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

TY - JOUR

T1 - 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

T2 - a randomized, placebo-controlled, double blind, crossover study

AU - Therwani, Safa

AU - Malmberg, My Emma Sofie

AU - Rosenbaek, Jeppe Bakkestroem

AU - Bech, Jesper Noergaard

AU - Pedersen, Erling Bjerregaard

PY - 2017/8/15

Y1 - 2017/8/15

N2 - 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.

AB - 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.

KW - Journal Article

KW - ADPKD

KW - AQP2

KW - Blood pressure

KW - ENaC

KW - Nitric oxide

KW - Tolvaptan

KW - Vasoactive hormones

UR - http://www.scopus.com/inward/record.url?scp=85027529313&partnerID=8YFLogxK

U2 - 10.1186/s12882-017-0686-3

DO - 10.1186/s12882-017-0686-3

M3 - Journal article

C2 - 28810844

SN - 1471-2369

VL - 18

JO - B M C Nephrology

JF - B M C Nephrology

IS - 1

M1 - 268

ER -