Urinary Exosomal Aquaporin-2 Expression and the Efficacy of Tolvaptan in Advanced CKD Patients with Congestive Heart Failure: An Interim Report

Abstract

Background: The efficacy of tolvaptan, a selective antagonist for vasopressin V2 receptor, on water diuresis has been reported in congestive heart failure (CHF) patients with chronic kidney disease (CKD). However, the mechanism of tolvaptan resistance is not well understood. In this study the effect of tolvaptan on urinary expression of exosomal aquaporin-2 (AQP-2) was examined in relation to effectiveness of tolvaptan. Methods: We examined 13 CHF patients with advanced CKD (M:F=11:2, age 49 to 81, serum creatinine 1.7 to 10.4 mg/dL, eGFR 3.5 to 69 ml/min/1.73 m2, median 9.2) who were not under control with conventional treatment including furosemide therapy (40 to 80 mg orally). Tolvaptan of 7.5 mg/day was instituted and blood and urine parameters were measured as well as urinary exosomal AQP-2 and Na-K-2Cl cotransporter (NKCC2). Responders were defined as increase in urine volume greater than 500 ml/day after the treatment. Results: Eight patients were diagnosed as responders who increased urine volume together with decrease in body weight within several days (p<0.05 vs. before treatment). Baseline data did not show the significant difference between both groups. Serum levels of creatinine and Na did not change over 1 week in either responders or non-responders. All responders showed a significant reduction in urinary exosomal AQP-2 after the treatment whereas non-responders showed rather increase in its expression. In contrast, urinary exosomal NKCC2 expression was unaltered in any case. Conclusions: Tolvaptan exerts its diuretic action in more than half the CHF patients complicated with advanced CKD. The responsiveness corroborates well with urinary exosomal AQP2 expression. The predictor for resistance to tolvaptan needs further examination.