Water and Electrolytes Content in HYpertension (WHYSKI) in the SKIn (WHYSKI)

March 18, 2024 updated by: Gian Paolo Rossi, MD, FAHA, FACC, University Hospital Padova

The Water and Electrolytes Content in Salt-dependent Human HYpertension (WHYSKI) in the SKIn Before and After Surgical Cure of Primary Aldosteronism

WHYSKI is a prospective within-patient observational clinical study designed to test the hypothesis that alterations of Na+, K+, water, and the lympho-angiogenetic transcription factor Tonicity Enhancing Binding Protein (TonEBP) mRNA take place in the interstitium of the skin compartment of patients with arterial hypertension due to primary aldosteronism in whom hypertension can be surgically cured.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Background. Given the key role of Na+ in the pathophysiology of HT, this study will test the hypothesis that in PA, which is the paradigm of salt-dependent hypertension, the skin, Na+, K+ and water content is altered and these alterations are corrected by surgical cure of PA with video-laparoscopic adrenalectomy. The investigators will use skin biopsies to directly examine the content of Na+, K+, water, and the lympho-angiogenetic transcription factor Tonicity Enhancing Binding Protein (TonEBP) mRNA in the skin, an important reservoir of body Na+, in primary aldosteronism (PA), the prototype of salt-dependent hypertension.

Methods. The investigators will measure Na+, K+, and water content (by chemical-physical methods) and TonEBP mRNA copy number (by droplet digital PCR) in skin biopsies from a sex-mixed cohort of consecutive consenting patients with unilateral PA treated with a mineralocorticoid receptor antagonist (MRA), before surgery, at doses that correct hypokalemia and HT in order to refer them for surgery with normokalemia and controlled high blood pressure, as per protocol at our institution. The participants will be reassessed in an identical way again after surgical cure.

The investigators expect the dry weight (DW) of the skin specimen obtained at surgery to be significantly higher than at follow-up and to correlate positively with skin Na+, K+, and water content. Hence, if these predictions will be verified, the skin cations and water content will need to be DW-adjusted in order to provide meaningful comparisons across specimen obtained at different time points. The investigators expect the TonEBP mRNA copy number to be markedly overexpressed compared to healthy subjects.

The WHYSKI study will provide solid knowledge of the skin Na+, K+ and water content in patients with arterial salt-dependent hypertension due to PA, PH, and on the effect of cure of the hyperaldosteronism on these variables. The investigators also expect to gather novel knowledge on the molecular and cellular mechanisms involved in the regulation of the content on Na+, K+ and water in a compartment as the skin interstitium that has been largely neglected thus far.

Study Type

Observational

Enrollment (Estimated)

35

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Patients referred to either the Endocrine Surgery unit, the Specialized Center for Blood Pressure Disorders of Regione Veneto of the Azienda Ospedale-Università di Padova, or other surgery departments of the same institution were recruited.

Description

Inclusion Criteria:

PA Group

  • Age: 18-75-year-old.
  • Signed informed consent form.

  • A diagnosis of PA defined as

    o Plasma aldosterone concentration > 15 ng/dL and aldosterone/renin ratio greater than 20.6 ng/mIU, measured after washout of interfering drugs or after changes of the drug treatment as previously detailed.

  • Unilateral or bilateral evidence of PA at adrenal vein sampling

PH Group

  • Age: from 18 to 75 years old
  • Signed and dated informed consent form

  • Diagnosis of essential hypertension defined either as:

    • Use of antihypertensive drug (s)
    • Arterial hypertension: in untreated patients this must be confirmed by daytime ambulatory blood pressure monitoring (ABPM), or home blood pressure monitoring, with blood pressure higher or equal to 135 mmHg for systolic blood pressure and/or higher or equal to 85 mmHg for diastolic blood pressure.
    • Exclusion of secondary hypertension by hormonal biochemical screening (aldosterone, renin, ARR<2.06 ng/dL:mIU/L, ACTH, 24h urine cortisol, morning plasma cortisol level, 24h urine metanephrines and catecholamines).

Control Group

  • Age: from 18 to 75 years old
  • Signed and dated informed consent form

  • Normal arterial blood pressure defined either as:

    • None anti-hypertensive drug (s)
    • Normal arterial hypertension confirmed by daytime ambulatory blood pressure monitoring (ABPM), or home blood pressure monitoring, with blood pressure lower or equal to 135 mmHg for systolic blood pressure and/or lower or equal to 85 mmHg for diastolic blood pressure.
    • Exclusion of secondary hypertension by hormonal biochemical screening (aldosterone, renin, ACTH, 24h urine cortisol, morning plasma cortisol level, 24h urine metanephrines and catecholamines).

Exclusion Criteria:

PA Group

  • history of allergy/intolerance to local anesthesia;
  • refusal of the patient to undergo skin biopsy;
  • refusal of the patient to undergo AVS, and/or contraindications to the general anesthesia that is required for laparoscopic adrenalectomy and/or to undergo adrenalectomy if indicated;
  • cortisol-aldosterone co-secreting adenoma or pheochromocytoma. PH Group and Control Group
  • Concurrent skin diseases, for example psoriasis, and any pathological conditions that, in the judgement of the investigators, could affect skin electrolyte and water content.
  • Subjects with diabetes mellitus type 1 and 2, as drugs affecting the renin-angiotensin-aldosterone system and/or renal Na+ handling as, for example, SGLT-2 inhibitors (gliflozins) 16 were considered to potentially bias results.
  • Other conditions characterized by possible lymphatic disruption such as lipedema, cyclic idiopathic edema, lymphedema, and malignancies were also exclusion criteria.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
PA group 1

conclusive diagnosis of unilateral PA by the "four corners" criteria:

  1. Biochemical evidence of PA
  2. Lateralization of aldosterone secretion at adrenal venous sampling.
  3. Correction of biochemical values and fall of blood pressure after adrenalectomy.
  4. Immunohistochemical demonstration of CYP11B2 positive nodule(s)
Procedure: Skin Biopsy
Skin biopsies were obtained in all recruited patients.
Procedure: Video-laparoscopic adrenalectomy
Video-laparoscopic adrenalectomy in those with unilateral PA. (PA group 1)
PA group 2
Presumed diagnosis of bilateral PA, defined as above but without evidence of lateralized aldosterone excess.
Procedure: Skin Biopsy
Skin biopsies were obtained in all recruited patients.
PH Group
Primary (essential) Hypertension (PH): conclusively ascertained high blood pressure and exclusion of secondary hypertension
Procedure: Skin Biopsy
Skin biopsies were obtained in all recruited patients.
Non Hypertensive Control Group
comprising patients submitted to surgery but free of hypertension
Procedure: Skin Biopsy
Skin biopsies were obtained in all recruited patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
measure the Na+, K+ and water content in the skin of patients with primary aldosteronism (PA, PA Group), primary (essential) hypertension HT patients (PH Group) and in normotensive patients (Control Group).
Time Frame: Baseline (Surgery), Month 1 after Surgery (for PA Group 1 only)

With validated chemical physical methods, we will measure the Na+, K+ and water content in the skin of patients with primary aldosteronism (PA, PA Group), primary (essential) hypertension HT patients (PH Group) and in normotensive patients (Control Group). The skin biopsy will be performed during adrenalectomy in consecutive patients with confirmed unilateral PA (PA Group) and in parallel in the same anatomical region in the PH group and in the Control Group, during surgery for benign diseases.

To verify if the cure of PA improves Na+, K+ and water skin clearance in the PA Group the skin biopsy obtained during adrenalectomy will be within-patient compared to that obtained one month after adrenalectomy (PA Group 1). In PA patients found not to have unilateral PA (PA Group 2), the biopsy will be obtained after one month of target medical treatment with canrenone, a mineralocorticoid receptor antagonist.
Baseline (Surgery), Month 1 after Surgery (for PA Group 1 only)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
mRNA content of Tonicity-Enhancing Binding Protein TonEBP (also known as NFAT5)
Time Frame: Baseline (Surgery), Month 1 after Surgery (for PA Group 1 only)
While the measurement of skin Na+, K+ and water is the main study outcome, an additional important goal will be to determine the molecular mechanisms driven by "skin sodium storage" that underlie the crosstalk between skin cells, macrophages and lymphatic vessels in the interstitium of the patient with PA (PA group 1) and essential hypertensive patients (EH Group) compared with the normotensive patient (Control Group). To this end we will explore the mRNA content of Tonicity-Enhancing Binding Protein TonEBP (also known as NFAT5), a transcription factor known to activate neo-lymphoangiogenesis, using molecular biology techniques.
Baseline (Surgery), Month 1 after Surgery (for PA Group 1 only)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Padova

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2021

Primary Completion (Estimated)

April 1, 2024

Study Completion (Estimated)

January 1, 2025

Study Registration Dates

First Submitted

October 13, 2023

First Submitted That Met QC Criteria

October 18, 2023

First Posted (Actual)

October 19, 2023

Study Record Updates

Last Update Posted (Actual)

March 19, 2024

Last Update Submitted That Met QC Criteria

March 18, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AOP1615

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

IPD available on reasonable request but if consistent with the ongoing privacy legislation.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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