A 28-year-old man from Mumbai presents with polyuria (8 L/day) and polydipsia for 3 weeks. Serum osmolality is 310 mOsm/kg and urine osmolality is 150 mOsm/kg despite normal plasma ADH levels. A water deprivation test shows no change in urine osmolality, but intranasal desmopressin administration increases urine osmolality to 600 mOsm/kg. Which segment of the nephron is primarily responsible for the concentrating defect in this patient?

Explanation

## Clinical Diagnosis: Nephrogenic Diabetes Insipidus (NDI) ### Pathophysiology The patient has **nephrogenic diabetes insipidus** — kidneys are unresponsive to ADH despite normal or elevated ADH levels. The water deprivation test failure followed by response to desmopressin (exogenous ADH) confirms the kidney's inability to respond to endogenous ADH. ### Nephron Segment Responsible for Urine Concentration **Key Point:** The **collecting duct** is the primary site of water reabsorption and urine concentration. ADH acts on V~2~ receptors on the principal cells of the collecting duct, increasing aquaporin-2 water channel expression and allowing water reabsorption down the osmotic gradient established by the loop of Henle and vasa recta. ### Why the Collecting Duct? | Segment | Function | ADH Responsiveness | |---------|----------|--------------------| | **Collecting duct** | Water reabsorption; final urine concentration | **Highly responsive** — primary target of ADH | | Thick ascending limb | Active Na⁺-K⁺-2Cl⁻ reabsorption; osmotic gradient | ADH-independent | | Distal convoluted tubule | Fine-tuning of Na⁺ and K⁺ reabsorption | Minimal water permeability | | Proximal convoluted tubule | Bulk reabsorption of water and solutes | Constitutively permeable; ADH-independent | ### Clinical Pearl In nephrogenic NDI, the collecting duct epithelium fails to respond to ADH due to: - Mutations in aquaporin-2 (AQP2) genes (congenital) - Medications (lithium, amphotericin B, demeclocycline) - Chronic kidney disease or post-obstructive diuresis The patient's response to desmopressin (synthetic ADH) in this case suggests a partial or acquired form; complete congenital NDI would not respond even to high-dose desmopressin. **High-Yield:** Collecting duct damage → inability to concentrate urine → polyuria + polydipsia + high serum osmolality + low urine osmolality (despite high ADH).