What is the first-line treatment for lithium-induced nephrogenic diabetes insipidus (DI) in addition to cessation of lithium?

Treatment of Lithium-Induced Nephrogenic Diabetes Insipidus

The first-line treatment for lithium-induced nephrogenic diabetes insipidus (NDI), in addition to cessation of lithium, is nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin. 1, 2

Pathophysiology and Treatment Approach

Lithium-induced NDI is characterized by the kidney's inability to respond to antidiuretic hormone, resulting in excessive urination and inability to concentrate urine. Treatment should follow a stepwise approach:

1. Discontinuation of lithium (when clinically appropriate)

   • This is the primary intervention, though NDI may persist for years after lithium cessation 3

2. First-line pharmacological therapy: NSAIDs

   • NSAIDs like indomethacin dramatically reduce urine volume within hours 1, 2
   • Can reduce urine flow to approximately 1/3 of baseline volume 1
   • Works by inhibiting prostaglandin synthesis, which plays a role in the pathogenesis of NDI 2

3. Supportive measures

   • Low salt (≤6 g/day) and protein diet (<1 g/kg/day) to reduce renal osmotic load 4
   • Ensure free access to fluids to prevent dehydration and hypernatremia 5

Evidence for NSAID Efficacy

• Studies have shown that indomethacin can produce an immediate decrease in urine volume and increase in urine osmolality that persists for several hours 2
• In emergency situations, indomethacin has been shown to be more effective than thiazides and amiloride in rapidly reducing polyuria 1
• Long-term (3 months) indomethacin therapy has demonstrated sustained favorable effects on polyuria without deleterious effects on renal function 2

Alternative and Adjunctive Therapies

Thiazide Diuretics

• Can be used as adjunctive therapy or when NSAIDs are contraindicated 6
• Can reduce diuresis by up to 50% when combined with a low-salt diet 5
• Often less effective than NSAIDs in acute management 1

Amiloride

• May be added to thiazide diuretics in patients who develop hypokalemia 5, 7
• Less effective as monotherapy compared to NSAIDs 1
• Can help mitigate lithium-induced renal toxicity 7

Desmopressin (DDAVP)

• Generally ineffective as monotherapy in nephrogenic DI 1
• May have some efficacy when used in combination with thiazides and NSAIDs 8
• More appropriate for central diabetes insipidus than nephrogenic forms 9

Monitoring and Precautions

• Monitor renal function when using NSAIDs, as they can rarely cause mild renal failure 1
• If renal function declines, consider reducing NSAID dose while maintaining therapeutic effect 1
• Monitor serum electrolytes, particularly when using diuretics 7
• In emergency situations with severe hypernatremia, consider controlled volume reduction if high urine output persists despite NSAID therapy 1

Special Considerations

• NSAIDs are contraindicated during pregnancy 4
• Consider discontinuing NSAIDs once patients reach adulthood or achieve complete continence 4
• For patients with persistent high urine output despite NSAID therapy, controlled fluid restriction may be necessary 1
• Each patient should have an emergency plan with instructions for intravenous fluid management 5

In conclusion, while multiple therapeutic options exist for lithium-induced NDI, NSAIDs like indomethacin have demonstrated superior efficacy in rapidly reducing urine volume and are therefore considered first-line therapy after lithium cessation.