High sodium intake, glomerular hyperfiltration, and protein catabolism in patients with essential hypertension

AIMS: A blood pressure (BP)-independent metabolic shift towards a catabolic state upon high sodium (Na(+)) diet, ultimately favouring body fluid preservation, has recently been described in pre-clinical controlled settings. We sought to investigate the real-life impact of high Na(+) intake on measures of renal Na(+)/water handling and metabolic signatures, as surrogates for cardiovascular risk, in hypertensive patients. METHODS AND RESULTS: We analysed clinical and biochemical data from 766 consecutive patients with essential hypertension, collected at the time of screening for secondary causes. The systematic screening protocol included 24 h urine (24 h-u-) collection on usual diet and avoidance of renin–angiotensin–aldosterone system-confounding medications. Urinary 24 h-Na(+) excretion, used to define classes of Na(+) intake (low ≤2.3 g/day; medium 2.3–5 g/day; high >5 g/day), was an independent predictor of glomerular filtration rate after correction for age, sex, BP, BMI, aldosterone, and potassium excretion [P = 0.001; low: 94.1 (69.9–118.8) vs. high: 127.5 (108.3–147.8) mL/min/1.73 m(2)]. Renal Na(+) and water handling diverged, with higher fractional excretion of Na(+) and lower fractional excretion of water in those with evidence of high Na(+) intake [FE(Na): low 0.39% (0.30–0.47) vs. high 0.81% (0.73–0.98), P < 0.001; FE(water): low 1.13% (0.73–1.72) vs. high 0.89% (0.69–1.12), P = 0.015]. Despite higher FE(Na), these patients showed higher absolute 24 h Na(+) reabsorption and higher associated tubular energy expenditure, estimated by tubular Na(+)/ATP stoichiometry, accordingly [Δhigh–low = 18 (12–24) kcal/day, P < 0.001]. At non-targeted liquid chromatography/mass spectrometry plasma metabolomics in an unselected subcohort (n = 67), metabolites which were more abundant in high versus low Na(+) intake (P < 0.05) mostly entailed intermediates or end products of protein catabolism/urea cycle. CONCLUSION: When exposed to high Na(+) intake, kidneys dissociate Na(+) and water handling. In hypertensive patients, this comes at the cost of higher glomerular filtration rate, increased tubular energy expenditure, and protein catabolism from endogenous (muscle) or excess exogenous (dietary) sources. Glomerular hyperfiltration and the metabolic shift may have broad implications on global cardiovascular risk independent of BP.