How does Tolvaptan (vasopressin V2 receptor antagonist) cause polyuria?

Mechanism of Tolvaptan-Induced Polyuria

Tolvaptan causes polyuria by selectively blocking vasopressin V2 receptors in the kidney's collecting ducts, preventing water reabsorption and resulting in aquaresis (excretion of electrolyte-free water). 1

Pharmacological Mechanism

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP), and its affinity for the V2-receptor is 29 times greater than for the V1a-receptor. 1 When administered orally at doses of 15 to 60 mg, tolvaptan antagonizes the effect of vasopressin on the principal cells of the collecting ducts, causing:

• Increased urine water excretion through aquaresis (excretion of free water without significant electrolyte loss) 1
• Increased free water clearance that results in decreased urine osmolality 1
• Increased serum sodium concentrations as a consequence of removing excess free body water 1
• No significant changes in urinary excretion of sodium and potassium or plasma potassium concentrations 1

Clinical Impact on Urine Volume

The aquaretic effect is substantial and predictable:

• Onset occurs within 2 to 4 hours post-dose, with peak effect observed between 4 and 8 hours 1
• Average urine output increases to approximately 6 liters per day in ADPKD patients treated with tolvaptan 2
• In clinical trials, patients experienced a median increase in urine volume of 128% (interquartile range 75%-202%), reaching 5,930±1,790 mL per day 2
• About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, though urinary excretion rate returns to baseline by this time 1

Key Determinant: Osmolar Excretion

The major determinant of urine volume in patients taking tolvaptan is 24-hour osmolar excretion (standardized β = 0.73; P < 0.001), not kidney function or total kidney volume. 2 This occurs because:

• Tolvaptan blocks the kidney's ability to concentrate urine by preventing water reabsorption 2
• Osmolar excretion is strongly associated with 24-hour urine volume during V2 receptor antagonist treatment 2
• The inability to concentrate urine means that all ingested osmoles must be excreted in dilute urine 2

Clinical Implications for Management

Patients must drink enough water to replace urinary losses to ensure long-term tolerability. 3 The KDIGO 2025 guidelines emphasize:

• Low osmolar intake reduces polyuria - patients should be counseled to drink liquids without sugar or fat and adopt a low-sodium intake 3
• Tolvaptan treatment should be interrupted in situations causing volume depletion or inability to compensate for aquaresis 3
• Patients need a "sick-day plan" to skip doses during situations with limited water access, increased fluid losses, or activities in warm weather 3

Common Side Effects Related to Aquaresis

The most commonly reported adverse events in clinical trials directly reflect the mechanism of action:

• Thirst (7.7%-40.3% of patients) 4
• Dry mouth (4.2%-23.0% of patients) 4
• Polyuria or pollakiuria (0.6%-31.7% of patients) 4, 1

These side effects are consistent with the drug's pharmacological action of promoting water excretion without electrolyte loss. 4