<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03034265</url>
  </required_header>
  <id_info>
    <org_study_id>Study 3003</org_study_id>
    <nct_id>NCT03034265</nct_id>
  </id_info>
  <brief_title>New Biomarkers and Difficult-to-treat Hypertension</brief_title>
  <official_title>Identification of New Biomarkers for the Classification and Monitoring of Difficult-to-treat Arterial Hypertension: Prospective Observational Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Zurich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the concentrations and variabilities of urinary&#xD;
      exosomal sodium channels and plasma angiotensins in patients with difficult-to-treat arterial&#xD;
      hypertension and to investigate their dependency on clinical parameters and sampling&#xD;
      conditions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Difficult-to-treat hypertension is characterized by uncontrolled blood pressure despite 2 or&#xD;
      more antihypertensive drugs. In many cases, abnormal renal Na and volume handling plays a&#xD;
      central role. Arterial vasoconstriction and renal function are regulated by the&#xD;
      renin-angiotensin-aldosterone system (RAAS) and its effector hormones angiotensin II and&#xD;
      aldosterone. Both control renal tubular function and Na excretion. Blocking the&#xD;
      renin-angiotensin-system pharmacologically is therefore a current standard approach to treat&#xD;
      hypertension. However, there is great clinical need to improve the classification of&#xD;
      hypertensive patients and to predict patient sensitivity to different therapeutic strategies&#xD;
      more precisely by new biomarkers that take into account tubular function and the various&#xD;
      bioactive angiotensin fragments.&#xD;
&#xD;
      Ang fragments generated by non-canonical enzymatic pathways such as Ang III co-exist with Ang&#xD;
      I and Ang II in plasma. Their profile could help classify hypertensive patients with greater&#xD;
      precision than plasma renin and aldosterone alone. Furthermore, urinary exosomes are small&#xD;
      membrane vesicles (&lt;0.1 μm) shed into the urine by tubular epithelial cells. They contain&#xD;
      tubular Na channels known as targets of furosemide and thiazide drugs used to treat volume&#xD;
      overload and arterial hypertension. Na channel concentrations in the tubules are regulated by&#xD;
      Ang II and aldosterone. Exosomal Na channel abundance could thus give valuable extra&#xD;
      information on the actual tubular functional status not provided by standard laboratory tests&#xD;
      of plasma renin and aldosterone or urinary electrolytes alone. Plasma Ang peptide profiles&#xD;
      and urinary exosomal Na channels could improve the classification of patients with&#xD;
      difficult-to-control hypertension and inform antihypertensive treatment decisions. The usual&#xD;
      concentrations and variabilities of these biomarkers are a prerequisite for the planning of&#xD;
      future validation studies. However, data are still lacking in this population.&#xD;
&#xD;
      Study aim:&#xD;
&#xD;
      This study aims to determine the concentration and interindividual variability of urinary&#xD;
      exosomal sodium channels and of plasma angiotensins (candidate biomarkers) in patients with&#xD;
      difficult-to-treat arterial hypertension and to determine their dependency on sampling&#xD;
      conditions, dietary salt intake, and plasma renin and aldosterone concentrations.&#xD;
&#xD;
      Candidate biomarker definition:&#xD;
&#xD;
        -  Plasma Ang peptides planned for determination in the study are Ang I and II and its&#xD;
           metabolites Ang 2-10, 2-8, 3-8, 1-7, 2-7, 3-7, 1-5 (Ang peptide profile).&#xD;
&#xD;
        -  Urinary exosomal Na channel proteins planned for determination are Na+-Cl- cotransporter&#xD;
           (NCC), epithelial sodium channel (ENaC) subunits and Na-K-Cl cotransporter type 2 (NKCC&#xD;
           2).&#xD;
&#xD;
      Study type:&#xD;
&#xD;
      This is an investigator initiated, monocentric observational pilot study in 24 ambulatory&#xD;
      patients with difficult-to-treat hypertension who meet the inclusion criteria and none of the&#xD;
      exclusion criteria.&#xD;
&#xD;
      Setting:&#xD;
&#xD;
      The study is performed at the outpatient hypertension clinic of the University clinic for&#xD;
      nephrology, hypertension and clinical pharmacology, Inselspital, Bern University Hospital,&#xD;
      Bern, Switzerland.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
        -  The primary objective of the study is to determine the concentration and interindividual&#xD;
           variability of urinary exosomal Na channels and of plasma angiotensin peptides under&#xD;
           standardized clinical sampling conditions in patients with difficult-to-treat&#xD;
           hypertension.&#xD;
&#xD;
        -  The secondary objectives of the study are&#xD;
&#xD;
             1. to determine the association of these candidate biomarkers with urinary Na&#xD;
                excretion, plasma renin and aldosterone concentrations, and aldosterone-to-renin&#xD;
                ratios on clinical visit 2,&#xD;
&#xD;
             2. to assess the repeatability of biomarker determinations under spontaneous (visit 1)&#xD;
                compared to standardized sampling conditions (visit 2).&#xD;
&#xD;
      Study plan and procedures:&#xD;
&#xD;
      The concentrations of the candidate biomarkers are determined in blood and spot urinary&#xD;
      samples obtained on the first clinical visit (visit 1) and again under standardized&#xD;
      laboratory conditions on the second clinical visit (visit 2) scheduled 5-31 days later and&#xD;
      after stopping RAAS inhibitory drugs, beta-adrenoceptor blockers, centrally acting&#xD;
      antihypertensives and diuretics for an appropriate period, as necessary. Ca-antagonists and&#xD;
      alpha-adrenoceptor blockers are allowed to treat hypertension.&#xD;
&#xD;
      Determinations of candidate biomarkers are made in parallel with clinical blood and urine&#xD;
      tests performed routinely. On visit 2, these tests include supine and standing plasma renin&#xD;
      and aldosterone measurements under standardized conditions in the morning after 1 h rest and&#xD;
      again after 1 hour walking .&#xD;
&#xD;
      Biological samples are processed according to standardized laboratory protocols. Plasma Ang&#xD;
      peptides are determined by gas chromatography-mass spectrometry. Urinary exosomal proteins&#xD;
      are determined by Western-Blot using specific antibodies. Blood concentrations of&#xD;
      antihypertensive drugs are determined by liquid chromatography mass spectrometry to analyze&#xD;
      medication use and adherence on visits 1 and 2. Clinical data and routine laboratory results&#xD;
      for visits 1 and 2 are obtained from patient files.&#xD;
&#xD;
      Recruitment of participants: consecutive ongoing participant recruitment is performed in&#xD;
      daily clinic practice by the investigators who check referrals for potential eligibility.&#xD;
&#xD;
      Participation: study participation begins with study inclusion on visit 1 and ends with&#xD;
      completion of visit 2.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2016</start_date>
  <completion_date type="Actual">May 2017</completion_date>
  <primary_completion_date type="Actual">May 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Plasma concentration of Ang peptides</measure>
    <time_frame>2nd scheduled visit (5 days to 4 weeks after 1st visit)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Urinary concentration of exosomal Na channel proteins</measure>
    <time_frame>2nd scheduled visit (5 days to 4 weeks after 1st visit)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>24h urinary Na excretion</measure>
    <time_frame>2nd scheduled visit (5 days to 4 weeks after 1st visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma renin concentration</measure>
    <time_frame>2nd scheduled visit (5 days to 4 weeks after 1st visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma aldosterone concentration</measure>
    <time_frame>2nd scheduled visit (5 days to 4 weeks after 1st visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Repeatability of Ang peptide and urinary exosomal Na channel concentrations under spontaneous vs. standardized laboratory conditions.</measure>
    <time_frame>1st visit vs. 2nd scheduled visit (5 days to 4 weeks after 1st visit)</time_frame>
    <description>Statistical agreement is tested.</description>
  </secondary_outcome>
  <enrollment type="Actual">24</enrollment>
  <condition>Hypertension</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      blood, urine&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Amblatory patients with difficult-to-treat hypertension referred to the hypertension clinic&#xD;
        for evaluation&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with ≥2 antihypertensive drugs for ≥3 months&#xD;
&#xD;
          -  Reported blood pressure ≥140/90 mmHg and/or patient reported as having medically&#xD;
             uncontrolled hypertension by the referring physician&#xD;
&#xD;
          -  Age ≥18 years, capacity to provide and granted written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Chronic stage 4-5 renal insufficiency; glomerulonephritis, liver insufficiency&#xD;
             (Child-Pugh B or C), chronic obstructive pulmonary disease Global Initiative for&#xD;
             Obstructive Lung Disease grade 4; chronic heart failure New York Heart Association&#xD;
             class IV&#xD;
&#xD;
          -  Known secondary hypertension&#xD;
&#xD;
          -  Mandatory RAAS-blockers (e.g. converting enzyme inhibitors, angiotensin type 1&#xD;
             receptor blockers), beta-adrenoceptor blockers, centrally acting sympatholytics and&#xD;
             diuretics that cannot be paused adequately before visit 2&#xD;
&#xD;
          -  Mean sitting office blood pressure &gt;190/110 mmHg measured 3x on visit 1&#xD;
&#xD;
          -  Normotension on visit 1 (mean seated office blood pressure measured 3x &lt;140/90 mmHg)&#xD;
&#xD;
          -  Insufficient knowledge of project language and absence of an interpreter for study&#xD;
             communications&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Scheduled clinical visit 2 outside routine workflow time-line (&lt;5 or &gt;31 days after&#xD;
             visit 1)&#xD;
&#xD;
          -  Inability to follow procedures (e.g. relevant psychiatric disorder or dementia)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jürgen Bohlender, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Inselspital, Bern University Hospital, Freiburgstr. 4, 3010 Bern, Switzerland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Nephrology and Hypertension, Inselspital, Bern University Hospital</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <reference>
    <citation>Campbell DJ, Nussberger J, Stowasser M, Danser AH, Morganti A, Frandsen E, Menard J. Activity assays and immunoassays for plasma Renin and prorenin: information provided and precautions necessary for accurate measurement. Clin Chem. 2009 May;55(5):867-77. doi: 10.1373/clinchem.2008.118000. Epub 2009 Mar 5.</citation>
    <PMID>19264850</PMID>
  </reference>
  <reference>
    <citation>Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011 Aug 30;124(9):1046-58. doi: 10.1161/CIRCULATIONAHA.111.030189. Epub 2011 Aug 8.</citation>
    <PMID>21824920</PMID>
  </reference>
  <reference>
    <citation>Glicklich D, Frishman WH. Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists. Drugs. 2015 Apr;75(5):473-85. doi: 10.1007/s40265-015-0372-3.</citation>
    <PMID>25787734</PMID>
  </reference>
  <reference>
    <citation>Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013 Jul;31(7):1281-357. doi: 10.1097/01.hjh.0000431740.32696.cc. No abstract available.</citation>
    <PMID>23817082</PMID>
  </reference>
  <reference>
    <citation>Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13368-73. doi: 10.1073/pnas.0403453101. Epub 2004 Aug 23.</citation>
    <PMID>15326289</PMID>
  </reference>
  <reference>
    <citation>Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH. Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res. 2015 Mar 13;116(6):960-75. doi: 10.1161/CIRCRESAHA.116.303587.</citation>
    <PMID>25767283</PMID>
  </reference>
  <reference>
    <citation>van der Lubbe N, Jansen PM, Salih M, Fenton RA, van den Meiracker AH, Danser AH, Zietse R, Hoorn EJ. The phosphorylated sodium chloride cotransporter in urinary exosomes is superior to prostasin as a marker for aldosteronism. Hypertension. 2012 Sep;60(3):741-8. doi: 10.1161/HYPERTENSIONAHA.112.198135. Epub 2012 Jul 30.</citation>
    <PMID>22851731</PMID>
  </reference>
  <reference>
    <citation>Wolley MJ, Stowasser M. Resistant Hypertension and Chronic Kidney Disease: a Dangerous Liaison. Curr Hypertens Rep. 2016 Apr;18(5):36. doi: 10.1007/s11906-016-0641-x.</citation>
    <PMID>27072829</PMID>
  </reference>
  <verification_date>December 2017</verification_date>
  <study_first_submitted>January 19, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 27, 2017</study_first_posted>
  <last_update_submitted>December 19, 2017</last_update_submitted>
  <last_update_submitted_qc>December 19, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">December 20, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>hypertension; exosome; angiotensin; sodium channel; kidney; aldosterone; renin; urine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_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.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03034265
org study id: Study 3003
nct id: NCT03034265
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
observational model: Cohort
time perspective: Prospective
measure: Plasma concentration of Ang peptides
time frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit)
measure: Urinary concentration of exosomal Na channel proteins
time frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit)
measure: 24h urinary Na excretion
time frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit)
measure: Plasma renin concentration
time frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit)
measure: Plasma aldosterone concentration
time frame: 2nd scheduled visit (5 days to 4 weeks after 1st visit)
measure: 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)
description: Statistical agreement is tested.
blood, urine
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jürgen Bohlender, M.D.
role: Principal Investigator
affiliation: Inselspital, Bern University Hospital, Freiburgstr. 4, 3010 Bern, Switzerland
facility: 
country: Switzerland
citation: Campbell DJ, Nussberger J, Stowasser M, Danser AH, Morganti A, Frandsen E, Menard J. Activity assays and immunoassays for plasma Renin and prorenin: information provided and precautions necessary for accurate measurement. Clin Chem. 2009 May;55(5):867-77. doi: 10.1373/clinchem.2008.118000. Epub 2009 Mar 5.
PMID: 19264850
citation: Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011 Aug 30;124(9):1046-58. doi: 10.1161/CIRCULATIONAHA.111.030189. Epub 2011 Aug 8.
PMID: 21824920
citation: Glicklich D, Frishman WH. Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists. Drugs. 2015 Apr;75(5):473-85. doi: 10.1007/s40265-015-0372-3.
PMID: 25787734
citation: Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013 Jul;31(7):1281-357. doi: 10.1097/01.hjh.0000431740.32696.cc. No abstract available.
PMID: 23817082
citation: Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13368-73. doi: 10.1073/pnas.0403453101. Epub 2004 Aug 23.
PMID: 15326289
citation: Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH. Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res. 2015 Mar 13;116(6):960-75. doi: 10.1161/CIRCRESAHA.116.303587.
PMID: 25767283
citation: van der Lubbe N, Jansen PM, Salih M, Fenton RA, van den Meiracker AH, Danser AH, Zietse R, Hoorn EJ. The phosphorylated sodium chloride cotransporter in urinary exosomes is superior to prostasin as a marker for aldosteronism. Hypertension. 2012 Sep;60(3):741-8. doi: 10.1161/HYPERTENSIONAHA.112.198135. Epub 2012 Jul 30.
PMID: 22851731
citation: Wolley MJ, Stowasser M. Resistant Hypertension and Chronic Kidney Disease: a Dangerous Liaison. Curr Hypertens Rep. 2016 Apr;18(5):36. doi: 10.1007/s11906-016-0641-x.
PMID: 27072829
responsible party type: Sponsor
mesh term: Hypertension
sharing ipd: Yes
ipd 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.