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The urine aquaporin-2 (U-AQP2) level relative to the plasma arginine vasopressin (P-AVP) level is a novel predictor of the responsiveness to the vasopressin type 2 receptor (V2R) antagonist tolvaptan (TLV). However, little has been reported about the concentration-time profile of U-AQP2 after TLV treatment. We evaluated 24 patients with decompensated stage D heart failure (HF) who had received 3.75 mg/day of TLV on a de novo basis for &gt; 7 days to treat congestion refractory to conventional diuretics. Seventeen patients were TLV-responders, whose 24-hour urine volume (UV) increased after TLV initiation; the other 7 patients were TLV-non-responders. The U-AQP2 of the TLV-responders, corrected for the urine creatinine concentration, decreased significantly at 4 hours after TLV administration without returning to the day-1 morning level on the morning of day-7. The TLV-non-responder U-AQP2 levels remained low even before the TLV treatment. On the morning of day-7, the TLV-responder U-AQP2/P-AVP ratio was comparable to that of the TLV-non-responders. Among 18 patients (11 responders and 7 non-responders), the day-7 TLV trough concentration was 64 ± 62 ng/mL and was negatively correlated with the estimated glomerular filtration rate (eGFR). TLV has antagonistic effects on the V2R over 24 hours in TLV-responders with advanced heart failure and chronic kidney disease, probably due to persistently elevated blood TLV concentration. The unresponsiveness to TLV in the TLV-non-responders is not attributable to malabsorption.

Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure