Effect of the Aquaretic Tolvaptan on Nitric Oxide System

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Autosomal Dominant Polycystic Kidney Disease

Intervention / Treatment
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* Drug: Tolvaptan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian men and women Age between 18-65 years ADPKD, diagnosed by genetic testing of PKD1 (>85%) or PKD2 mutations, or by ultrasonography: 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. 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. Kidney function corresponding to CKD stages 1-3(eGFR> 30 mL/min/1,73 m2), BMI between 18.5 and 35.5 kg/m2. Exclusion Criteria: Clinical signs of diseases in the heart, lungs, endocrine organs, brain or neoplastic disease, clinically significant abnormalities in blood or urine sample at the inclusion previous cerebrovascular insults, previous clinical evidence for aneurysm Alcohol or drug abuse, smoking, pregnancy or breastfeeding, clinically significant changes in the electrocardiogram, medication except antihypertensive agents and oral contraceptives, blood pressure>170/105 mmHg despite treatment with metoprolol and/or amlodipine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 60 mg Tolvaptan<br>Oral administration of 60 mg tolvaptan on each examination day. | Drug: Tolvaptan<br>* 60 mg Tolvaptan pr day for 1 day<br>* Other names: Samsca;|
| Placebo Comparator: Placebo<br>Oral administration of a Unikalk tablet. | Drug: Placebo<br>* 1 tablet Unikalk pr day for 1 day<br>* Other names: Unikalk;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CH2O (Measurement of H2O clearance) | Measurement of H2O clearance at baseline, during and after L-NMMA infusion | 5-6 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine biomarkers(Aquaporins and Epithelial Sodium Channels γ) |  | 5-6 Hours | 
| Central and brachial blood pressure |  | 5-6 Hours | 
| Augmentation Index |  | 5-6 Hours | 
| Vasoactive Hormones( Angiotensin II, Aldosterone, Endothelin, Atrial Natriuretic Peptide, Brain Natriuretic Peptide, Arginin Vasopressin) |  | 5-6 Hours | 
| Fractional sodium excretion | Measurement of Sodium excretion at baseline, during and after L-NMMA infusion. | 5-6 Hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tolvaptan, L-NMMA, ADPKD