Low sodium intake increases plasma renin activity

Reducing sodium intake to low levels (<2 g/day, 5 g/day of salt) is recommended in the entire adult population by the WHO [[1]World Health Organization (WHO)Guideline: sodium intake for adults and children. World Health Organization (WHO), 2012http://www.who.int/nutrition/publications/guidelines/sodium_intake_printversion.pdfGoogle Scholar], which will require substantial reductions in mean sodium intake globally (current mean: 3·9 g/day). The recommended low sodium intake target is based on short-term randomized clinical trials, reporting a reduction in blood pressure with reductions in sodium intake to low intake levels. It is assumed, but unproven, that sustained low sodium intake will translate into reductions in cardiovascular events, on the premise that reducing sodium intake will not have adverse effects. Over the past decade, a series of prospective cohort studies have failed to report a reduction in cardiovascular events associated with low sodium intake (compared to moderate/average intake, 2.3–4.6 g/day) and many studies have reported a higher risk of cardiovascular events and death associated with low sodium intake [[2]O'Donnell M. Mente A. Alderman M.H. et al.Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake.Eur Heart J. 2020; 41: 3363-3373Crossref PubMed Scopus (25) Google Scholar]. Overall, evidence from prospective cohort studies supports a J-shaped association of sodium intake with cardiovascular disease, with the lowest risk observed at a moderate intake range. While some suggest that the increased risk in those consuming low sodium intake may be attributable to reverse causation or residual confounding [[3]Cobb Laura K. Anderson Cheryl A.M. Paul Elliott et al.Methodological issues in cohort studies that relate sodium intake to cardiovascular disease outcomes.Circulation. 2014; 129: 1173-1186Crossref PubMed Scopus (192) Google Scholar], others advance the argument that extreme reductions in an essential electrolyte may have adverse consequences that offset benefits of modest blood pressure lowering [[4]Heaney R.P. Sodium: how and how not to set a nutrient intake recommendation.Am J Hypertens. 2013; 26: 1194-1197Crossref PubMed Scopus (28) Google Scholar]. The results of a meta-analysis by Graudal et al. [[5]Graudal N. Hubeck-Graudal T. Jurgens G. Influence of sodium intake and change in sodium intake on plasma-renin in man.EClinicalMedicine. 2021; 33100750Summary Full Text Full Text PDF Scopus (2) Google Scholar] published in EClinicalMedicine provides evidence that lowering sodium intake, from moderate to low intake levels, results in an increase in plasma renin activity, in short-term clinical trials, and suggest a larger effect in normotensive populations than in hypertensive populations. In contrast, the authors reported no effect of reducing sodium intake from high to moderate intake on plasma renin levels. An increase in renin activity with low urinary sodium excretion was described almost 50 year ago in a cross-sectional study [[6]Weidmann P. Beretta-Piccoli C. Ziegler W.H. Keusch G. Glück Z. Reubi F.C. Age versus urinary sodium for judging renin, aldosterone, and catecholamine levels: studies in normal subjects and patients with essential hypertension.Kidney Int. 1978; 14: 619-628Summary Full Text PDF PubMed Scopus (170) Google Scholar]. Increases in renin are associated with increases in blood pressure secondary to angiotensin-II-mediated vasoconstriction and aldosterone-mediated sodium retention in the kidney. Increases in plasma renin activity have been associated with an increased risk of cardiovascular events, first described 30 years ago, and replicated in numerous prospective studies [[7]Alderman M.H. Madhavan S. Ooi W.L. Cohen H. Sealey J.E. Laragh J.H. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension.N Engl J Med. 1991; 324: 1098-1104Crossref PubMed Scopus (681) Google Scholar]. However, some antihypertensive agents (e.g. thiazide diuretics) also increase renin but are effective in reducing cardiovascular events in patients with hypertension, suggesting a contextual pattern of association and consequence. Sodium is essential to numerous physiologic processes, and subject to negative feedback loops to maintain homeostasis [[4]Heaney R.P. Sodium: how and how not to set a nutrient intake recommendation.Am J Hypertens. 2013; 26: 1194-1197Crossref PubMed Scopus (28) Google Scholar]. An assessment of compensatory physiologic mechanisms provide key insights into establishing a ‘deficient’ state, analogous to the approach taken in determining adequate thyroid hormone replacement, which is based on thyroid stimulating hormone levels. Therefore, the point at which reducing sodium intake evokes a compensatory effect on plasma renin activity may inform the location of a lower limit of the ‘normal’ range of sodium intake [[4]Heaney R.P. Sodium: how and how not to set a nutrient intake recommendation.Am J Hypertens. 2013; 26: 1194-1197Crossref PubMed Scopus (28) Google Scholar]. Activation of compensatory mechanisms likely explain the observation that blood pressure reduction with reducing sodium intake diminishes at lower sodium intake ranges. It also provides a biological rationale for increased cardiovascular risk associated with low sodium intake, where activation of plasma renin may offset the potential benefits of blood pressure lowering in this sodium intake range. In contrast, reductions in sodium intake from high to moderate intake ranges are not associated with changes in plasma renin activity, a range where associations with blood pressure and cardiovascular risk are consistent. A limitation in the available evidence, reported by Gradual et al., is the relatively short duration of clinical trials (4–42 days), precluding an assessment of the long-term effect of changing sodium intake on plasma renin activity. The optimal range of sodium intake for human health has been a subject of considerable debate. The case for recommending low sodium intake (< 2 g/day) necessitates an exclusionary focus on the association of sodium intake and blood pressure, while the case for recommending a moderate range (i.e., reducing sodium intake in those consuming intakes above 4·6 g/day) is based on the additional inclusion of evidence from prospective cohort studies and physiologic effects of low sodium intake, such as reported by Graudal et al. It is proposed that resolving the controversy will require a large Phase III randomized clinical trial, comparing the effect of moderate to low sodium intake on cardiovascular events and mortality. However, a major challenge to such a trial is maintaining sustained low sodium intake in a large cohort of community-dwelling individuals, which has not been achieved in longer-term trials, even those employing intensive dietary counselling [[8]Whelton P.K. Appel L.J. Espeland M.A. et al.Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE collaborative research group.JAMA. 1998; 279: 839-846Crossref PubMed Scopus (944) Google Scholar,[9]Cook N.R. Cutler J.A. Obarzanek E. et al.Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP).BMJ. 2007; 334: 885Crossref PubMed Scopus (870) Google Scholar]. This inability to achieve sustained low sodium intake in populations may also relate to neurohormonal control mechanisms governing the maintenance of sodium homeostasis, and disputes the feasibility of low sodium intake in the general population [[10]McCarron D.A. Geerling J.C. Alderman M.H. Urinary sodium excretion measures and health outcomes.Lancet. 2019; 393: 1294-1295Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. The meta-analysis by Gradual et al. provides summary evidence that low sodium intake may not be a physiologically ‘normal’ intake range and adds further support to the contention that public health policy should target a moderate range of sodium intake [[2]O'Donnell M. Mente A. Alderman M.H. et al.Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake.Eur Heart J. 2020; 41: 3363-3373Crossref PubMed Scopus (25) Google Scholar]. The authors declared no conflict of interest. Both authors wrote the commentary and approved the final version of the manuscript. CJ was supported by the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z). MOD is supported by the European Research Council COSIP Grant 640580. Influence of sodium intake and change in sodium intake on plasma-renin in manThe accelerating effect of sodium reduction on PRA towards a sodium intake of zero mmol/24 h probably explains the interstudy variability. Further studies are needed to test whether this stimulating effect on PRA reflects a physiological disadvantage potentially associated with increased mortality Full-Text PDF Open Access

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