Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study

Abstract

Background: Tolvaptan slows progression of autosomal dominant polycystic kidney disease (ADPKD) by antagonizing the vasopressin-cAMP axis. Nitric oxide (NO) stimulates natriuresis and diuresis, but its role is unknown during tolvaptan treatment in ADPKD.

Methods: Eighteen patients with ADPKD received tolvaptan 60 mg or placebo in a randomized, placebo-controlled, double blind, crossover study. L-NMMA (L-NG-monomethyl-arginine) was given as a bolus followed by continuous infusion during 60 min. We measured: GFR, urine output (UO), free water clearance (C_H2O), fractional excretion of sodium (FE_Na), urinary excretion of aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensinII (p-AngII), aldosterone (p-Aldo), and central blood pressure (cBP).

Results: During tolvaptan with NO-inhibition, a more pronounced decrease was measured in UO, C_H2O (61% vs 43%) and FE_Na (46% vs 41%) after placebo than after tolvaptan; GFR and u-AQP2 decreased to the same extent; p-AVP increased three fold, whereas u-ENaC_γ, PRC, p-AngII, and p-Aldo remained unchanged. After NO-inhibition, GFR increased after placebo and remained unchanged after tolvaptan (5% vs -6%). Central diastolic BP (CDBP) increased to a higher level after placebo than tolvaptan. Body weight fell during tolvaptan treatment.

Conclusions: During NO inhibition, tolvaptan antagonized both the antidiuretic and the antinatriuretic effect of L-NMMA, partly via an AVP-dependent mechanism. U-AQP2 was not changed by tolvaptan, presumeably due to a counteracting effect of elevated p-AVP. The reduced GFR during tolvaptan most likely is caused by the reduction in extracellular fluid volume and blood pressure.

Trial registration: Clinical Trial no: NCT02527863 . Registered 18 February 2015.

Keywords: ADPKD; AQP2; Blood pressure; ENaC; Nitric oxide; Tolvaptan; Vasoactive hormones.

Fig. 1

Effect of tolvaptan 60 mg during and after NO inhibition on GFR (⁵¹ Cr-EDTA-clearance) (a), UO (b), C_H2O (c) and u-AQP2 (d) in ADPKD. Data are given as mean ± SEM or medians with 25th and 75th percentiles. General linear model (GLM) with repeated measures was performed for comparison within and between groups. Paired t-test was used for comparison between tolvaptan and placebo treatment during L-NMMA infusion period (90–150 min) and post infusion period (150–210 min)

Fig. 2

Effect of tolvaptan 60 mg during and after NO inhibition on FE_Na (a) and u-ENaCγ (b) in ADPKD. Data are given as medians with 25th and 75th percentiles. General linear model (GLM) with repeated measures was performed for comparison within and between groups. Paired t-test was used for comparison between tolvaptan and placebo treatment during L-NMMA infusion period (90–150 min) and post infusion period (150–210 min)

Fig. 3

Effect of tolvaptan 60 mg on p-AVP at baseline, during and after NO inhibition in ADPKD. Data are given as median with 25th and 75th percentiles. Wilcoxon’s signed rank test used for comparison between treatment groups prior to L-NMMA infusion, at the end of L-NMMA infusion and 1 h after the end of L-NMMA infusion