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

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, 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.