A 52-year-old woman with bipolar disorder has been on lithium 900 mg daily for 3 years with good mood stabilization. She presents with polyuria and polydipsia for the past 6 months. Serum lithium level is 0.8 mEq/L (therapeutic range). What is the most common cause of polyuria in chronic lithium therapy?

## Lithium-Induced Polyuria: Mechanism and Epidemiology **Key Point:** Nephrogenic diabetes insipidus (NDI) is the most common renal complication of chronic lithium therapy, occurring in 20–40% of patients on long-term lithium. ### Pathophysiology Lithium causes NDI through two mechanisms: 1. **Acute phase (reversible):** Lithium enters collecting duct principal cells via ENaC channels and inhibits cAMP-mediated aquaporin-2 (AQP-2) insertion, reducing water reabsorption. 2. **Chronic phase (partially irreversible):** Chronic lithium exposure leads to: - Downregulation of AQP-2 expression - Structural damage to collecting duct epithelium - Fibrosis and atrophy of the distal tubule and collecting duct - Loss of responsiveness to vasopressin ### Clinical Features - **Polyuria:** Often 3–10 L/day (compared to normal 1–2 L/day) - **Polydipsia:** Compensatory thirst - **Serum osmolality:** Elevated (>295 mOsm/kg) - **Urine osmolality:** Low (<300 mOsm/kg) despite hypernatremia — diagnostic of NDI - **Serum sodium:** May be elevated (hypernatremia) **Clinical Pearl:** Lithium-induced NDI can occur even at therapeutic serum levels (0.6–1.2 mEq/L), as demonstrated in this case. The duration of therapy is a risk factor — longer exposure increases incidence. ### Diagnostic Approach | Feature | Lithium-Induced NDI | Central DI | Primary Polydipsia | |---------|-------------------|-----------|-------------------| | **Urine osmolality** | <300 mOsm/kg | <300 mOsm/kg | >600 mOsm/kg | | **Response to desmopressin** | None or minimal | Complete | Minimal | | **Serum sodium** | High or normal | High | Low or normal | | **Serum osmolality** | High | High | Low | | **Lithium level** | Therapeutic | N/A | N/A | ### Management 1. **First-line:** Amiloride (5–10 mg daily) — blocks lithium entry into collecting duct cells via ENaC inhibition. Most effective for lithium-induced NDI. 2. **Alternative:** NSAIDs (indomethacin) — reduce prostaglandin-mediated cAMP, but risk of renal impairment. 3. **Supportive:** Adequate hydration, low-sodium diet, monitor renal function and serum sodium. 4. **Consider lithium discontinuation** if NDI is severe or unresponsive to amiloride. **High-Yield:** Amiloride is the drug of choice for lithium-induced NDI because it selectively blocks lithium entry into the collecting duct without affecting sodium reabsorption (unlike thiazide diuretics, which paradoxically worsen NDI). **Mnemonic:** **LEND** — **L**ithium → **E**arly (acute, reversible) and **N**ephrogenic **D**iabetes Insipidus.