Salt sensitivity: When do we get too much of a good thing?

Salt or sodium chloride is an essential nutrient for life. According to an old Chinese proverb, dating back to the Song dynasty (1126 AD), it is part of the seven necessities to start a day. Once an essential substance for food preservation, salt has been important economically throughout history, lending its name to the word ‘salary’. Although its commercial importance has now abated, the potential role of salt in health and disease still causes heated debate among physicians and researchers. Increased blood pressure is the leading global contributor to premature mortality, accounting for almost 10 million deaths per year and 200 million disability-adjusted life years.1 The Intersalt study in 1988 showed a highly significant positive correlation between 24 h urinary sodium excretion and systolic blood pressure.2 Different studies have since corroborated this finding, yet the strength of association seems highly variable across populations.3 Dietary sodium restriction is more effective in lowering blood pressure in patients with hypertension when compared to individuals with normal blood pressure and a very low salt intake might even be harmful in healthy people.3,4 To date, no prospective randomised clinical trial has provided conclusive evidence about the optimal level of sodium intake to minimize cardiovascular events and all-cause mortality. Current European Society of Cardiology guidelines recommend dietary salt restriction < 5 g per day (corresponding to a daily sodium intake < 2 g) in patients with an office blood pressure > 130/85 mmHg (class I, level of evidence B).5 The study by Kim et al.6, published in this issue, provides further insight in the pathophysiology of salt sensitivity, i.e. the relationship between sodium intake and blood pressure. Notably, the study participants were Asian and the findings cannot necessarily be extrapolated to populations of different races. A particular strength of the study was that 24 h ambulatory blood pressure monitoring was used, which allows the assessment of night-time blood pressure, which has the strongest association with cardiovascular outcomes.7,8 Sodium intake was assessed through a single 24 h urine collection. Ideally, multiple collections are needed to account for the day-to-day variability in sodium excretion and salt intake – a limitation that has been correctly acknowledged by the authors. However, even single 24 h urine collections provide a more robust estimate of sodium intake than spot urinary samples or dietary questionnaires. The authors should be congratulated for achieving these cumbersome measurements in a large study population of 1128 people. An important finding of the study by Kim et al.6 is that sodium sensitivity, defined as a positive correlation between sodium intake and blood pressure, was almost absent in patients < 55 years of age. It would have been interesting to assess whether this was also true for the subgroup with hypertension within this population (n = 177 (34%)). If so, this would make a strong argument for a differential pathophysiology of hypertension according to age. Indeed, it is well-known that elderly patients with hypertension, as well as black patients with hypertension, have a more favourable blood pressure response when treated with diuretics. This group also benefits most from dietary salt restriction with respect to their blood pressure response. Low plasma renin activity might help to predict this response and was associated with the treatment effect of add-on therapy with spironolactone for drug-resistant hypertension in the Prevention And Treatment of Hypertension With Algorithm-based therapy 2 (PATHWAY-2) trial.9,10 Based on the results of the current study, we might anticipate that a young hypertensive population with presumably high plasma renin activity would not benefit much from dietary sodium restriction. However, the relationship between sodium intake, plasma renin activity, blood pressure response and plasma volume should be investigated further in contemporary populations. The age cut-off of 55 years for ‘elderly’ patients applied by Kim et al.6 warrants some discussion. It should be noted that very few patients > 65 years were enrolled in this study, so basically the group of ‘elderly’ patients was aged predominantly 55–65 years. It is clear from the results that sodium sensitivity is already prevalent in this age group, at least in patients of Asian race. Interestingly, the pulse pressure as a marker of vascular stiffness started to increase from the age of 55 years in the study participants. It has been shown previously that sodium stiffens the vascular endothelium and reduces nitric oxide release.11 An integral endothelial glycocalyx shields the healthy endothelium from plasma sodium, with negatively charged proteins in the interstitial matrix functioning as an effective buffer.12 In addition, a higher excretory capacity for sodium and chloride is present with a higher glomerular filtration rate, explaining the absence of sodium sensitivity in the younger population and its onset with ageing (Figure 1). Onset of sodium sensitivity with ageing. Kim et al.6 clearly show that night-time blood pressure is much more strongly influenced by sodium sensitivity than daytime blood pressure. Intriguingly, night-time blood pressure is also a stronger predictor of clinical outcomes.6 As sodium sensitivity and hypertension are often intertwined in clinical practice, it is tempting to speculate that the former rather than the latter may be responsible for adverse clinical outcomes, yet this hypothesis certainly requires more mechanistic study. Meanwhile, it makes sense to keep advising our patients with hypertension to avoid foods containing high levels of sodium. Innovative strategies, such as smartphone-based applications, may be effective tools to help people achieve this goal.13 For patients in whom pharmacological treatment is eventually needed, the success stories of novel therapies targeting sodium homeostasis and natriuresis, such as sodium-glucose transporter-2 and neprilysin inhibitors, should maintain our continued interest in this ordinary substance of salt. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.