TRAMPOLINE: Treatment of Vascular Stiffness in ADPKD
Study Details
Study Description
Brief Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease characterized by cystic kidneys and caused by mutations in the polycystic kidney disease and other rare genes. It is associated with salt-sensitive hypertension, which accounts for the majority of morbidity and mortality. About 70% of patients with ADPKD develop hypertension, prior to the onset of kidney function decline. Early onset hypertension, despite its treatment, is independently associated with rapid kidney function decline. The investigators hypothesize that a high-sodium diet in patients with ADPKD is required for the development of vascular stiffness, which precedes hypertension, and that treatment with amiloride reverses this phenomenon.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
Objective of the study:
The investigators aim to investigate if arterial stiffness is exacerbated due to a high-salt diet in patients with ADPKD. The investigators also aim to explore whether treatment with amiloride prevents the arterial stiffness caused by a high-salt diet.
Study design:
Randomized, double blinded and placebo-controlled clinical trial with open-label treatment with amiloride
Study population:
Adults with ADPKD with an estimated glomerular filtration rate (CKD-EPI) of ≥ 60 ml/min/1.73m2
Intervention:
All participants will be subjected to a low-salt diet (3,5 grams/day) throughout the study for a total of 6 weeks. After a run-in period of 2 weeks, participants will be randomized into two treatment groups:
Group 1: Sodium chloride capsules (6 grams/day) for 2 weeks, combined with amiloride (20 mg/day) in last 2 weeks Group 2: Placebo capsules for 2 weeks, combined with amiloride (20 mg/day) in last 2 weeks.
Primary study parameters/outcome of the study:
The three primary outcomes of this study are a difference in central arterial stiffness (pulse wave velocity, PWV) between:
-
The high-salt group versus low-salt group;
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The high-salt group: before versus after amiloride treatment;
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The low-salt group: before versus after amiloride treatment.
The burden of participation includes:
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A dietary salt restriction of 3.5 grams/day for a total period of 6 weeks
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Salt supplementation or placebo for a total period of 4 weeks
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Drug intervention with amiloride during the last 2 weeks
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Hospital visits
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: High-salt group (group 1) All participants will be subjected to a low-salt diet (3.5 grams/day) for six weeks. Group 1 will receive sodium chloride capsules (6 grams/day) for four weeks. In the last two weeks of the trial, all participants will be treated with amiloride tablets (20 mg daily) in open-label setting. |
Dietary Supplement: Sodium chloride (NaCl)
Sodium chloride capsules 6 grams per day for 4 weeks.
Other Names:
Drug: Amiloride Hcl 5mg Tab
Amiloride 5mg tablets, 20 mg per day for two weeks in open-label setting.
Other Names:
|
| Placebo Comparator: Low-salt group (group 2) All participants will be subjected to a low-salt diet (3.5 grams/day) for six weeks. Group 2 will receive placebo capsules (6 grams/day) for four weeks. In the last two weeks of the trial, all participants will be treated with amiloride tablets (20 mg daily) in open-label setting. |
Dietary Supplement: Placebo
Placebo capsules, 6 grams per day for 4 weeks.
Drug: Amiloride Hcl 5mg Tab
Amiloride 5mg tablets, 20 mg per day for two weeks in open-label setting.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Arterial stiffness induced by high salt diet [At week 3, week 5]
Difference in central arterial stiffness, measured as the pulse wave velocity (PWV), in high-salt group versus low-salt group.
- Effect of treatment with amiloride on arterial stiffness in high-salt group [At week 5 and at week 7]
Difference in central arterial stiffness, measured as the pulse wave velocity (PWV), before versus after amiloride treatment in high-salt group.
- Effect of treatment with amiloride on arterial stiffness in low-salt group [At week 5 and at week 7]
Difference in central arterial stiffness, measured as the pulse wave velocity (PWV), before versus after amiloride treatment in low-salt group.
Secondary Outcome Measures
- Blood pressure [At week 3, week 5 and at at week 7]
24-hours ambulatory blood pressure measurement (Mobil-O-Graph).
- Salt tasting thresholds [At inclusion, week 3, week 5 and at week 7]
Sodium chloride (NaCl) solutions with different concentrations to assess the salt tasting thresholds.
- Skin sodium accumulation [At week 3, week 5 and at week 7]
In a subgroup of participants, tissue sodium concentration (23Na) will be assessed noninvasively using a contrast-free 23 Na-MRI scan.
- Markers of (vascular) inflammation and endothelial dysfunction [At inclusion, week 3, week 5 and at week 7]
Blood biomaterials will be collected at the visits. We will measure inflammatory markers including the high-sensitivity C-reactive protein, interleukin-6 and tumor necrosis factor-α, and other relevant markers for endothelial dysfunction including the adhesion molecules intercellular cell adhesion molecules-1, vascular cell adhesion molecules-1 and endothelin-1.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adults with typical ADPKD diagnosed based on Ravine criteria and/or a documented Pkd 1 or 2 mutation
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Chronic kidney disease epidemiology collaboration equation estimated glomerular filtration rate ≥60 ml/min/1.73m2
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Ability to provide informed consent
Exclusion Criteria:
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Uncontrolled hypertension, defined as an office blood pressure of ≥160/ ≥90 mmHg with or without antihypertensive treatment
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Concomitant use of ≥ 3 antihypertensive medications
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When antihypertensive treatment is prescribed for any other treatment indication than hypertension (e.g. cardia arrhythmia)
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Serum potassium levels >5.5 mmol/L (measured within last 6 months)
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History of liver disease (excluding liver cysts due to ADPKD)
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History of heart failure (cardiac ejection fraction < 35%) or cardiac arrhythmia
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History of diabetes mellitus
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Active infection or antibiotic therapy
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Immunosuppressive therapy within the last year
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Concomitant use of drugs that could influence blood pressure and/or disease progression (Tolvaptan/non-steroidal anti-inflammatory drugs (NSAIDs)/chemotherapy), excluding < 3 antihypertensive drugs
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Actual pregnancy or unwillingness to adhere to reproductive precautions during the duration of the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Erasmus University Medical Centre Rotterdam | Rotterdam | South-Holland | Netherlands | 3015GD |
Sponsors and Collaborators
- Erasmus Medical Center
Investigators
- Principal Investigator: M. Salih, MD, PhD, Erasmus Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NL72836.340.10