New Biomarkers and Difficult-to-treat Hypertension

Hypertension Clinical Trial

Official title:

Identification of New Biomarkers for the Classification and Monitoring of Difficult-to-treat Arterial Hypertension: Prospective Observational Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03034265
• Other study ID #: Study 3003
• Status: Completed
• Phase: N/A
• First received: January 19, 2017
• Last updated: December 19, 2017
• Start date: May 2016
• Est. completion date: May 2017

Study information

• Verified date: December 2017
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: May 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Hypertension

Locations

Country	Name	City	State
Switzerland	Department of Nephrology and Hypertension, Inselspital, Bern University Hospital	Bern

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	University of Zurich

Country where clinical trial is conducted

Switzerland, 

References & Publications (8)

Campbell DJ, Nussberger J, Stowasser M, Danser AH, Morganti A, Frandsen E, Ménard 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. Review. — View 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. — View 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. Review. — View Citation

Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm 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. — View 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. Epub 2004 Aug 23. — View 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. Review. — View 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. — View 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma concentration of Ang peptides		2nd scheduled visit (5 days to 4 weeks after 1st visit)
Primary	Urinary concentration of exosomal Na channel proteins		2nd scheduled visit (5 days to 4 weeks after 1st visit)
Secondary	24h urinary Na excretion		2nd scheduled visit (5 days to 4 weeks after 1st visit)
Secondary	Plasma renin concentration		2nd scheduled visit (5 days to 4 weeks after 1st visit)
Secondary	Plasma aldosterone concentration		2nd scheduled visit (5 days to 4 weeks after 1st visit)
Secondary	Repeatability of Ang peptide and urinary exosomal Na channel concentrations under spontaneous vs. standardized laboratory conditions.	Statistical agreement is tested.	1st visit vs. 2nd scheduled visit (5 days to 4 weeks after 1st visit)