A 38-year-old woman with bipolar I disorder has been on lithium 900 mg daily for 3 years with good mood stabilization. She now presents with polyuria and polydipsia. Serum lithium level is 0.8 mEq/L (therapeutic range). What is the most common cause of polyuria in chronic lithium therapy?

## Lithium and Polyuria **Key Point:** Nephrogenic diabetes insipidus (NDI) is the most common renal side effect of chronic lithium therapy, occurring in 20–40% of patients on long-term lithium. ### Mechanism of Lithium-Induced NDI 1. Lithium accumulates in collecting duct principal cells 2. Inhibits adenylyl cyclase → reduced cAMP production 3. Impairs aquaporin-2 water channel insertion into apical membrane 4. Results in resistance to antidiuretic hormone (ADH) 5. Polyuria (often 2–3 L/day) and compensatory polydipsia develop **High-Yield:** This is a **functional** (reversible in early stages) form of NDI, distinct from structural kidney damage. Early detection and intervention (adequate hydration, amiloride, or NSAIDs) can halt progression. ### Clinical Features | Feature | Lithium-Induced NDI | |---------|--------------------| | **Onset** | Months to years of therapy | | **Serum lithium level** | Can occur even at therapeutic levels (0.6–1.2 mEq/L) | | **Urine osmolality** | Low (< 300 mOsm/kg) despite high serum osmolality | | **Response to desmopressin** | Poor or absent (true NDI) | | **Reversibility** | Partial if caught early; may persist after drug withdrawal | **Clinical Pearl:** Patients on chronic lithium should be counselled about maintaining adequate fluid intake and monitored with baseline and periodic renal function tests and urinalysis. **Mnemonic:** **LEND** = **L**ithium → **E**ndocrine & **N**ephric **D**amage (NDI is the classic renal complication).