Clinical trial NCT02527863: Effect of the Aquaretic Tolvaptan on Nitric Oxide System
Official title: The Effects of Tolvaptan on Renal Handling of Water and Sodium, Vasoactive Hormones and Central Hemodynamics During Baseline Conditions and After Inhibition of the Nitric Oxide System in Patients With Autosomal Dominant Polycystic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autosomal Dominant Polycystic Kidney Disease
Keywords: Tolvaptan
L-NMMA
ADPKD
Lead sponsor: Regional Hospital Holstebro
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
First posted: 2015-08-19
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water and sodium excretion. Inhibition of V2R increases vasopressin concentration in plasma, which stimulates V1-receptors in the vascular bed and may change both central and brachial hemodynamics and plasma concentration of vasoactive hormones.

The purpose of the study is to measure the effects of tolvaptan on renal handling of water and sodium, systemic hemodynamics and vasoactive hormones at baseline and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA) in patients with autosomal dominant polycystic kidney disease.


Eligibility criteria: Inclusion Criteria:

1. Caucasian men and women
2. Age between 18-65 years
3. ADPKD, diagnosed by genetic testing of PKD1 (\>85%) or PKD2 mutations, or by ultrasonography:

   1. patients with negative family history for ADKPD and more than 10 cysts in each kidney and no extrarenal or renal findings that suggest causes to cyst formation.
   2. patients with positive family history for ADPKD:

      * 15-39 yr of age and at least 3 or more unilateral or bilateral.
      * 40-59 yr of age and 2 or more cysts in each kidney.
      * 60 yr of age and at least 4 cysts in each kidney.
4. Kidney function corresponding to CKD stages 1-3(eGFR\> 30 mL/min/1,73 m2),
5. BMI between 18.5 and 35.5 kg/m2.

Exclusion Criteria:

1. Clinical signs of diseases in the heart, lungs, endocrine organs, brain or neoplastic disease,
2. clinically significant abnormalities in blood or urine sample at the inclusion
3. previous cerebrovascular insults,
4. previous clinical evidence for aneurysm
5. Alcohol or drug abuse,
6. smoking,
7. pregnancy or breastfeeding,
8. clinically significant changes in the electrocardiogram,
9. medication except antihypertensive agents and oral contraceptives,
10. blood pressure\>170/105 mmHg despite treatment with metoprolol and/or amlodipine.

Primary outcomes:
measure: CH2O (Measurement of H2O clearance)
timeFrame: 5-6 Hours
Secondary outcomes:
measure: Urine biomarkers(Aquaporins and Epithelial Sodium Channels γ)
timeFrame: 5-6 Hours
measure: Central and brachial blood pressure
timeFrame: 5-6 Hours
measure: Augmentation Index
timeFrame: 5-6 Hours
measure: Vasoactive Hormones( Angiotensin II, Aldosterone, Endothelin, Atrial Natriuretic Peptide, Brain Natriuretic Peptide, Arginin Vasopressin)
timeFrame: 5-6 Hours
measure: Fractional sodium excretion
timeFrame: 5-6 Hours
Other outcomes:
Locations:
city: Holstebro
country: Denmark
facility: Department of Medical Research and Medicine, Holstebro Regional Hospital
Study officials:
affiliation: Department of Medical Research and Medicine, Holstebro Regional Hospital Holstebro, Holstebro, Denmark, 7500
name: Erling B Pedersen
role: STUDY_CHAIR
References:
citation: Al Therwani S, Malmberg MES, Rosenbaek JB, Bech JN, Pedersen EB. 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. BMC Nephrol. 2017 Aug 15;18(1):268. doi: 10.1186/s12882-017-0686-3.