Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

New Biomarkers and Difficult-to-treat Hypertension

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03034265
Recruitment Status : Completed
First Posted : January 27, 2017
Last Update Posted : December 20, 2017
Sponsor:
Collaborator:
University of Zurich
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

Brief Summary:
The purpose of this study is to determine the concentrations and variabilities of urinary exosomal sodium channels and plasma angiotensins in patients with difficult-to-treat arterial hypertension and to investigate their dependency on clinical parameters and sampling conditions.

Condition or disease
Hypertension

  Hide Detailed Description

Detailed Description:

Background:

Difficult-to-treat hypertension is characterized by uncontrolled blood pressure despite 2 or more antihypertensive drugs. In many cases, abnormal renal Na and volume handling plays a central role. Arterial vasoconstriction and renal function are regulated by the renin-angiotensin-aldosterone system (RAAS) and its effector hormones angiotensin II and aldosterone. Both control renal tubular function and Na excretion. Blocking the renin-angiotensin-system pharmacologically is therefore a current standard approach to treat hypertension. However, there is great clinical need to improve the classification of hypertensive patients and to predict patient sensitivity to different therapeutic strategies more precisely by new biomarkers that take into account tubular function and the various bioactive angiotensin fragments.

Ang fragments generated by non-canonical enzymatic pathways such as Ang III co-exist with Ang I and Ang II in plasma. Their profile could help classify hypertensive patients with greater precision than plasma renin and aldosterone alone. Furthermore, urinary exosomes are small membrane vesicles (<0.1 μm) shed into the urine by tubular epithelial cells. They contain tubular Na channels known as targets of furosemide and thiazide drugs used to treat volume overload and arterial hypertension. Na channel concentrations in the tubules are regulated by Ang II and aldosterone. Exosomal Na channel abundance could thus give valuable extra information on the actual tubular functional status not provided by standard laboratory tests of plasma renin and aldosterone or urinary electrolytes alone. Plasma Ang peptide profiles and urinary exosomal Na channels could improve the classification of patients with difficult-to-control hypertension and inform antihypertensive treatment decisions. The usual concentrations and variabilities of these biomarkers are a prerequisite for the planning of future validation studies. However, data are still lacking in this population.

Study aim:

This study aims to determine the concentration and interindividual variability of urinary exosomal sodium channels and of plasma angiotensins (candidate biomarkers) in patients with difficult-to-treat arterial hypertension and to determine their dependency on sampling conditions, dietary salt intake, and plasma renin and aldosterone concentrations.

Candidate biomarker definition:

  • Plasma Ang peptides planned for determination in the study are Ang I and II and its metabolites Ang 2-10, 2-8, 3-8, 1-7, 2-7, 3-7, 1-5 (Ang peptide profile).
  • Urinary exosomal Na channel proteins planned for determination are Na+-Cl− cotransporter (NCC), epithelial sodium channel (ENaC) subunits and Na-K-Cl cotransporter type 2 (NKCC 2).

Study type:

This is an investigator initiated, monocentric observational pilot study in 24 ambulatory patients with difficult-to-treat hypertension who meet the inclusion criteria and none of the exclusion criteria.

Setting:

The study is performed at the outpatient hypertension clinic of the University clinic for nephrology, hypertension and clinical pharmacology, Inselspital, Bern University Hospital, Bern, Switzerland.

Objectives:

  • The primary objective of the study is to determine the concentration and interindividual variability of urinary exosomal Na channels and of plasma angiotensin peptides under standardized clinical sampling conditions in patients with difficult-to-treat hypertension.
  • The secondary objectives of the study are

    1. to determine the association of these candidate biomarkers with urinary Na excretion, plasma renin and aldosterone concentrations, and aldosterone-to-renin ratios on clinical visit 2,
    2. to assess the repeatability of biomarker determinations under spontaneous (visit 1) compared to standardized sampling conditions (visit 2).

Study plan and procedures:

The concentrations of the candidate biomarkers are determined in blood and spot urinary samples obtained on the first clinical visit (visit 1) and again under standardized laboratory conditions on the second clinical visit (visit 2) scheduled 5-31 days later and after stopping RAAS inhibitory drugs, beta-adrenoceptor blockers, centrally acting antihypertensives and diuretics for an appropriate period, as necessary. Ca-antagonists and alpha-adrenoceptor blockers are allowed to treat hypertension.

Determinations of candidate biomarkers are made in parallel with clinical blood and urine tests performed routinely. On visit 2, these tests include supine and standing plasma renin and aldosterone measurements under standardized conditions in the morning after 1 h rest and again after 1 hour walking .

Biological samples are processed according to standardized laboratory protocols. Plasma Ang peptides are determined by gas chromatography-mass spectrometry. Urinary exosomal proteins are determined by Western-Blot using specific antibodies. Blood concentrations of antihypertensive drugs are determined by liquid chromatography mass spectrometry to analyze medication use and adherence on visits 1 and 2. Clinical data and routine laboratory results for visits 1 and 2 are obtained from patient files.

Recruitment of participants: consecutive ongoing participant recruitment is performed in daily clinic practice by the investigators who check referrals for potential eligibility.

Participation: study participation begins with study inclusion on visit 1 and ends with completion of visit 2.


Layout table for study information
Study Type : Observational
Actual Enrollment : 24 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Identification of New Biomarkers for the Classification and Monitoring of Difficult-to-treat Arterial Hypertension: Prospective Observational Study
Actual Study Start Date : May 2016
Actual Primary Completion Date : May 2017
Actual Study Completion Date : May 2017

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. Plasma concentration of Ang peptides [ Time Frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit) ]
  2. Urinary concentration of exosomal Na channel proteins [ Time Frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit) ]

Secondary Outcome Measures :
  1. 24h urinary Na excretion [ Time Frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit) ]
  2. Plasma renin concentration [ Time Frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit) ]
  3. Plasma aldosterone concentration [ Time Frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit) ]
  4. Repeatability of Ang peptide and urinary exosomal Na channel concentrations under spontaneous vs. standardized laboratory conditions. [ Time Frame: 1st visit vs. 2nd scheduled visit (5 days to 4 weeks after 1st visit) ]
    Statistical agreement is tested.


Biospecimen Retention:   Samples Without DNA
blood, urine


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Amblatory patients with difficult-to-treat hypertension referred to the hypertension clinic for evaluation
Criteria

Inclusion Criteria:

  • Patients with ≥2 antihypertensive drugs for ≥3 months
  • Reported blood pressure ≥140/90 mmHg and/or patient reported as having medically uncontrolled hypertension by the referring physician
  • Age ≥18 years, capacity to provide and granted written informed consent

Exclusion Criteria:

  • Chronic stage 4-5 renal insufficiency; glomerulonephritis, liver insufficiency (Child-Pugh B or C), chronic obstructive pulmonary disease Global Initiative for Obstructive Lung Disease grade 4; chronic heart failure New York Heart Association class IV
  • Known secondary hypertension
  • Mandatory RAAS-blockers (e.g. converting enzyme inhibitors, angiotensin type 1 receptor blockers), beta-adrenoceptor blockers, centrally acting sympatholytics and diuretics that cannot be paused adequately before visit 2
  • Mean sitting office blood pressure >190/110 mmHg measured 3x on visit 1
  • Normotension on visit 1 (mean seated office blood pressure measured 3x <140/90 mmHg)
  • Insufficient knowledge of project language and absence of an interpreter for study communications
  • Pregnancy or lactation
  • Scheduled clinical visit 2 outside routine workflow time-line (<5 or >31 days after visit 1)
  • Inability to follow procedures (e.g. relevant psychiatric disorder or dementia)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03034265


Locations
Layout table for location information
Switzerland
Department of Nephrology and Hypertension, Inselspital, Bern University Hospital
Bern, Switzerland, 3010
Sponsors and Collaborators
University Hospital Inselspital, Berne
University of Zurich
Investigators
Layout table for investigator information
Principal Investigator: Jürgen Bohlender, M.D. Inselspital, Bern University Hospital, Freiburgstr. 4, 3010 Bern, Switzerland

Publications:

Layout table for additonal information
Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT03034265     History of Changes
Other Study ID Numbers: Study 3003
First Posted: January 27, 2017    Key Record Dates
Last Update Posted: December 20, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Interested third parties may have access to project data by contacting the leading investigator. Only anonymous data are shared, also in case with third parties with lower data protection standards than Swiss or European Union, to safeguard confidentiality.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital Inselspital, Berne:
hypertension; exosome; angiotensin; sodium channel; kidney; aldosterone; renin; urine
Additional relevant MeSH terms:
Layout table for MeSH terms
Hypertension
Vascular Diseases
Cardiovascular Diseases