Efficacy of tolvaptan on advanced chronic kidney disease with heart failure: a randomized controlled trial

Abstract

Background: Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective. However, it is not clear whether TLV addition is effective for advanced CKD patients with heart failure.

Methods: An open-label, parallel-group randomized trial was performed. The subjects were 33 patients with CKD stage G3-G5 who had fluid overload despite taking 20-100 mg/day FUR. They were divided into two groups: a group administered 15 mg/day TLV plus their original FUR dose for 7 days (TLV group), and a group administered 120-200 mg/day FUR (i.e., 100 mg/day over their previous dose) for 7 days (FUR group).

Results: The mean change in urine volume was significantly higher in the TLV group compared to the FUR group (637 ml vs 119 ml; p < 0.05). The difference was greater when the urine osmolality before treatment was high. Serum creatinine was increased only in the FUR group. The incidence of worsening renal function (WRF) was significantly lower in the TLV group (18.8% vs 58.8%; p < 0.05). Serum sodium decreased significantly in the FUR group, but did not change in the TLV group.

Conclusions: In patients with advanced CKD with fluid overload, the addition of TLV achieved a significantly higher urine volume with less adverse effects on renal function compared with increasing the dose of FUR. The efficacy and safety of TLV were higher in patients who had higher urine osmolality and lower serum sodium before treatment.

Clinical trial registration: UMIN000014763.

Keywords: Chronic kidney disease; Furosemide; Heart failure; Tolvaptan; Urine osmolality; Worsening renal function.

Fig. 1

a Time course of urine volume during the treatment period compared to the observation period in the TLV group (n = 16) and FUR group (n = 17). *p < 0.05 vs baseline. b Comparison of TLV group and FUR group of average urine volume increase from the observation period

Fig. 2

a Correlation between urine osmolality at the start of treatment and the change in urine volume from baseline in the TLV group (n = 14). b Correlation between urine osmolality at the start of treatment and the change in urine volume from baseline in the FUR group (n = 17). c Correlation between urine specific gravity at the start of treatment and the change in urine volume from baseline in the TLV group (n = 15). d Correlation between urine specific gravity at the start of treatment and the change in urine volume from baseline in the FUR group (n = 17)

Fig. 3

a Comparison of changes in urine volume from baseline (ml/day) in the high urine osmolality (> 313.5 mOsm/kg) patients in the TLV and FUR groups. b Comparison of changes in urine volume from baseline (ml/day) in the low urine osmolality (< 313.5 mOsm/kg) patients in the TLV and FUR groups

Fig. 4

Incidence of worsening renal function in the TLV and FUR groups

Fig. 5

a Alterations in serum Na levels before and after treatment in the TLV and FUR groups. b Correlation between serum sodium levels at the start of treatment and the change in the serum sodium from baseline in the TLV group (n = 16). c Correlation between serum sodium levels at the start of treatment and the change in the serum sodium from baseline in the FUR group (n = 17)