HIGH SODIUM INTAKE INDUCES A CATABOLIC STATE VIA GLOMERULAR HYPERFILTRATION AND ENHANCED GLOMERULOTUBULAR BALANCE IN PATIENTS WITH ESSENTIAL HYPERTENSION

Abstract

Objective: A blood pressure (BP)-independent catabolic shift upon high sodium (Na+) diet, ultimately favouring body fluid preservation, has recently been described in pre-clinical controlled settings. This study sought to investigate the real-life impact of high Na+ intake on measures of renal Na+/water handling and metabolic signatures in patients with hypertension. Design and method: We analysed clinical and biochemical data collected at the time of screening for secondary causes from consecutive patients with a final diagnosis of essential hypertension. The systematic screening protocol included 24 h urine collection on usual diet and avoidance or washout from medications affecting the renin-angiotensin-aldosterone system. Classes of Na+ intake (Low < 2.3 g/d; Medium 2.3–5 g/d; High > 5 g/d) were defined based on urinary 24 h Na+ excretion. Tubular energy expenditure was estimated by measured Na+ reabsorption and Na+/ATP stoichiometry. Non-targeted liquid chromatography – mass spectrometry (LC-MS) metabolomics was conducted on plasma samples from an unselected subcohort. Results: We included 766 patients (428 males, 55.9%; age, 47 ± 13 years; BMI, 25.6 [23.0–29.0] kg/m2). Urinary 24h-Na+ excretion was an independent predictor of glomerular filtration rate (GFR, estimated by creatinine clearance; Low: 94.1 [69.9–118.8], Medium: 103.8 [86.9–126.0], High: 127.5 [108.3–147.8] ml/min/1.73m2; p < 0.001 for comparisons) after correction for age, sex, BP, body mass index, aldosterone and potassium excretion (p = 0.001). With increasing Na+ intake, the fractional excretion (FE) of free water decreased (Low: 1.13% [0.73–1.72] vs. High: 0.89% [0.69–1.12], p = 0.015), while FE of Na+ increased (Low: 0.39% [0.30–0.47] vs. High: 0.81% [0.73–0.98], p < 0.001); however, absolute 24 h tubular Na+ reabsorption and the associated energy expenditure similarly increased (δ High vs. Low = 18 [12–24] kcal/d, p < 0.001). At LC/MS metabolomics (n = 67), metabolites which were more abundant in High vs. Low Na+ intake (p < 0.05) mostly entailed intermediates or end products of protein catabolism/urea cycle. Conclusions: When exposed to high Na+ intake, kidneys effectively dissociate Na+ and water handling at the cost of higher GFR, increased tubular energy expenditure and, ultimately, protein catabolism from endogenous (muscle) or excess exogenous (dietary) sources. Glomerular hyperfiltration and this metabolic shift may have broad implications on global cardiovascular risk.