Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) results from the kidney's inability to respond to antidiuretic hormone (ADH/vasopressin), leading to excretion of large volumes of dilute urine despite normal or elevated circulating ADH levels. Normally, ADH binds to vasopressin V2 receptors (AVPR2) on the basolateral membrane of principal cells in the collecting duct, activating adenylyl cyclase and increasing intracellular cAMP. This triggers protein kinase A-mediated phosphorylation and translocation of aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical membrane, creating a water-permeable pathway. Water then flows osmotically from the tubular lumen through AQP2 into the hypertonic medullary interstitium (maintained by the countercurrent multiplier system) and exits via basolateral AQP3 and AQP4 channels into the peritubular capillaries. In NDI, this pathway is disrupted: congenital X-linked NDI (most common hereditary form, affecting male infants) involves loss-of-function mutations in the AVPR2 gene, rendering the V2 receptor non-functional; autosomal recessive NDI involves mutations in the AQP2 gene, producing defective water channels. Lithium is the most common acquired cause, affecting up to 40% of patients on chronic therapy: lithium enters principal cells through epithelial sodium channels (ENaC)...