David A. McCarron

Can Dietary Sodium Intake Be Modified by Public Policy

Sodium chloride holds a unique position in the annals of human existence and science (1). For thousands of years, salts high value has made it the foundation of a society, a currency of trade, and cause for wars. Over the past century, sodium chloride has been the subject of intense scientific research to understand its role in human physiology and its impact on health. The latter has focused primarily on salts role in BP regulation, an issue fraught with controversy, as documented a decade ago (2) and still evident in the scientific literature (3,4).nnSince the first Surgeon Generals Report Healthy People: Promotion and Disease Prevention published in 1979 (5), public health guidelines have recommended that adults consume less salt. This culminated in 2003 with the Institute of Medicine (IOM) Electrolyte DRI Committee targeting 2300 mg/d as the safe upper level of sodium in the diet (6). The 2005 Dietary Guidelines recommended this same level for healthy adults and 1500 mg/d for individuals at risk of hypertension (7).nnAs increasingly more restrictive guidelines have been introduced over the past 30 yr, scientific research has continued to provide new insights regarding the effectiveness and safety of lowering sodium intake. Some, but certainly not all, of the newer data have supported the sodium guidelines (8,9), although the feasibility of their implementation remains in question. It has been assumed that if adults better understood how to reduce sodium in their diets and if more low-sodium foods were available, more individuals would be able to achieve these levels. Public health experts throughout the world have devised strategies targeting greater compliance with the lower sodium recommendations.nnIn the United States (US), a special IOM committee has recently been charged to formulate such strategies (10). Great Britain initiated an intense …

Normal Range of Human Dietary Sodium Intake: A Perspective Based on 24-Hour Urinary Sodium Excretion Worldwide

BACKGROUNDnThe recommendation to restrict dietary sodium for management of hypertensive cardiovascular disease assumes that sodium intake exceeds physiologic need, that it can be significantly reduced, and that the reduction can be maintained over time. In contrast, neuroscientists have identified neural circuits in vertebrate animals that regulate sodium appetite within a narrow physiologic range. This study further validates our previous report that sodium intake, consistent with the neuroscience, tracks within a narrow range, consistent over time and across cultures.nnnMETHODSnPeer-reviewed publications reporting 24-hour urinary sodium excretion (UNaV) in a defined population that were not included in our 2009 publication were identified from the medical literature. These datasets were combined with those in our previous report of worldwide dietary sodium consumption.nnnRESULTSnThe new data included 129 surveys, representing 50,060 participants. The mean value and range of 24-hour UNaV in each of these datasets were within 1 SD of our previous estimate. The combined mean and normal range of sodium intake of the 129 datasets were nearly identical to that we previously reported (mean = 158.3±22.5 vs. 162.4±22.4 mmol/d). Merging the previous and new datasets (n = 190) yielded sodium consumption of 159.4±22.3 mmol/d (range = 114-210 mmol/d; 2,622-4,830mg/d).nnnCONCLUSIONSnHuman sodium intake, as defined by 24-hour UNaV, is characterized by a narrow range that is remarkably reproducible over at least 5 decades and across 45 countries. As documented here, this range is determined by physiologic needs rather than environmental factors. Future guidelines should be based on this biologically determined range.

Gestational calcium supplementation and blood pressure in the offspring

BACKGROUNDnThe current study examined the relationship between calcium supplementation during pregnancy and blood pressure (BP) in the mother and offspring at 3 months and at 2 years postpartum.nnnMETHODSnNulliparous pregnant women were assigned to either receive 2 g of calcium or placebo daily beginning between weeks 13 to 21 of gestation and continuing until delivery. Blood pressure was measured in children and their mothers at 3 months (n = 260) and (n = 57) at 2 years postpartum. Systolic BP was measured in the infants using a sphygmomanometer with ultrasonic amplification. For the toddlers, three supine BP measurements were taken from the right arm using a Critikon automated sphygmomanometer just after measurement of left ventricular wall thickness.nnnRESULTSnSystolic BP in the calcium-supplemented infants was 2.2 mm Hg lower than in the placebo group (P >.05). At 2 years of age, systolic BP was 4.8 mm Hg lower in the calcium supplemented group (P <.05), whereas diastolic BP was 3 mm Hg lower (P >.05). There was no difference in left ventricular mass index between groups, although there was a significant correlation between systolic BP and wall thickness (P <.05). Maternal BP was positively correlated with circulating 1,25(OH)(2)D3 (P <.001) but did not differ between calcium groups at 3 months postpartum.nnnCONCLUSIONSnThe data on BP in the children are in agreement with previous studies and argue strongly for additional research into the effects of prenatal calcium supplementation on BP regulation in the offspring.

The Significance of Duration and Amount of Sodium Reduction Intervention in Normotensive and Hypertensive Individuals: A Meta-Analysis

The purpose of this meta-analysis was to establish the time for achievement of maximal blood pressure (BP) efficacy of a sodium reduction (SR) intervention and the relation between the amount of SR and the BP response in individuals with hypertension and normal BP. Relevant studies were retrieved from a pool of 167 randomized controlled trials (RCTs) published in the period 1973-2010 and integrated in meta-analyses. Fifteen relevant RCTs were included in the maximal efficacy analysis. After initiation of sodium reduction (range: 55-118 mmol/d), there were no significant differences in systolic blood pressure (SBP) or diastolic blood pressure (DBP) between measurements at weeks 1 and 2 (∆SBP: -0.18 mmHg/∆DBP: 0.12 mmHg), weeks 1 and 4 (∆SBP: -0.50 mmHg/∆DBP: 0.35 mmHg), weeks 2 and 4 (∆SBP: -0.20 mmHg/∆DBP: -0.10 mmHg), weeks 2 and 6 (∆SBP: -0.50 mmHg/∆DBP: -0.42 mmHg), and weeks 4 and 6 (∆SBP: 0.39 mmHg/∆DBP: -0.22 mmHg). Eight relevant RCTs were included in the dose-response analysis, which showed that within the established usual range of sodium intake [<248 mmol/d (5700 mg/d)], there was no relation between the amount of SR (range: 136-188 mmol) and BP outcome in normotensive populations [∆SBP: 0.99 mm Hg (95% CI: -2.12, 4.10 mm Hg), [corrected] P = 0.53; ∆DBP: -0.49 mm Hg (95% CI: -4.0, 3.03), P = 0.79]. In contrast, prehypertensive and hypertensive populations showed a significant dose-response relation (range of sodium reduction: 77-140 mmol/d) [∆SBP: 6.87 mmHg (95% CI: 5.61, 8.12, P < 0.00001); ∆DBP: 3.61 mmHg (95% CI: 2.83, 4.39, P < 0.00001)]. Consequently, the importance of kinetic and dynamic properties of sodium reduction, as well as baseline BP, should probably be considered when establishing a policy of sodium reduction.

Dietary sodium and cardiovascular and renal disease risk factors: dark horse or phantom entry?

Identifying a nutritional cause of cardiovascular disease (CVD), a nutrient that could be manipulated to reverse CVD morbidity and mortality, would be finding the Holy Grail of nutrition and CV science. Cardiovascular researchers and public policy advocates have long labeled dietary sodium as this nutrient, what they consider the primary dietary factor in the pathogenesis of high blood pressure (BP) and subsequent CVD, despite the lack of valid scientific data to bear this out [1]. While Mimran et al. [2] promulgate this claim in their commentary in this issue, they fail to acknowledge the defects in their supporting evidence or the more carefully derived evidence demonstrating that dietary sodium holds no more than an ancillary, if any, role in the development of cardiovascular or renal disease in the general population. That assessment is not to suggest that the management of many patients with chronic kidney disease, congestive heart failure and liver disease among other specific medical conditions should not include sodium restriction. In these highly selected populations, though, the need for or, indeed, the benefits of reduced sodium intake are not universal either.

Physiology, Not Policy, Drives Sodium Intake

In determining what constitutes “normal” sodium intake for humans, the disciplines of medicine and public health long ago fell prey to the “emperor’s new clothes” syndrome; For decades a theoretical case has been built on assumptions that sodium intake has been increasing over time, is at levels far in excess of physiological needs, is a major cause of cardiovascular disease, and is modifiable by public policy.1 Just as the emperor found out about his clothes, these suppositions do not reflect reality. A frequent claim by the advocates of lower sodium intake is that the current average intake of 3,400 mg/d far exceeds the US guidelines.1,2 That is true, as 2,300 mg/d is the current recommendation for healthy adults aged <50 years, and 1,500 mg/d is recommended for those at risk of cardiovascular disease and/or aged ≥50 years. The advocates’ claim is only relevant, however, if i) the current guidelines are based on reproducible evidence of benefit in terms of health outcomes, ii) the current 3,400 mg/d average sodium intake is an aberration of physiology, and iii) it is physiologically possible for freeliving individuals to achieve the recommended levels of dietary sodium on a consistent basis. On each count the scientific evidence is unequivocal: the current guidelines are physiologically irrelevant. Thus, the mantra of the advocates that current sodium intakes are excessive is also irrelevant and, thus, misguided in its intent to frame public policy on sodium intake; at the core of the science that refutes the advocates’ claim is 8 decades of neuroscience research that has defined the neural networks involved in regulating sodium intake in vertebrates.3 These primal networks are interfaced with peripheral signals that inform the brain of the adequacy of organ perfusion (i.e., intravascular volume status). The renin angiotensin system and its generation of angiotensin II and aldosterone are the primary stimuli activating the neural networks that control sodium intake.3 These well-established physiologic pathways provide the biological basis of the fact that actual human sodium intake is set by physiology and not public policy. It is true, and obviously so, that when sodium intake is measured by the best techniques (24-hour urinary sodium excretion), there is a reproducible average intake with a “normal” distribution for the population.4–6 That average—3,600 mg/d, with a range of 2,600–5,000 mg/d—is a mean intake that has been recorded consistently over 5 decades, across 45 countries, and in multiple ethnic groups.6 It has also been verified by a number of National Institutes of Health–sponsored, controlled trials intended to decrease sodium intake and numerous governmental surveys monitoring sodium intake over time.4–6 As with hemoglobin, fasting blood glucose, and many other physiologically set parameters, sodium intake as a critical determinant of intravascular volume regulation is set within a normal range in healthy individuals. This range of sodium intake appears fundamental to survival because intravascular volume is dependent on sodium and water. Although angiotensin II and other critical hormonal responses that modulate vasoconstriction can maintain organ perfusion as a rescue response to inadequate volume, there is little debate in terms of cardiovascular pathophysiology that dependence on vasoconstriction as opposed to volume maintenance for organ perfusion is associated with adverse health outcomes. That reality was elegantly established, although not commented upon, in a 1972 New England Journal of Medicine report that documented 2 important physiologic principles.7 First, as 24-hour urinary sodium excretion decreased, there was a logarithmic increase in plasma renin activity (PRA), and, second, in persons whose PRA was most increased, there was an increase in cardiovascular disease morbidity and mortality. What was not commented on, but recently noted by us,6 was that the point at which the confidence interval of the PRA parabolic curve was intersected by the asymptote of the curve represented the lowest level of 24-hour urinary sodium excretion associated with maximal suppression of PRA (Figure 1). This observation demonstrates the physiologic coordination between sodium intake and the regulation of PRA and subsequent generation of angiotensin II. As noted above, the stimulation of angiotensin II and aldosterone release by low sodium intake is the proximate and most powerful input to the neural circuits to provoke an increase in dietary sodium appetite.3 Based on this physiologic regulatory loop between peripheral sensors of sodium adequacy and the regulation of sodium appetite, it follows that sodium intake in humans should be expressed by a classic normal distribution. That distribution, as with all essential nutrients, is characterized by a bell-shaped curve,6,8 as we recently reported (Figure 2). The distribution is defined at both the lower and upper ends by a relatively strict cutoff. We observed that <1% of the free-living general population consumed <2,600 mg/d of dietary sodium or >5,000 mg/d, consistent with physiologic regulation within a defined and limited range. This scientifically Correspondence: David A. McCarron (dmccarron@mccarrongroup.com).

Public Policy and Dietary Sodium Restriction

children 6 years later. We speculate that the increase here largely reflects the detection of most of these problems in middle childhood, rather than at younger ages. We agree that obesity is a risk factor for a range of problems later in life, and treatments for obesity aim to prevent these problems rather than minimize active symptoms. However, there is evidence to support that treating obesity at earlier ages is needed to stave off the adverse effects later in life. This substantiates the argument for ongoing efforts to better prevent, detect, and treat childhood obesity in health care settings and in communities and schools. Although other methods of assessing obesity exist, BMI has had much study and is linked to adverse health outcomes in later childhood and adulthood. Furthermore, BMI is recommended and used for obesity assessment in clinical practice. We acknowledge that some parents reported these measurements, and our study conducted sensitivity analyses using objectively obtained data, which showed that parental report did not substantially change our findings.

Data rather than opinion dictates that a definitive clinical trial must determine if the us government's sodium guideline is safe and effective.

T he 2010 US Dietary Guidelines1 recommend that all Americans over age 50 and all individuals with, or at risk of, a variety of common health conditions restrict their sodium intake to <1,500 mg/day (65 mEq/day). Healthy persons under 50 were advised to limit sodium to 2,300 mg/day (100 mEq/day). The discussion surrounding these guidelines claimed dramatic benefits in terms of reduced morbidity and mortality as well as billions in healthcare cost savings annually. The evolution of these guidelines has relied on the opinions and interpretation of the published science by a limited number of government-funded scientists working in tangent with various agencies and/or review entities supported by federal funds. These guidelines have not been based on appropriate science, i.e., morbidity and mortality data derived from properly designed, prospectively executed, long-term studies in a large representative population. The paper by Taylor et al.2 in this issue documents the unquestionable need for such a trial. Based on the seven trials that met the criteria of their Cochrane review, the authors could not identify any significant cardiovascular disease benefit of sodium reduction. Further, they were unable to document the claimed benefit from earlier meta-analyses or trials that advocates of sodium restriction frequently cite. Finally, they noted that in the one randomized control trial involving high-risk patients (congestive heart failure (CHF)), modest sodium restriction actually significantly increased morbidity and mortality. Two recent developments based on multiple reports have profound implications for the current US sodium policy and add greater urgency to Taylor et al.’s call for a definitive trial of sodium reduction in the general population. Three prospective studies—one in healthy middle-aged Europeans,3 one in persons with type 1 diabetes,4 and one in type 2 diabetes5—have identified a significant increase in mortality and, in the case of diabetes, disease progression associated with lower sodium intakes. These reports involve over 7,000 persons from seven ethnically unique populations followed for 8–10 years. The second recent development is the characterization by us6 and others of a “normal range” of sodium intake based on government-funded surveys in healthy subjects that measured 24-h urinary sodium excretion (UNaV), span 5 decades, and include >30 countries and >50,000 subjects. The reproducible mean of this normal range of UNaV is ~155 mEq/day (3,500 mg/day) with a range of 100–210 mEq/day (2,300–4,800 mg/day). A narrow, reproducible, and stable range of human sodium intake is consistent with decades of basic science research7 that provides a physiologic basis for its neuroregulation. Of even greater concern is that the lower sodium intake associated with an increased risk of death identified in the three recent publications3–5 and that of Taylor et al.2 is within the lower end of this apparent normal range. Increased mortality was associated with sodium intake levels 20–30% greater than what the US Dietary Guidelines call the “safe upper limit” for healthy individuals under age 50 and more than twice that recommended for those over 50 and/or those with specific disease states such as CHF and diabetes, populations whose risk of death has now been linked to the very level of sodium intake current US nutrition policy advocates.1,8 If sodium restriction were a pharmaceutical intervention, its feasibility and safety would now be challenged by some of the same federal agencies and their leaders who have promoted it. Their dismissive public comments8 surrounding these recent developments and those of the “experts” they have funded8 are not only irresponsible but, until proven otherwise, are likely harmful to millions of Americans. Proof to the contrary can only come from the very clinical trial called for by Taylor et al.2 which government and its spokespersons have long opposed.8 It is a clinical trial whose time has come and the straw man excuse that the food industry is the culprit preventing it8 can no longer withstand the winds of science.

Hypertension and Cardiovascular Disease

The link between calcium metabolism and hypertension, initially developed in the early 1980s, was based on clinical observations documenting an association between perturbations in calcium homeostasis and elevated arterial pressure in humans (1). Reports of this relationship prompted analyses of prospective studies of dietary calcium intake and blood pressure (BP) status which confirmed the association between low calcium intake and higher BP (2,3). The plausibility of the calcium intakeCBP hypothesis was strengthened by randomized trials that initially used calcium supplements, and confirmed that this intervention lowered arterial pressure (2,3).

Can We End the Salt Wars With a Randomized Clinical Trial in a Controlled Environment

The 2013 Institute of Medicine (IOM; now the National Academy of Medicine) Report: Sodium intake in populations recommended that “clinical trials might focus on examining the effects of a range of sodium levels on risk of cardiovascular events, stroke, and mortality among patients in controlled environments.”1 This recommendation was specific in 2 regards. It recommends a cardiovascular outcomes trial of dietary sodium reduction, and it recommends this be done in people in controlled environments. There are important reasons behind these specific recommendations.nnDespite the large body of data on the relationship between cardiovascular disease and dietary sodium from observational studies and the positive impact on blood pressure in randomized controlled clinical trials and current national guidelines recommending daily sodium intakes of ≤2300 mg/d, mean daily intake for Americans remains in the 3400 to 3500 mg/d range.2 Some scientists have questioned the justification for a reduced intake of dietary sodium.3 This disagreement within the scientific community has been reported in the lay press, leading both clinicians and some in the public to express uncertainty on the issue.4–6nnThe IOM is not alone in calling for an outcomes clinical trial on dietary sodium. The World Heart Federation, the European Society of Hypertension, and the European Public Health Association joined together to call for a definitive clinical trial of sodium restriction.7 Indeed, for years, leading voices in this area of research have noted the absence of evidence from an outcomes-based clinical trial and advocated for execution of such a trial.nnThe reason this trial has not been accomplished can be seen in the second specificity of the IOM recommendations: that the trial be performed in “patients in controlled environments.” This statement recognizes the …