Nephrogenic Diabetes Insipidus
A form of diabetes insipidus where the kidneys fail to respond to vasopressin despite adequate hormone levels. Unlike central DI, nephrogenic DI does not respond to desmopressin. Treatment focuses on addressing the underlying cause and managing fluid balance.
Technical Context
Nephrogenic DI: kidneys fail to respond to vasopressin despite adequate hormone levels. Causes: genetic (X-linked AVPR2 gene mutations — V2 receptor defect, 90%; autosomal AQP2 gene mutations — aquaporin-2 water channel defect, 10%), acquired (lithium — most common acquired cause, affects ~20-40% of long-term users; hypercalcaemia, hypokalaemia, chronic kidney disease, ureteral obstruction, and various drugs). Pathophysiology: V2 receptor activation normally → Gαs → cAMP → PKA → aquaporin-2 vesicle translocation to collecting duct apical membrane → water reabsorption. Nephrogenic DI disrupts this pathway. Desmopressin is INEFFECTIVE (the target V2R system is non-functional). Treatment: manage underlying cause, thiazide diuretics (paradoxically reduce urine output by increasing proximal tubule reabsorption — reducing delivery of fluid to the collecting duct), amiloride (especially for lithium-induced — blocks lithium entry into collecting duct cells via ENaC), NSAIDs (reduce prostaglandin-mediated antagonism of vasopressin), and adequate hydration.