress to hyperosmolar states or DKA with true AKI. The kidney lesion is therefore hemodynamic/metabolic rather than a direct tubular or glomerular toxicity.

Rising fasting glucose within days to a few weeks of starting therapy, polyuria, polydipsia and weight loss; rising creatinine with a bland sediment, high urine osmolality and low FeNa typical of a prerenal state. In extreme cases: hyperosmolar hyperglycemic state or ketoacidosis with anion-gap metabolic acidosis and acute tubular injury.

Hyperglycemia typically within the first 1-2 weeks; prerenal AKI follows volume depletion or a hyperglycemic crisis.

Selective oral inhibitor of the p110-alpha catalytic isoform of class I PI3K (PIK3CA). In PIK3CA-mutated hormone-receptor-positive, HER2-negative breast cancer it blocks PI3K/AKT/mTOR signaling downstream of the activated receptor, restoring sensitivity to endocrine therapy (fulvestrant).

Treat the hyperglycemia aggressively (metformin first-line; add SGLT2 inhibitor, insulin or others for grade 3/4), maintain euvolemia with fluids, and hold or reduce alpelisib until glucose is controlled. Manage DKA/HHS in the usual way with IV fluids and insulin; the AKI generally resolves with restoration of volume and glycemic control. Involve endocrinology for refractory hyperglycemia.