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. 2020 Sep 10;22(10):e13958. doi: 10.1111/jch.13958

Further evidence that methods based on spot urine samples should not be used to examine sodium‐disease relationships from the Science of Salt: A regularly updated systematic review of salt and health outcomes (November 2018 to August 2019)

Kristina S Petersen 1, Daniela Malta 2,✉, Sarah Rae 3, Sarah Dash 4, Jacqui Webster 5, Rachael McLean 6, Sudhir Raj Thout 7, Norm R C Campbell 8, JoAnne Arcand 9
PMCID: PMC8029798  PMID: 32964622

Abstract

The aim of this eighth Science of Salt outcomes review is to identify, summarize, and critically appraise studies on dietary sodium and health outcomes published between November 1, 2018, and August 31, 2019, to extend this series published in the Journal since 2016. The standardized Science of Salt search strategy was conducted. Studies were screened based on a priori defined criteria to identify publications eligible for detailed critical appraisal. The search strategy resulted in 2621 citations with 27 studies on dietary sodium and health outcomes identified. Two studies met the criteria for detailed critical appraisal and commentary. We report more evidence that high sodium intake has detrimental health effects. A post hoc analysis of the Dietary Approaches to Stop Hypertension (DASH) sodium trial showed that lightheadedness occurred at a greater frequency with a high sodium DASH diet compared to a low sodium DASH diet. In addition, evidence from a post‐trial analysis of the Trials of Hypertension (TOHP) I and II cohorts showed that estimates of sodium intake from methods based on spot urine samples are inaccurate and this method alters the linearity of the sodium‐mortality association. Compared to measurement of 24‐hour sodium excretion using three to seven 24‐hour urine collections, estimation of average 24‐hour sodium excretion with the Kawasaki equation appeared to change the mortality association from linear to J‐shaped. Only two high‐quality studies were identified during the review period, both were secondary analyses of previously conducted trials, highlighting the lack of new methodologically sound studies examining sodium and health outcomes.

Keywords: blood pressure, mortality, review, salt, sodium

1. INTRODUCTION

Cardiovascular disease (CVD) is the number one cause of death and disability worldwide accounting for 32% of all deaths and 15% of disability‐adjusted life years. 1 Sodium intake is causally and positively associated with blood pressure and CVD in a dose‐response manner. 2 , 3 Recent estimates suggest that high sodium intake is the leading contributor to diet‐related death worldwide accounting for approximately 27% of all diet‐related mortality; dietary factors account for 22% of deaths globally with approximately 91% of these deaths attributed to CVD. 4 Thus, reducing sodium intake is a target for CVD prevention and management. 2 , 5 , 6 , 7

Among scientists, however, there is some debate about the level of sodium reduction that confers health benefit and minimizes possible harmful effects. 8 The majority of this discourse originates from studies that have methodological limitations that make the results prone to systematic error, reverse causation, and residual confounding. 9 Thus, it is imperative that the methodological quality of studies is critically evaluated, especially when study findings are unexpected or inconsistent with previous evidence.

To keep scientific, clinical, and policy stakeholders up to date with the quantity and quality of publications in the rapidly growing area of sodium and health outcomes, regularly updated reviews and critical appraisals are published in the Journal. 10 The objective of this eighth Science of Salt health outcomes review is to build on previous reviews in this series 11 , 12 , 13 , 14 , 15 , 16 , 17 and summarize published articles on sodium and health outcomes from November 1, 2018, to August 31, 2019, and to highlight and critically appraise articles that meet pre‐specified methodological criteria. 14

2. METHODOLOGY

A detailed description of the methodological approach used to identify published articles for this review has been previously reported. 10 Briefly, a MEDLINE search strategy was conducted on a weekly basis. This is a standardized search strategy that was developed for the Science of Salt systematic review series 10 , 14 based on an adaption from a previous systematic review used in the development of the WHO guideline on dietary sodium. 5 , 18 Table S1 shows the criteria for inclusion and exclusion of studies identified in the weekly search for this review. This review includes health outcome studies identified during the weeks of November 1, 2018, to August 31, 2019. All of the identified articles that met the inclusion criteria were screened independently and in duplicate (SR, SD, KSP) to determine whether they met the criteria, 14 based on the outcomes examined and methodological quality, for detailed critical appraisal. These outcome and methodological criteria are shown in Tables S2 and S3.

Firstly, articles were assessed based on a hierarchy of health outcomes. These are outcomes identified as highly relevant to patients: (a) mortality; (b) morbidity; (c) symptoms/quality of life/functional status; and (d) the diagnosis, prevention, or treatment of hypertension and other clinical surrogate outcomes considered important. Studies of physiologic surrogate outcomes were not eligible for detailed critical appraisal (Table S2). Secondly, a series of methodological criteria were used to identify articles eligible for critical appraisal (Table S3). Briefly, eligible studies were randomized controlled trials (RCTs) that allocated at least one group of subjects to reduced or high sodium intake (control group), achieved an intake difference of ≥920 mg sodium (2 g salt) between the intervention and control group, were ≥4 weeks in duration, measured sodium intake with at least one 24‐hour urine collection, and had no concomitant interventions (ie, anti‐hypertensive drugs, other dietary interventions). Studies with a primary outcome of blood pressure were only eligible for detailed review if they met the minimum methodological criteria for RCTs. Cohort studies included in the detailed appraisals were ≥1 year in duration, included ≥400 participants (continuous outcomes) or events (dichotomous outcomes), and measured sodium intake with at least one 24‐hour urine collection, food record, or 24‐hour food recall. Studies that used food frequency questionnaires (FFQ) were excluded based on a review showing poor agreement between FFQs and 24‐hour urine collections for the estimation of sodium intake. 19 Additionally, sodium intake or excretion alone had to be the exposure variable. Articles that only included sodium‐to‐potassium ratio or related variables, such as salty food preference, were not eligible for detailed appraisal. Meta‐analyses of RCTs or cohort studies had to meet the criteria outlined for these respective study designs.

Articles selected for detailed critical appraisal were assessed for risk of bias by two independent reviewers. RCTs were assessed using the Cochrane risk of bias tool. 20 Observational, non‐randomized studies were assessed using a modified Cochrane risk of bias tool. 21

3. RESULTS

The weekly searches identified 2621 citations, of which 38 underwent full‐text review (Figure 1). Following full‐text review, 27 studies were identified that focused on dietary sodium and health outcomes, and were assessed against the eligibility criteria. Studies assessed for eligibility were meta‐analyses (n = 3), prospective cohort studies (n = 10), cross‐sectional studies (n = 9), post hoc analyses of RCT’s (n = 1), quasi‐experimental studies (n = 2), and modeling analyses (n = 2). Three studies assessed mortality outcomes, 22 , 23 , 24 six studies assessed morbidity outcomes, 25 , 26 , 27 , 28 , 29 , 30 15 studies assessed clinically relevant surrogate outcomes, 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 including 12 that assessed blood pressure outcomes, 31 , 32 , 33 , 34 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 and three studies assessed physiologic outcomes. 46 , 47 , 48 Of these studies, only two met the minimum methodological criteria for detailed critical appraisal (Table 1).

FIGURE 1.

FIGURE 1

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Flow diagram for studies identified from November 1, 2018, to August 31, 2019

Table 1.

Summary of the 27 studies identified from November 1, 2018, to August 31, 2019, and eligibility for detailed critical appraisal

Study (Country) Study design Study duration Method of sodium intake measurement Outcomes Eligible for detailed critical appraisal Reason for exclusion from detailed critical appraisal
Category I—Mortality outcomes
Zhang et al 22 (China) Modeling analysis based on a cross‐sectional dataset 1 y 24‐h urine CVD deaths No

Study design: cross‐sectional;

estimate of potential health impact rather than health outcome
He et al 23 (United States) Prospective cohort 24 y

  1. mean of three to seven 24‐h urinary sodium measurements during follow‐up;

  2. estimated 24‐h sodium excretion from sodium concentration of three to seven 24‐h urines using the Kawasaki formula;

  3. baseline 24‐h urinary sodium

  4. baseline 24‐h urinary sodium estimated from sodium concentration of the first 24‐h urine using the Kawasaki formula.

 Mortality Yes
Zhu et al 24 (China) Systematic review/meta‐analysis of prospective cohort studies 3.5‐19 y 24‐h urine, FFQ Cardiac death, total mortality, stroke, or stroke mortality No Method of sodium assessment: some included studies used FFQs
Category II—Morbidity outcomes
Jayedi et al 25 (Iran) Systematic review/meta‐analysis 2.8‐24 y 24‐h urine, diet recalls, FFQ Stroke No Sample size: <400 subjects for cohort studies
Thapa et al 26 (Columbia) Prospective cohort 11‐12 y Spot urine urinary sodium/creatinine ratio, self‐reported frequency of adding salt to food, and total added table salt Gastric precancerous lesions No Method of sodium assessment: spot urine
Hendriksen et al 27 (The Netherlands) Modeling analysis 20 y Two consecutive 24‐h urine samples Chronic kidney disease No Design: estimate of potential health impact rather than health outcome
Liu et al 28 (China) Prospective cohort 18.6 y Three consecutive 8‐h (overnight) urine samples CVD events and mortality No Method of sodium assessment: 8‐h urine sample
Koo et al 29 (Korea) Prospective cohort 5 y 24‐h urine sodium: potassium Chronic kidney disease progression No Exposure variable: sodium: potassium; sodium not reported
O’Donnell et al 30 (18 Countries a ) Prospective cohort 8.2 y Fasting spot urine and Kawasaki formula Major CVD events and all‐cause mortality No Method of sodium assessment: spot urine
Category III—Symptoms/Quality of life/Functional status outcomes
None
Category IV—Clinical surrogate outcomes (Blood pressure)
Mill et al 32 (Brazil) Cross‐sectional ‐ 12‐h overnight urine collection Blood Pressure No

Study design: cross‐sectional

Method of sodium assessment: 12‐h urine collection
Watanabe et al 31 (Japan) Cross‐sectional ‐ Spot urine Blood Pressure No

Study design: cross‐sectional

Method of sodium assessment: spot urine
Rios‐Leyvraz et al 38 (Switzerland) Systematic review and meta‐analysis of observational and experimental studies 2‐52 wk Any method Blood pressure No

Study design: many of the included studies were cross‐sectional

Method of sodium assessment: many of the included studies used low‐quality methods
Koh et al 39 (Malaysia) Quasi‐experimental 1 mo and 1.5 y 24‐h urine Blood pressure No Study design: non‐controlled trial
Ponce‐Martínez et al 40 (Mexico) Cross‐sectional ‐ FFQ Elevated blood pressure No

Study design: cross‐sectional

Method of sodium assessment: FFQ
Peng et al 41 (United States) Post hoc analysis of RCT 4 wk 24‐h urine Postural lightheadedness Yes
Nguyen et al 42 (Japan) Prospective cohort 5 y Spot urine and Tanaka formula Blood pressure No Method of sodium assessment: spot urine
Iida et al 43 (Japan) Cross‐sectional ‐ Spot urine and Tanaka formula Blood pressure No

Study design: cross‐sectional

Method of sodium assessment: spot urine
Overwyk et al 44 (United States) Cross‐sectional ‐ Up to two up to two 24‐h dietary recalls Blood pressure No Study design: cross‐sectional
Pereira et al 45 (Brazil) Prospective cohort 4 y 12‐h nocturnal urine sample Blood pressure No

Method of sodium assessment: 8‐h urine sample

Exposure variable: Sodium: potassium
Reynoso‐Marreros et al 33 (Peru) Quasi‐experimental 4 wk Not measured Blood pressure No

Study design: non‐controlled trial

Method of sodium assessment: not measured
Rhee et al 34 (Korea) Cross‐sectional ‐ 24‐h urine 24‐h ambulatory blood pressure No Study design: cross‐sectional
Category IV—Clinical surrogate outcomes (Other)
Rafie et al 35 (Iran) Cross‐sectional ‐ Single 24‐h urine sodium Overweight/obesity No Study design: cross‐sectional
Zhao et al 36 (United States) Cross‐sectional ‐ 24‐h urine sodium BMI and central adiposity No Study design: cross‐sectional
Nowak et al 37 (United States) Prospective cohort 6.9 y FFQ Cerebrovascular function and cerebral blood flow No Method of sodium assessment: FFQ
Category V—Physiologic surrogate outcomes
Sugiura et al 46 (Japan) Prospective cohort 4.8 y Spot urine and Kamata formula eGFR No Method of sodium assessment: spot urine
Torres et al 47 (Australia) Cross‐sectional ‐ 24‐h urine sodium Free cortisol and cortisol metabolites No Study design: cross‐sectional
Jung et al 48 (South Korea) Prospective cohort 5.3 y FFQ Brachial‐ankle pulse wave velocity (baPWV) and carotid intima‐media thickness (cIMT) No Method of sodium assessment: FFQ
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a

Bangladesh, India, Pakistan, Zimbabwe, Argentina, Brazil, Chile, Malaysia, Poland, South Africa, Turkey, China, Colombia, Iran, Canada, Sweden, Palestinian territories occupied by Israel, and United Arab Emirates.

Fourteen studies were not eligible for detailed critical appraisal because of the study design (cross‐sectional n = 10; quasi‐experimental n = 2; modeling analysis n = 2) and of these studies, five assessed sodium intake using low‐quality methods (spot urine samples n = 2; overnight urine samples n = 1; FFQ n = 1; combination of low‐quality methods n = 1). Other reasons for exclusion from critical appraisal were as follows: The primary exposure was not sodium (n = 1), sodium intake assessed by spot urine sample (n = 4), FFQ (n = 3) or by overnight urine sample (n = 2), or cohort studies with a sample size <400 (n = 1).

Of the two studies that were eligible for detailed critical appraisal, one was a prospective cohort study 23 and the other was a post hoc analysis of a previously conducted RCT. 41 These studies show high sodium intake is associated with higher risk of mortality and increased odds of lightheadedness. He et al 23 reported that in the Trials of Hypertension (TOHP) I and II studies, estimates of sodium intake from the Kawasaki equation, a spot urine‐based method, are inaccurate and prone to systematic error. Furthermore, it was shown that compared to measurement of 24‐hour sodium excretion using three to seven 24‐hour urine collections, estimation of average 24‐hour sodium excretion with the Kawasaki equation appeared to change the sodium‐mortality association from linear to J‐shaped.

In a post hoc analysis of the Dietary Approaches to Stop Hypertension (DASH) sodium trial, Peng et al 41 reported that lightheadedness occurred at a greater frequency with a high sodium DASH diet compared to a low sodium DASH diet. No differences in lightheadedness were observed between the DASH diet and the control average American diet, or between differing levels of sodium intake in the control arm.

The risk of bias assessments for the two studies that were critically appraised is included in Table S4A, B, and a summary of study characteristics and results are presented in Table 2. Written critical appraisals for these studies are below.

Table 2.

Summary of articles critically appraised

Study (Country) Study design Participants Study duration Dietary sodium “dose” (actual mean intake per day) Method of sodium intake measurement Outcomes Results
Category I—Mortality outcomes
He et al 23 (United States) Prospective cohort Individuals aged 30‐54 y with pre‐hypertension (TOHP I and II) 24‐y

Average measured 24‐h: 3769 ± 1282 mg/d

Average estimated 24‐h: 5066 ± 843 mg/d

First measured 24‐h: 3940 ± 1813 mg/d

First estimated 24‐h: 5028 ± 1074 mg/d

Average measured 24‐h: mean of 3‐7 24‐h urinary sodium measurements during follow‐up.

Average estimated 24‐h: estimated 24‐h sodium excretion from sodium concentration of 3‐7 24‐h urines using the Kawasaki formula.

First measured 24‐h: baseline 24‐h urinary sodium.

First estimated 24‐h: baseline 24‐h urinary sodium estimated from sodium concentration of the first 24‐h urine using the Kawasaki formula.

 Mortality

Linear relationship (P for linearity = .047, P for non‐linearity = .87) between average measured sodium excretion and mortality (per 1000 mg/d increase HR 1.12, 95% CI 1.00‐1.26, P = .052).

Estimated average sodium excretion associated with mortality (per 1000 mg/d increase HR 1.29, 95% CI 1.06‐1.57, P = .011). Relationship was linear (P for linearity = .006) but appeared J‐shaped.

When sodium was measured or estimated from the first sample no relationship was observed between sodium intake and mortality.

Average sodium excretion over‐estimated by 1297 mg/d (95% CI 1267‐1326) when estimated vs measured.

Sodium excretion over‐estimated by 1088 mg/d (95% CI 1042‐1134) when estimated vs measured from the first sample.
Category II—Morbidity outcomes
None
Category III—Symptoms/Quality of life/Functional status outcomes
None
Category IV—Clinical surrogate outcomes
Peng et al 41 (United States) Post hoc analysis of RCT n = 412 adults with untreated elevated or stage 1 hypertension 2‐wk run‐in high‐sodium control diet, following by randomization to each sodium level for 30 d. Each diet period was separated by an, on average, 5 d wash‐out period

Low: 1495 mg/d

Mid: 2461 mg/d

High: 3266 mg/d

 One 24‐ h urine collection during the last week of each diet period Lightheadedness assessed using a questionnaire administered during the last 7‐d of the run‐in period, and the three diet periods

No difference in lightheadedness with the DASH diet vs control diet. No difference in lightheadedness with the control diet at difference levels of sodium intake.

DASH diet:

High vs low sodium intake increased lightheadedness (OR 1.71, 95% CI 1.01, 2.90) and severity of lightheadedness (P = .02)

Subgroup analyses:

DASH diet, high vs low sodium

Age interaction (P = .04): <60 y OR 1.99, 95% CI: 1.13, 3.50; >60 y OR 0.30, 95% CI 0.06, 1.68)

BMI interaction (P = .01): BMI ≤ 30 kg/m2 OR 0.93, 95% CI 0.51, 1.68; BMI > 30 kg/m2 OR 5.16, 95% CI 1.65, 16.1)
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Detailed critical appraisals of studies that met the methodological quality criteria:

1. Spot urine estimates of sodium intake are inaccurate as individual measures of usual sodium intake and alter the sodium‐mortality association.

Feng J He, Norm RC Campbell, Yuan Ma, Graham A MacGregor, Mary E Cogswell and Nancy R Cook. Errors in estimating usual sodium intake by the Kawasaki formula alter its relationship with mortality: implications for public health. International Journal of Epidemiology 2018. https://doi.org/10.1093/ije/dyy114.

Design: Prospective observational study: a secondary analysis of post‐trial follow‐up data from participants in the Trials of Hypertension (TOHP) I and II studies. The original aim of TOPH I was to examine the effect of seven nonpharmacologic interventions (weight loss; sodium reduction; stress management; calcium supplementation; magnesium supplementation; potassium supplementation; and fish oil supplementation) on diastolic blood pressure. 49 TOPH II examined the effect of weight loss alone, sodium reduction alone, weight loss plus sodium reduction (combined), or usual care (control) on systolic and diastolic blood pressure. 50

Setting: Ten US clinical centers participating in the TOHP I and 9 US clinical centers participating in the TOHP II study.

Participants: Pre‐hypertensive individuals from TOPH I and II, not assigned to the sodium intervention. TOHP I (n = 1844; 30% women) recruited between September 1987 and January 1990, and TOHP II (n = 1167; 34% women) recruited from December 1990 to March 1995. In TOHP I, participants were aged 30‐54 years with pre‐hypertension (defined as diastolic blood pressure 80‐89 mm Hg, not taking anti‐hypertensive drugs). In TOHP II, participants had elevated blood pressure (defined as diastolic blood pressure 83‐89 mm Hg, systolic blood pressure < 140 mm Hg, and not taking anti‐hypertensive drugs), and a body mass index of 110%‐165% of desirable body weight.

Exposure: Sodium intake, estimated by four methods:

  • "Average measured sodium excretion"—the mean of three to seven 24‐hour urine samples during the trial period.

  • "Average estimated sodium excretion"—estimated 24‐hour sodium excretion from the sodium concentration of three to seven 24‐hour urine samples using the Kawasaki formula.

  • "First measured sodium excretion"—the first 24‐hour urine sample for each participant.

  • "First estimated sodium excretion"—estimated 24‐hour sodium excretion from the sodium concentration of the first 24‐hour urine sample using the Kawasaki formula.

Bland‐Altman plots were presented comparing "average measured sodium excretion" and "average estimated sodium excretion," as well as "first measured sodium excretion" and "first estimated sodium excretion" data.

Outcomes: Mortality data up to December 2013 collected from examination of the National Death Index.

Risk of bias

  • Sampling: High risk.

  • Representativeness: Unclear risk.

  • Reliability/validity of exposure: Low risk (measured intake)/high risk (estimated intake).

  • Reliability/validity of outcome: Low risk.

  • Blinding of outcome assessment: Low risk.

  • Risk of selective outcome reporting: Low risk.

  • Confounding: High risk.

Sources of funding: TOHP I and TOHP II were supported by the National Heart, Lung, and Blood Institute, and National Institutes of Health. The TOHP follow‐up study was supported by the National Heart, Lung, and Blood Institute and the American Heart Association.

Summary of results: Bland‐Altman plots demonstrated poor agreement between average measured and average estimated 24‐hour sodium excretion, and between the first measured and first estimated sodium excretion. Systematic bias was observed for estimated (average and first) sodium excretion with over‐estimation at lower levels of excretion and under‐estimation at higher levels of sodium excretion. Mean post‐trial follow‐up time was 24 years for TOHP I and 19 years for TOHP II, during which 272 deaths occurred. A linear relationship between sodium excretion and mortality was observed for "averaged measured sodium excretion"; however, this relationship was flattened for "first measured sodium excretion" and mortality. A J‐shaped relationship between "average estimated sodium excretion" and "first estimated sodium excretion" and mortality was observed. Mortality analyses were all adjusted for age, sex, race/ethnicity, clinic, treatment assignment, education status, baseline weight, alcohol use, smoking exercise, 24‐hour urinary potassium excretion, and family history of CVD.

Comment: In this study, a significant linear relationship between dietary sodium excretion and mortality was observed when sodium excretion was assessed using three to seven 24‐hour urine collections, an approach associated with the lowest level of random and systematic error. Importantly, this study adds to the increasing body of literature showing that estimates of 24‐hour urinary sodium excretion from spot urine‐based methods are inaccurate at the individual level. In this study, the Kawasaki formula 51 was used to convert the sodium concentration from a single 24‐hour urine sample, and an average of three to seven 24‐hour urine samples to estimates of usual sodium intake. When compared with measured 24‐hour urine sodium, the estimates were found to be generally inaccurate with wide limits of agreement on Bland‐Altman plots, 52 and systematically biased. These results are of importance because the measurement error associated with using the Kawasaki formula distorted the observed linear association between measured sodium excretion and mortality, producing a J‐shaped curve. A number of recently published studies using spot urine samples and the Kawasaki formula to estimate usual sodium intake have also shown a J‐shaped association with mortality. 53 , 54 , 55 The current study shows the importance of accurate measurement (preferably using multiple 24‐hour urine collections) of sodium intake in epidemiological studies, and casts doubt on the findings of studies using inaccurate measures such as spot urine estimates.

2. Higher sodium intake was associated with more frequent and severe lightheadedness

Allison W. Peng, Larry J. Appel, Noel T. Mueller, Olive Tang, Edgar R. Miller III, Stephen P. Juraschek. Effects of sodium intake on postural lightheadedness: Results from the DASH‐sodium trial. The Journal of Clinical Hypertension 2019, 21, 355‐362.

Design: Single‐blinded RCT.

Setting: Four clinical centers in the United States.

Study duration: Fourteen‐day run‐in period on a high sodium control diet followed by three 30‐day diet periods, separated by breaks of up to 5 days.

Participants: Four hundred and twelve healthy, community‐dwelling adult men and women, aged 22 years, or older, who had blood pressure 120‐159 mm Hg systolic and 80 to 95 mm Hg diastolic.

Intervention: This was a controlled feeding study where subjects were randomized to either a DASH diet or a control diet representative of average American intake. Within their diet allocation, three levels of sodium were provided for 30 days each: 50 mmol/d (1150 mg sodium; 2.9 g salt), 100 mmol/d (2300 mg sodium; 5.8 g salt), and 150 mmol/d (3450 mg sodium; 8.6 g salt) per 2100 kcal.

Achieved sodium intake: Sodium intake was measured by a single 24‐hour urine collection during the last week of the diet periods. Sodium excretion was 65 mmol/d (1495 mg sodium; 3.7 g salt), 107 mmol/d (2461 mg sodium; 6.2 g salt), and 142 mmol/d (3266 mg sodium; 8.2 g salt) in the low, mid, and high sodium containing diets, respectively.

Outcomes: Lightheadedness assessed using an investigator‐created questionnaire that was administered during the last 7 days of the run‐in period, and the three diet periods. Subjects were asked to select one of the following in response to being asked if they felt “lightheadedness when standing up”: (1) none (no experience of side effect); (2) mild (symptom occurred but did not interfere with usual activities); (3) moderate (occurrence of symptom somewhat interfered with usual activities); and (4) severe (occurrence of symptom resulted in an inability to perform usual activities). Lightheadedness was defined as having mild, moderate, or severe symptoms, and the change in severity was defined as the difference in severity scores (values 1 through 4) at the end of each diet period relative to baseline. Generalized estimating equation regression models were used to determine the odds of lightheadedness with each diet.

Risk of bias

  • Random sequence generation: Unclear risk.

  • Allocation concealment: Unclear risk.

  • Blinding of participants and personnel: High risk (participants)/low risk (personnel).

  • Blinding of outcome assessors: Low risk.

  • Incomplete outcome reporting: Low risk.

  • Selective reporting: High risk.

  • Other sources of bias: Low risk.

Source of funding: National Heart, Lung, and Blood Institute; General Clinical Research Center Program of the National Center for Research Resources.

Summary of results: Lightheadedness did not differ between the DASH diet and the control diet. Lightheadedness was different by diet and sodium intake (diet × sodium interaction P = .03). Subjects randomized to the high sodium DASH diet had greater odds of reporting lightheadedness vs the low sodium DASH diet (OR 1.71; 95% CI 1.01, 2.90). Reporting of lightheadedness increased from baseline with the high sodium DASH diet relative to the low sodium DASH diet (P = .02). In the control group, there was no difference in lightheadedness by sodium intake. The authors also conducted analyses to examine the effect of the diets and sodium intake on lightheadedness by age, race, sex, BMI, and hypertension. In subjects <60 years, odds of lightheadedness were twofold higher on the high vs low sodium DASH diet; subjects >60 years did not experience a difference in lightheadedness by sodium intake. In addition, in subjects with a BMI > 30 kg/m2, the high sodium DASH diet increased the odds of lightheadedness by fivefold relative to the low sodium DASH diet; no association between sodium intake and lightheadedness was observed in subjects with a BMI ≤ 30 kg/m2. No other differences were observed in stratified analyses.

Comment: This is one of the largest randomized controlled feeding trials ever conducted and comprises a diverse sample of individuals with elevated or stage 1 hypertension (average systolic blood pressure of 120‐159 mm Hg and an average diastolic blood pressure of 80‐95 mm Hg). The study has many strengths, including the highly controlled design whereby participants were provided a complete menu and sodium excretion was monitored by 24‐hour urine collections. However, in this post hoc analysis a questionnaire was used to examine lightheadedness following the control and DASH diet at low, mid, and high sodium intake. It is unclear if this questionnaire was validated and there are limitations associated with self‐report of symptoms, especially in the absence of subject blinding. Furthermore, postural blood pressure measurements were not taken to confirm the subjective assessment method. Thus, further research is required to confirm these findings. Nevertheless, Peng et al report that lightheadedness occurred at a greater frequency with a high sodium DASH diet vs a low sodium DASH diet. This finding is in contrast to conventional treatment of postural lightheadedness with a high sodium diet. Interestingly, with the control diet, representative of an average American diet, no differences were observed in reported lightheadedness at different levels of sodium intake. This suggests that higher sodium intake may not reduce postural lightheadedness; however, these results should be interpreted cautiously because <10% of the participants reported lightheadedness at baseline and this was an exploratory analysis using self‐reported measures of lightheadedness.

4. DISCUSSION

In this eighth Science of Salt outcome review, we identified 27 studies that focused on dietary sodium and health outcomes published from November 1, 2018, to August 31, 2019. However, only two studies met the eligibility criteria for detailed critical appraisal. Interestingly, both of these publications comprise secondary analyses of trials conducted over two decades ago. This highlights the lack of methodologically rigorous, novel, and original investigations in this area. While only two studies met our a priori criteria for appraisals, we identified 27 publications focused on sodium and health outcomes during the review period indicating that there is still significant scientific interest in this area. However, over one‐third of these studies were cross‐sectional (n = 10) and over half (n = 14) used low‐quality methods to assess sodium intake. The goal of the Science of Salt systematic reviews is to provide scientists, clinicians, and public health advocates with a regularly updated review of recent publications in the area of sodium and health outcomes, and only direct attention to studies that meet predefined criteria for outcomes assessed and methodology to assist in interpretation of this evidence base. 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 In this field of study, poor methodological approaches have yielded results that contrast with evidence from studies using more rigorous methods. 9 Therefore, the critical importance of appropriate methodology cannot be overstated, and while we acknowledge all the published studies in the area, only those studies that meet a priori criteria are appraised.

The findings of this eighth Science of Salt review are consistent with previous reviews in this series and show that most high‐quality studies report favorable health effects of sodium reduction and adverse effects of excess sodium intake. 11 , 12 , 13 , 14 , 15 , 16 , 17 He et al 23 report that sodium intake, assessed by three to seven 24‐hour urine collections, is linearly associated with all‐cause mortality. In addition, in a post hoc analysis of the DASH sodium trial, Peng et al 41 showed lightheadedness occurred at a greater frequency with a high sodium DASH diet compared to a low sodium DASH diet. A common treatment for lightheadedness is to increase sodium intake. However, the series of analyses conducted by Peng and colleagues does not support this recommendation, and suggests a worsening of this symptom with higher sodium intake. Given the exploratory nature of this analysis, future investigations are required.

He and colleagues report further evidence that estimates of sodium intake from methods based on spot urine samples are inaccurate and biased by systematic error, 23 which is consistent with previous findings in diverse populations. 56 , 57 , 58 , 59 , 60 Furthermore, for the first time, He et al 23 provide novel data suggesting that the use of the Kawasaki equation, a spot urine‐based estimate, changes the linearity of the sodium‐mortality association. Despite, concordant evidence showing high sodium intake is associated with increased risk of CVD, 2 some prospective studies estimating sodium intake with the Kawasaki equation show higher risk of all‐cause and CVD mortality with lower levels of sodium intake, 53 , 54 , 55 , 61 which has been a source of confusion and has led to debate about the safety of sodium reduction. The analyses by He et al 23 suggest that the non‐linear (or J‐ or U‐shaped) associations observed are likely attributable to the use of spot urine‐based methods to assess sodium intake. However, in the analyses by He et al, 23 the concentration of sodium in a single or multiple 24‐hour urine collections was used to estimate 24‐hour sodium excretion using the Kawasaki equation rather than a spot urine collection, which is usually the case. Their data may therefore under‐estimate the true impact of using spot urine samples to estimate sodium intake; a calculation based on a 24‐hour urine collection is more likely to resemble usual intake compared to a spot urine collection. These analyses call into question the results of previous studies using spot urine samples to investigate the relationship between sodium and health outcomes, and confirm that methods based on spot urine samples should not be used to assess sodium‐disease associations. 62 , 63

The finding that the method used to measure sodium intake exposure can distort the sodium‐disease relationship is consistent with a previous analysis examining sodium excretion measurement with a single 24‐hour urine sample vs multiple collections. 64 Olde Engberink et al 64 found that when long‐term sodium intake exposure was estimated with a single 24‐hour urine sample at baseline, no association was observed between sodium and cardiovascular endpoints (HR 1.09, 95% CI 0.61‐1.95 low vs high intake), and the continuous relationship appeared U‐shaped. Conversely, when sodium exposure was estimated from additional 24‐hour urine samples collected during the first and fifth year of follow‐up, high sodium intake was associated with increased risk of a cardiovascular endpoint occurring relative to lower sodium intake (1‐year HR 1.80, 95% CI 1.03‐3.13; 5‐year HR 1.73, 95% CI 1.00‐2.99). Notably, average population sodium intake was not different when estimated from a single vs multiple 24‐hour urine collections. 64 However, at the individual level, a single baseline 24‐hour urine sample only classified approximately 50% of the cohort in the same sodium intake tertile (ie, low, moderate, or high) as multiple 24‐hour urine collections; likely explaining why discrepancies were observed when individual‐level sodium intake estimates from multiple vs a single 24‐hour urine sample were related to cardiovascular risk.

Together, these data show that it is critical that the method used to measure sodium intake exposure aligns with the research question 62 , 63 because the use of inappropriate methods has the potential to alter the directionality and/or result of hypothesis testing. 9 If the goal is to examine the relationship between sodium intake and health outcomes, then multiple, non‐consecutive, complete 24‐hour urine samples are required over the duration of follow‐up to adequately characterize usual sodium intake and thus exposure to sodium. If the research objective is surveillance focused, then a single complete 24‐hour urine sample can be used to assess average population sodium intake. However, if the aim is to assess sodium exposure at the individual level then at least 3 non‐consecutive, complete 24‐hour samples are required. 62 , 63

While evidence from epidemiological studies using methods prone to systematic error, residual confounding, and reverse causation has generated debate about the safety of reducing sodium intake to <3 g/d, the 2019 Committee that reviewed the Dietary Reference Intakes for Sodium and Potassium for the National Academies of Sciences, Engineering, and Medicine concluded that there is high strength evidence that lowering sodium intake to 2300 mg/d reduces chronic disease risk. This was based on evidence from 3 high‐quality RCTs and 1 low‐risk‐of‐bias observational study showing that per 1000 mg/d reduction in sodium, CVD, and hypertension risk are reduced by 27 and 20%, respectively. Furthermore, data from 21 RCTs demonstrated systolic blood pressure lowering of 2.8 mm Hg per 1000 mg/d reduction in sodium, and evidence from 20 RCTs showed diastolic blood pressure lowering of 1.2 mm Hg per 1000 mg/d reduction in sodium. Thus, strong evidence exists for the health benefits of sodium reduction, and studies with a high risk of bias should not detract from the critical public health importance of lowering sodium to recommended levels. This is imperative because in nearly every country worldwide sodium intake exceeds recommended levels, by an average of 86%, and therefore, strategies to lower sodium intake should remain a priority. 4

5. CONCLUSIONS

This review provides further up to date evidence showing that high sodium intake has a detrimental effect on health. It also demonstrates that estimates of sodium intake from methods based on spot urine samples are inaccurate and this method changes the linearity of the sodium‐mortality association. The few high‐quality studies identified during this review period highlights the urgent need for greater publication of well‐conducted rigorous studies. Critically, appropriate methods that minimize bias should be used to assess sodium intake exposure.

CONFLICT OF INTEREST

NRCC was a paid consultant to the Novartis Foundation (2016‐2017) to support their program to improve hypertension control in low‐ to middle‐income countries which includes travel support for site visits and a contract to develop a survey. NRCC has provided paid consultative advice on accurate blood pressure assessment to Midway Corporation (2017) and is an unpaid member of World Action on Salt and Health (WASH). JW is Director of the World Health Organization Collaborating Centre on Salt Reduction and receives funding for work on salt reduction from the World Health Organization, the National Health and Medical Research Council, The National Heart Foundation of Australia, and The Victorian Health Promotion Foundation. DM, KSP, SR, SD, RM, and TSR have no conflicts of interest to declare.

AUTHOR CONTRIBUTIONS

Sudhir Raj Thout performed the weekly systematic search and identified articles on sodium and health outcomes. Sarah Rae, Sarah Dash, and Kristina S. Petersen screened the identified articles and determined article eligibility for detailed critical appraisal. Rachael McLean, JoAnne Arcand, Daniela Malta, Sarah Rae, and Kristina S Petersen conducted the detailed critical appraisals and study risk of bias assessments. Kristina S Petersen wrote the manuscript. All authors critically reviewed the manuscript.

Supporting information

Table S1‐S4

Click here for additional data file. (25.8KB, docx)

ACKNOWLEDGMENTS

The process to provide regular updates on the science of sodium is supported by the World Hypertension League, World Health Organization Collaborating Centre on Population Salt Reduction (George Institute for Global Health), Pan American Health Organization/WHO Technical Advisory Group on Cardiovascular Disease Prevention through Dietary Sodium, and World Action on Salt and Health.

Petersen KS, Malta D, Rae S, et al. Further evidence that methods based on spot urine samples should not be used to examine sodium‐disease relationships from the Science of Salt: A regularly updated systematic review of salt and health outcomes (November 2018 to August 2019). J Clin Hypertens. 2020;22:1741–1753. 10.1111/jch.13958

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Supplementary Materials

Table S1‐S4

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