Water and Electrolyte Content in Hypertension in the Skin (WHYSKI) in Primary Aldosteronism

Abstract

Background: Primary aldosteronism (PA), the most common curable salt-dependent form of arterial hypertension, features renal K⁺ loss and enhanced Na⁺ reabsorption. We investigated whether the electrolyte, water, and TonEBP (tonicity-responsive enhancer binding protein)/NFAT5 (nuclear factor of activated T cells 5) content is altered in the skin of patients with PA and corrected by surgical cure.

Methods: We obtained skin biopsies from 80 subjects: 49 consecutive patients with PA, optimally treated with a mineralocorticoid receptor antagonist; 6 essential hypertensives; and 25 normotensive controls. We measured Na⁺, K⁺, water content with atomic absorption spectroscopy after ashing, and NFAT5 mRNA with digital droplet polymerase chain reaction. The patients with PA were retested after adrenalectomy.

Results: We discovered a higher dry weight of the skin biopsy specimen at surgery than at follow-up (P<0.001) and a direct correlation with electrolyte and water content (all P<0.01), indicating the need for dry weight adjustment of electrolyte and water data. Surgical cure of PA markedly increased skin dry weight-adjusted K⁺ (from 1.14±0.1 to 2.81±0.27 µg/mg; P<0.001) and water content (from 2.92±1.4 to 3.85±0.23 mg/mg; P<0.001), but left dry weight-adjusted skin Na⁺ content unaffected. In patients with PA at baseline, NFAT5 mRNA was higher (P=0.031) than in normotensive controls and decreased after surgery (P=0.035).

Conclusions: Despite mineralocorticoid receptor antagonist treatment ensuring normokalemia, the patients with PA had a skin cell K⁺ depletion that was corrected by adrenalectomy. The activated NFAT5/TonEBP pathway during mineralocorticoid receptor antagonist administration suggests enhanced skin Na⁺ lymphatic drainage and can explain the lack of overt skin Na⁺ accumulation in patients with PA. Its deactivation after surgical cure can account for the lack of skin Na⁺ decrease postadrenalectomy.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06090617.

Keywords: NFATC transcription factors; electrolytes; hyperaldosteronism; hypertension; sodium.