Thiazide diuretics use in the management of nephrogenic diabetes insipidus Thiazide diuretics, paradoxically, serve as a cornerstone in the management of nephrogenic diabetes insipidus (NDI), a condition characterized by the kidneys' inability to respond to antidiuretic hormone (ADH), leading to excessive urination (polyuria) and thirst (polydipsia). While their primary function as diuretics is to increase urine output, in NDI, they achieve a remarkable antidiuretic effect. The precise mechanism, though still under extensive research, is largely attributed to their action on the distal convoluted tubule. By inhibiting the Na-Cl cotransporter in this segment, thiazides reduce sodium reabsorption, leading to mild extracellular fluid volume depletion. This volume contraction then triggers a compensatory increase in proximal tubular reabsorption of both sodium and water. Consequently, less fluid is delivered to the collecting ducts, the site where ADH would normally exert its water-retaining effect but is ineffective in NDI. This reduced distal delivery of fluid ultimately decreases the overall urine volume. Additionally, some evidence suggests thiazides may directly or indirectly affect aquaporin-2 (AQP2) expression and other renal sodium transporters, contributing to their beneficial effect. It is crucial to combine thiazide therapy with a low-sodium diet to enhance their efficacy. However, careful monitoring for potential adverse effects, such as hypokalemia, hyponatremia, and hypercalcemia, is essential, and potassium-sparing diuretics like amiloride are often co-administered to mitigate hypokalemia, particularly in lithium-induced NDI, where amiloride can also directly block lithium entry into collecting duct cells.