Skin Na+ Excess in Hypertensive Patients: Isotonic Nature and Clinical Correlates

Abstract

Objective: Our traditionally nephrocentric view of Na+ homeostasis has recently been challenged by the concept of Na+ accumulation in tissues, predominantly skin, observed in hypertension. Its proposed water-independent (hypertonic) nature, carrying pathogenic potential, lacks firm demonstration. This study investigates the nature and clinical correlates of skin Na+ accumulation in hypertensive patients. Design and method: Responses to a validated salt intake questionnaire, measures of transepidermal water loss (TEWL), blood samples and a skin punch biopsy were collected from adult, non-pregnant and consenting hypertensive patients at the Glasgow Blood Pressure Clinic. Histochemical analysis was conducted by splitting the skin into epidermis/superficial dermis (ESD) and deep dermis (DD) layers. Water was measured by gravimetric approach (wet weight – dry weight), and Na+ and K+ by flame photometry. Results: Seventy-six patients consented to skin biopsy (age: 58 ± 15, range 22–86 years; females = 47.4%; BMI: 30.3, IQR 27.5–36.3). Na+ concentration ([Na+]) and K+ concentration ([K+]) was lower and higher in ESD (richer in cellularity) compared to DD, respectively (112.6 ± 8.57 and 30.17 ± 4.88 vs 119.0 ± 11.81 and 17.28 ± 3.62 mmol/l), respectively (p < 0.001 for both). Virtually none of the patients had [Na++K+] exceeding normal physiological levels in either layer, thus excluding hypertonic extracellular Na+ accumulation. Water content was positively and negatively correlated with Na+ and K+, respectively. Female DD, which is richer in fat content, contained less water, Na+ and K+ than male dermis (p < 0.01 for all), with no difference in concentrations or in ESD. Age was associated with an increase in ESD water and [Na+], and a decrease in [K+] in both layers, suggestive of oedema accumulation and independent of sex, BMI and estimated Na intake (padj < 0.005). The latter independently predicted epidermal water content (padj = 0.017). Patients with uncontrolled BP had higher ESD [Na+] (padj = 0.02). NT-proBNP levels mirrored all measures of skin oedema accumulation, while no significant interaction with medications or TEWL was observed. Conclusions: Skin Na+ accumulation in hypertensive patients is isotonic, prevalent and reflects subclinical oedema. Tissue architecture considerably impacts on Na+ content and concentration, whereas TEWL has minimal effect. These results have mechanistic, diagnostic and therapeutic implications.