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University of Toronto, Toronto, Ontario, CANADA
Address reprint requests to: Alexander G. Logan, M.D., Mount Sinai Hospital, 435-600 University Avenue, Toronto, ON M5G 1X5, CANADA. E-mail: alogan{at}mtsinai.on.ca
There is little doubt that an adequate intake of salt is required to maintain good health [1]. Concerns about its health consequences arose more than 40 years ago in response to ecologic, epidemiological and clinical studies linking Western levels of sodium intake to a variety of adverse effects [1,2]. Since these initial observations considerable scientific effort has substantially increased our understanding of the relationship of salt intake to human health. The articles in the supplement to this issue of the Journal of the American College of Nutrition summarize much of what is known and indicate the wide areas of agreement. Nonetheless, they also point out that many important questions remain unanswered.
Sodium is an essential nutrient. It is the principal cation of extracellular fluid and a major determinant of intravascular fluid volume. Plasma volume constitutes roughly 20% of the extracellular fluid compartment, and its maintenance is essential for adequate tissue perfusion and normal cellular metabolism [3]. The defence of extracellular fluid volume is an important physiologic function of the body. Changes are sensed by strategically located vascular stretch receptors that are linked to a series of effectors. The kidney is the primary long-term effector that efficiently regulates sodium and water excretion. Through hemodynamic, neural and hormonal influences it responds appropriately to a wide range of sodium intakes. An abrupt and sustained increase in dietary salt intake expands asymptotically the extracellular fluid space by inducing thirst and water drinking and causing, through its osmotic action, an internal redistribution of fluid from the intra- to extracellular compartment. After three to four days a new steady state is reached in which renal sodium excretion matches intake. Healthy individuals accommodate the extra fluid and the expanded extracellular sodium space without a change in blood pressure [4–6]. This is achieved by a variety of means including the inhibition of vasoconstricting neural-hormonal systems such as the renin-angiotensin-aldosterone axis and the sympathetic nervous system. This sequence of changes goes in the reverse direction on a low sodium diet. Thus, in normal humans complex physiological mechanisms operate to prevent blood pressure from changing in response to large variations in sodium intake.
A critical issue, and one that continues to provoke considerable debate, is the level of sodium required by normal subjects to maintain a vigorous healthy life. Epidemiological data indicate that the usual intake in developed societies ranges from about 100 mmol (2400 mg) to 225 mmol (5175 mg) sodium per day [7]. However, there are many isolated physically active population groups such as the people living in the highlands of Papua New Guinea, the rainforests of Brazil and remote rural communities in Africa that live on a level of salt that rarely rises above 50 mmol (1150 mg) sodium per day [7,8]. In these unacculturated societies, blood pressure is low and does not increase with age, and hypertension is uncommon. The Intersalt investigators, however, have not reported on the survival advantages in low salt societies. From the scanty evidence available, life expectancy appears to be shorter and mortality rate, higher [8]. This may reflect the overriding influence of other environmental factors on life expectancy. On the other hand, the decreased life expectancy in these communities may be the result of sudden environmental changes. For example, animals fed a salt poor diet are more vulnerable to cardiovascular collapse with acute blood loss and have impaired sympathetic cardiovascular adjustments to mental stress [9]. This suggests that the body’s ability to respond effectively to environmental challenges may be severely compromised in the setting of a low sodium diet where the extracellular sodium space is markedly reduced [10] and the vasoconstricting neuro-hormonal systems are intensely stimulated [8].
In the supplement, Dr. Rick Sharp explores the role of sodium in fluid homeostasis with exercise [11]. He provides evidence that vigorous exercise for one hour in a hot environment results in sodium loss from sweating that greatly exceeds the recommended daily sodium intake for sedentary persons. He points out that the necessity to ensure an adequate intake of both sodium and fluid in people actively engaged in daily exercise or who work in occupations that involve prolonged physical activity in hot, humid environments. Without adequate and appropriate replacement, people are at increased risk to develop symptomatic hyponatremia such as lethargy, excess fatigue and profound tiredness, hyperthermia as body heat storage rises, and heat illness when core temperature reaches dangerous levels. These threats to health are amplified in individuals on a low salt diet and magnified further when the function of physiological response systems like the renin-angiotensin-aldosterone axis is hobbled by aging, medications or disease [12].
Evidence from many sources suggests a possible relationship between excess salt ingestion and human hypertension [13]. In the article by Hollenberg in the supplement he reviews the data from observational studies and concludes that the salt intake to blood pressure relationship is present, modest and inconsistent [14]. He points out the formidable array of methodological problems including the reliability of current measures of daily sodium intake, the narrow range of sodium intake within communities and between societies and the difficulties in controlling for other factors that modify the physiological actions of sodium. These conspire to make it unlikely that this investigative approach will ever provide an unambiguous answer. He further examines the data from intervention studies and distinguishes studies that focus on reducing dietary salt intake from those that examine the consequences of sequential salt loading. In the latter group of experiments, a stepped increase in intake to 350 mmol (8050 mg) sodium per day had no effect on blood pressure [6], but a further increase to 800 mmol (18400 mg) sodium per day was associated an increase in pressure, especially in the black normotensive subjects [13]. Among young white volunteers, an intake of more than 1200 mmol (27600 mg) sodium per day still had little impact on blood pressure [4,5,13], raising the possibility of genetic predisposition to salt sensitivity of blood pressure. In the sodium loading experiments there was significant weight gain at each level of increased intake and at higher levels, peripheral edema and occasionally pulmonary congestion were observed. Thus, even in healthy young people the kidneys’ ability to maintain sodium homeostasis begins to falter at very high levels of sodium intake.
Hollenberg raises the issue of a threshold effect that could explain the observation in the Intersalt study of a positive relationship between sodium intake and blood pressure when all 52 centers are included in the analysis and the inverse relationship when the analysis was confined to the 48 centers in developed societies [7]. Support for the threshold concept also comes from the DASH-sodium trial that demonstrated more than twice as great an effect on systolic blood pressure when sodium intake was reduced from the ‘intermediate’ level (roughly 105 mmol per day) to the ‘low’ level (65 mmol per day) as it did with reducing sodium intake from the ‘high’ level to the ‘intermediate’ level [15].
For individuals, rather than population groups, a different picture on the sodium-blood pressure relationship is emerging. In a meta-analysis of randomized controlled trials, Midgley et al noted marked heterogeneity in the blood pressure response to changes in sodium intake [16]. In some trials, large changes had little or no effect on blood pressure, whereas in others, a small reduction lowered blood pressure dramatically. The articles of Hollenberg [14] and Franco and Oparil [17] address the issue of salt-sensitivity and conclude that in some individuals the influence of salt on blood pressure is substantial and cannot be ignored. Susceptible people tend to be older, black or obese and have hypertension, diabetes mellitus, lower plasma renin levels or a family history of salt-sensitivity [18]. They are also more likely to have other cardiovascular risk factors including microalbuminuria, chronic kidney disease and dyslipidemia and are at greater risk for a cardiovascular event [18,19]. The Canadian Hypertension Education Program, in recognition that subsets of the general population are more salt sensitive, recommends a low sodium diet for susceptible people at risk to develop hypertension [20].
Reduced nephron mass and enhanced renal tubular sodium reabsorption are often posited as being responsible for the development of salt-sensitivity [21]. There is mounting evidence that it is not an immutable trait, a concept that many investigators in the past have championed [22,23], but the outcome of one or more acquired factors including a poor quality diet. Hollenberg cites the landmark study of Rocchini et al that convincingly demonstrated the virtual elimination of salt-sensitivity in a group of obese adolescents who successfully lost weight in a formal 20-week weight loss program [24]. Franco and Oparil’s article refers to the results of the DASH-sodium trial that showed the blood pressure lowering effects of a high quality diet in both normotensive and hypertensive individuals [15], and this beneficial action was accompanied by a marked reduction in salt-sensitivity [25]. They point out that the DASH diet when combined with modest dietary sodium restriction (2400 mg per day) produced an equal or greater fall in blood pressure than was obtained by restricting sodium intake to 1500 mmol per day as an isolated intervention [15].
In the article by Alderman [26], he persuasively argues that public policy recommendations on dietary salt restriction should be based on health outcomes rather than surrogate end-points such as blood pressure. While there is little doubt that the level of blood pressure is related to clinically important end-points and lowering it confers benefit [27], a low salt diet induces many physiologic changes including activation of the renin-angiotensin-aldosterone axis [12], increased resistance to the metabolic actions of insulin [28] and a paradoxical rise in blood pressure in some normotensive people [29]. These responses may in themselves have adverse consequences. For example, there is wealth of information showing that an upregulated renin-angiotensin system is a major mediator of cardiovascular disease progression and is associated with accelerated renal injury in susceptible individuals. Moreover clinical trials indicate that its blockade provides protection that is independent of changes in blood pressure [30–32].
Alderman calls for a properly designed and adequately powered randomized controlled clinical trial of a low sodium diet in a nationally representative cohort to determine whether this intervention actually saves lives, reduces cardiovascular events and improves quality of life. He is not persuaded by arguments that such a trial is too expensive or not feasible. He goes on to state that in public health, unlike the clinical arena where the application of a potentially risky intervention represents a tradeoff between its harmful effects and benefits, the demonstration of safety is paramount as interventions are being applied equally to individuals who are well and free of health problems. It is therefore incumbent upon makers of public policy to ensure that their recommendations do not place people at risk. With respect to a low sodium diet, unlike data related to cigarette smoking, Alderman concludes that the evidence on its health benefits and safety is weak, heterogeneous, inconclusive and inconsistent. Alderman is not alone in calling for further research on the health consequences of dietary salt restriction. Many experts in the field including the Institute of Medicine’s panel on dietary reference intakes for electrolytes and water acknowledge that this gap exists and agree that additional research is required [1,33].
Over the past two decades many groups and organizations have focused on the science of making rational health policy [34,35] and the methods for developing guidelines have evolved dramatically during this time [36]. These developments have been supported by users who were disenchanted with the vagaries of expert opinions and dismayed by the pressure tactics of advocates of a particular viewpoint. They wanted a process that is objective, critical, comprehensive and explicit. In the article by Woolf [37], he outlines the principles of making dietary guidelines that meet rigorous scientific standards. He points out the six essential steps, addresses the thorny issue of weighing the evidence, and describes the systems for rating evidence and grading recommendations. He also discusses sensitive matters such as membership selection on guideline committees and the economic and political dimensions of guideline development. Unchecked, these non-scientific influences can have a major impact on the process of building consensus and color the final product.
A substantial body of evidence has documented a strong interaction between sodium and other dietary minerals such as potassium, calcium and magnesium, and these interactive effects are further modified by the accompanying anion [38]. The original DASH trial demonstrated that a diet rich in fruit and vegetables and high in dietary calcium intake dramatically lowers blood pressure independent of changes in dietary sodium intake and weight loss [39]. High quality diets like DASH also have other benefits such as reducing insulin resistance, improving blood lipid profile and enhancing bone mineral metabolism [40]. In the DASH trials the control or reference diet was not the typical American diet as is often stated [15,39], but one carefully crafted to exaggerate deficiencies in many dietary electrolytes such as potassium and calcium. Because the composition of the DASH diet involved multiple dietary changes it is difficult to disentangle the adverse effects and beneficial actions of single nutrients. The article by Morris and Sebastian summarizes the results of studies assessing the effects of single dietary salts on several physiologic and metabolic parameters [41]. These authors document the evidence, much their own, showing that a high potassium diet lowers blood pressure, reduces salt-sensitivity and mitigates the hypercalciuric action of sodium and that these effects are modified by the accompanying anion. Potassium interdicts the physiologic and metabolic consequences of a high salt diet when coupled with bicarbonate or its precursors, but not as a chloride salt. Moreover the beneficial effects of bicarbonate are observed only when the accompanying cation is potassium and not sodium. Given the complexities of human nutrition, failure to consider nutrient interactions and the context of dietary interventions may lead to erroneous conclusions and recommendations.
The insightful studies of Morris and colleagues on the physiological actions of dietary salts have important clinical implications on non-cardiovascular diseases as well. One area is kidney stone disease, a common cause of human suffering and a substantial economic burden. It is often argued that a high salt diet promotes the development of calcium-containing kidney stones based on the high prevalence of hypercalciuria in stone-formers and the direct relationship between sodium intake and urinary calcium excretion [22,42]. The evidence supporting this proposition, however, is weak and inconsistent. For example, Curhan et al in a prospective cohort study of 45,619 men, 40 to 75 years of age, found no relation between dietary sodium intake and the risk of kidney stone disease [43], although they did find a relationship in women [44]. In both studies there was a strong inverse relationship with dietary potassium. More recently, Timio et al in a case-control study, found that daily urinary sodium excretion was lower in renal stone patients than in population controls, even though urinary calcium excretion was almost twice as high [45]. Although it is often stated that a low salt diet reduces stone recurrence in kidney stone patients with idiopathic hypercalciuria [42], the evidence for this assertion comes largely from a trial that applied simultaneously multiple dietary maneuvers including sodium restriction and increased fruit and vegetable intake as a means of reducing risk [46]. Unfortunately, the impact of the dietary intervention on potassium balance and the molar ratio of sodium to potassium was not evaluated to determine the importance of changes in these factors on outcome. This is a major oversight since, as Morris and Sebastian point out, other studies had previously shown that the administration of potassium citrate significantly lowers urinary calcium excretion and the incidence of kidney stones [47].
It has been argued that a high salt intake is a major risk factor for osteoporosis and that a reduction in salt intake may have beneficial effects on bone metabolism [48,49]. In the article by Heaney [50], observations supporting these claims are discussed. He points out that sodium chloride-induced hypercalciuria, a relationship that is now well documented [51] albeit in a subgroup of subjects [52], cannot, in itself, be taken as evidence of an adverse effect on bone metabolism. In the presence of an adequate intake of dietary calcium there is an adaptive increase in calcium absorption from the gastrointestinal tract, which likely compensates for increased urinary calcium excretion. While some have implicated increased bone resorption as the major compensatory response to urinary calcium loss [22,48], Heaney states that the evidence linking high salt to bone mineral loss is weak and inconsistent, and at this point, conjectural. Moreover, he concludes that the evidence supporting a beneficial action of potassium and food precursors of bicarbonate on bone health, while exciting [53], is too meager to make specific recommendations. The recent report from the Institute of Medicine on dietary potassium and sodium chloride reached the same conclusions and recommended additional research to test the main and interactive effects of sodium and potassium intake on bone mineral density and, if feasible, bone fractures [1].
In conclusion, the articles in the supplement provide an up-to-date summary on the relation of dietary sodium and mineral nutrition to human health and the process to make dietary guidelines. While great strides have been made over many decades to improve our knowledge in these areas, significant gaps still exist. For those who make public policy recommendations it is vitally important to know whether a low sodium diet improves health outcomes (in terms of survival, function and quality of life) in the general population and does not place physically active people at risk. Better identification of individuals who are sensitive to the blood pressure effects of salt will permit more efficient targeting of interventions. For health care providers the development of better methods to measure electrolyte intake reliably is a crucial step to overcome nutrient deficiencies in the American diet. A greater understanding of the interactive effects of potassium and calcium on sodium metabolism may provide new insights on ways to reduce the burden of suffering from cardiovascular and non-cardiovascular diseases. Until better information is available, evidence supports a public health dietary policy that focuses on improving diet quality in the entire population and recommends different target intake levels for sodium based on individual susceptibility to salt.
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