Bartter Syndrome (SLC12A1/KCNJ1, AR)

A 2-week-old male neonate born at 33 weeks gestation presents with polyuria, severe dehydration, and failure to thrive. Maternal history is significant for polyhydramnios. Laboratory investigations reveal serum potassium 2.4 mEq/L, HCO3− 34 mEq/L, hypercalciuria, and elevated plasma renin activity with normal blood pressure. Renal ultrasound shows medullary nephrocalcinosis. Genetic testing confirms a homozygous mutation in the gene located on **chromosome 15** (marked **A** in the diagram), encoding the sodium-potassium-chloride cotransporter (NKCC2) of the thick ascending limb. Which of the following best explains the pathophysiology of this condition?