A 45-year-old male with bipolar disorder on chronic lithium therapy presents with polyuria (8 L/day) and polydipsia. Serum osmolality is 295 mOsm/kg and serum sodium is 142 mEq/L. A water deprivation test shows minimal increase in urine osmolality (from 150 to 165 mOsm/kg), which does not improve further after intravenous desmopressin (DDAVP). The structure marked **D** in the diagram (Aquaporin-2) fails to respond appropriately to ADH signaling. Which of the following best explains the pathophysiology in this patient?

Explanation

## Why option 1 is correct Lithium is the most common acquired cause of nephrogenic diabetes insipidus (NDI). It interferes with the V2 receptor–Gs–cAMP–PKA signaling cascade, preventing phosphorylation-mediated translocation of AQP2 from intracellular vesicles to the apical membrane of collecting duct principal cells. Without AQP2 at the apical surface, water cannot be reabsorbed despite normal or elevated ADH levels. The water deprivation test result (minimal response to DDAVP) is pathognomonic for nephrogenic DI: the kidneys are unresponsive to exogenous ADH because the signaling defect (not ADH deficiency) is the problem. This patient's clinical presentation—chronic lithium use, polyuria, hypernatremia, and failure of DDAVP to concentrate urine—is the classic picture of lithium-induced nephrogenic DI (Guyton & Hall 14e Ch 28, 75; Harrison 21e Ch 384). ## Why each distractor is wrong - **Option 2 (Central DI)**: Central DI results from deficient ADH production (hypothalamic or pituitary pathology). In central DI, the water deprivation test shows poor urine concentration, BUT urine osmolality rises >50% after DDAVP administration because the kidneys are intact and respond to exogenous ADH. This patient's urine osmolality did NOT improve with DDAVP, ruling out central DI. - **Option 3 (Genetic AQP2 mutation)**: Congenital nephrogenic DI from AQP2 mutations is rare and would present in infancy or early childhood with severe polyuria. This patient's late-onset polyuria directly temporally related to lithium initiation makes acquired lithium-induced NDI far more likely. Additionally, genetic NDI would not be reversible upon lithium cessation, whereas lithium-induced NDI can partially recover. - **Option 4 (Excessive ADH)**: This describes SIADH, which causes euvolemic hyponatremia (low serum sodium), not hypernatremia. This patient has hypernatremia (142 mEq/L) and dilute urine, which is incompatible with excess ADH action. **High-Yield:** Lithium-induced nephrogenic DI = failure of DDAVP response on water deprivation test; distinguish from central DI (DDAVP-responsive) by the desmopressin challenge. [cite: Guyton & Hall 14e Ch 28, 75; Harrison 21e Ch 384]