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HTN: Sodium (2015)

Citation:
Mente A, O'Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, Morrison H, Li W, Wang X, Di C, Mony P, Devanath A, Rosengren A, Oguz A, Zatonska K, Yusufali AH, Lopez-Jaramillo P, Avezum A, Ismail N, Lanas F, Puoane T, Diaz R, Kelishadi R, Iqbal R, Yusuf R, Chifamba J, Khatib R, Teo K, Yusuf S; PURE Investigators. Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med. 2014 Aug; 371(7): 601-611. PubMed ID: 25119606
 
Study Design:
Cross-Sectional Study
Class:
D - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To use the Prospective Urban Rural Epidemiology (PURE) study data to estimate sodium and potassium intake in study participants and describe their association with blood pressure, both overall and according to key sub-groups.
Inclusion Criteria:
  • Inclusion in the PURE study: 157,543 adults aged 35-70 from 667 communities in 18 low, middle and high income countries
  • Valid baseline fasting morning urine sample
Exclusion Criteria:
  • Non-enrollment in the PURE study
  • Invalid baseline urine sample
Description of Study Protocol:

Recruitment

  • Participants were recruited from enrolled PURE study participants, including a distribution from countries with different income levels:
    • Low income: Bangladesh, India, Pakistan and Zimbabwe
    • Lower-middle income: China (42% of final sample), Colombia, Iran and the Occupied Palestinian Territory
    • Upper-middle income: Argentina, Brazil, Chile, Malaysia, Poland, South Africa and Turkey
    • High income: Canada, Sweden and the United Arab Emirates.
  • All participants selected were adults between the ages of 35 years and 70 years
  • Baseline characteristics of participants were generally similar to those of the PURE study.
Design

A single fasting 24-hour morning urine specimen was taken; sodium and potassium were analyzed as a surrogate for dietary intake. Examining overall and group data, the relationship between electrolyte excretion and blood pressure was measured and analyzed.

Statistical Analysis

  • Mean estimated sodium excretion and potassium excretion was used to analyze the overall cohort, as well as sub-groups (sex, urban vs. rural, country income level, geographic region) with adjustment for age and sex as appropriate
  • Multivariable linear regression was used to assess the association between electrolyte excretion and blood pressure:
    • Difference in systolic blood pressure and diastolic blood pressure per 1g of sodium excretion or 1g of potassium excretion
    • Participants divided into groups based on increments (1g per day sodium excretion; 0.25g per day potassium excretion)
    • Analysis of covariance, with tests for linear trends, to compare mean blood pressure among those groups; adjustment for covariates associated with blood pressure (age, sex, educational level, alcohol intake and geographic region).
  • Used tests of interaction to examine influence of age, geographic location, hypertension status, alcohol intake, body-mass index and potassium excretion
  • Secondary analysis to examine effect of regression dilution bias, using estimated usual sodium and potassium excretion, described by the Prospective Studies Collaboration:
    • Linear regression was used to assess the association of urinary sodium-to-potassium ratio with blood pressure, adjusting for the same covariates.
Data Collection Summary:

Timing of Measurements

Upon clinic arrival in the morning, participants:
  • Provided a single, fasting mid-stream urine specimen,which was frozen and sent to a regional laboratory for analysis with standardized methods
  •  Provided height, weight and resting blood pressure (two times) measurements.

Dependent Variables

Blood pressure among cohort and various sub-groupings.

Independent Variables

Estimates of sodium and potassium intake, calculated from a fasting morning 24-hour urine specimen using the Kawasaki formula.
 
Description of Actual Data Sample:

Initial N

PURE study participants: N=157,543 (66,760 males, 90,783 females).

Attrition (Final N)

PURE study participants with valid urine samples: N=102,216 (43,752 males, 58,464 females).

Age

Aged 51.0±9.7 years.

Ethnicity

Not noted, but 42.1% of sample noted were from China.

Other Relevant Demographics

Income:
  • Low income: N=7,293 (7.1%)
  • Lower-middle income: N=54,737 [53.6% to 42.1% (China only)]
  • Upper-middle income: N=25,705 (25.1%)
  • High income: N=14,481 (14.2%).

Anthropometrics

  • BMI: 26.1±5.1
  • Blood pressure:
    • Systolic: 131.7±21.5mm Hg
    • Diastolic: 81.9±12.2mm Hg
  • Sodium excretion: 4.93±1.73g per day
  • Potassium excretion: 2.12±0.60g per day
  • Creatinine excretion: 1.30±0.37g per day
  • Self-reported hypertension or blood pressure 140/90mm Hg or higher: 42,987 (42.0%)
  • Blood pressure 140/90mm Hg or higher: 35,521 (34.8%)
  • Blood pressure medication: 14,856 (14.5%)
  • Statin medication: 3,475 (3.4%).

Location

PURE study participants from countries, strata based on income:

  • Low income: Bangladesh, India, Pakistan, Zimbabwe
  • Lower middle income: China, Colombia, Iran, Occupied Palestinian Territory
  • Upper-middle income: Argentina, Brazil, Chile, Malaysia, Poland, South Africa, Turkey
  • High income: Canada, Sweden, United Arab Emirates.
Summary of Results:

Key Findings

Overall

  • Mean sodium excretion: 4.93±1.73
  • Mean potassium excretion: 2.12±0.60
  • Higher excretion in men than in women for both sodium and potassium (both P<0.001, respectively).
Patterns of Sodium and Potassium Excretion
  • Estimated sodium excretion was higher in rural vs. urban areas (P<0.001)
  • Estimated potassium excretion was higher in urban vs. rural areas (P<0.001)
  • Per capita gross national income was:
    • Inversely associated with estimated sodium excretion (P<0.001)
    • Positively associated with estimated potassium excretion (P<0.001).
  • Mean estimated sodium excretion: 3.78g to 5.59g per day
  • Mean estimated potassium excretion: 1.70g to 2.46g per day.
Urinary Sodium Excretion and Blood Pressure
  • After adjusting for covariates, there was a positive association between sodium excretion and systolic blood pressure and diastolic blood pressure (both P<0.001, respectively)
  • For each 1g increment in estimated sodium excretion, there was a 1.46mm Hg increment in systolic blood pressure (P<0.001) and 0.54mm Hg increment in diastolic blood pressure (P<0.001)
  • After adjusting for regression dilution bias, the slope was steeper, with a 2.11mm Hg increment in systolic blood pressure (P<0.001) and 0.78mm Hg increment in diastolic blood pressure (P<0.001)
  • Positive relationship observed between sodium excretion and blood pressure was true for all geographic regions, but was less steep in the Middle East  than most of the other regions studied (P<0.001 for interaction)
  • Relationship of estimated sodium and blood pressure was non-linear, and steeper at excretion of more than 5g per day compared to other groups
  • Results were similar for diastolic blood pressure.
Urinary Potassium Excretion and Blood Pressure
  • For each 1g increment in estimated potassium excretion, there was a 0.75mm Hg decrement in systolic blood pressure (P<0.001) and 0.06mm Hg increment in diastolic blood pressure (P=0.33)
  • After adjusting for covariates, there was a significant inverse association between estimated potassium excretion and systolic blood pressure (P<0.001)
  • After adjusting for regression dilution bias, the slope was steeper, with a 1.08mm Hg increment in systolic blood pressure and 0.09mm Hg increment in diastolic blood pressure (statistical significance not noted)
  • There was a stronger inverse relationship between potassium excretion and blood pressure in China than in other geographic regions (P<0.001 for interaction).
Sodium-to-Potassium Ratio and Blood Pressure
  • After adjusting for covariates, a strong and linear association was observed between the estimated sodium to potassium ratio for both systolic (P<0.001 for trend) and diastolic (P<0.001 for trend) blood pressure
  • Each 1SD increment in estimated sodium-to-potassium ratio (3.26) was associated with increments of 2.30mm Hg in systolic blood pressure (P<0.001) and 0.78mm Hg in diastolic blood pressure (P<0.001)
  • The slope was significantly steeper for China than in other countries (P<0.001 for interaction)
  • The highest blood pressures were observed in the group with the highest estimated sodium excretion and the lowest estimated potassium excretion (P<0.001 for interaction).
Sensitivity and Sub-group Analysis
  • Analysis excluding those participants with cardiovascular disease, those receiving antihypertensive therapy, or those participants from China, did not appreciably alter the findings of association
  • Estimated sodium excretion was more strongly associated with increased systolic blood pressure and diastolic blood pressure in persons with hypertension (P<0.001 for interaction)
  • Trend according to age was significant, with a steeper slope of association in estimated sodium excretion in persons older than 55 years of age than in those 45 years to 55 years or less than 45 years (P<0.001 for interaction)
  • Higher estimated potassium excretion was associated with a steeper inverse relationship with systolic and diastolic blood pressure among persons with increased levels of sodium excretion, as well as older persons, those with hypertension, and those with increased BMI (P<0.001 for interaction, for all respectively).
Author Conclusion:
The association of estimated intake of sodium and potassium with blood pressure was not linear and most notable in people eating a high-sodium diet, people with hypertension and older people. 
Funding Source:
Government: Canadian Institutes of Health Research
Industry:
AstraZeneca, Sanofi-Aventis, Servier, GlaxoSmithKline, Novartis, King Pharma
Pharmaceutical/Dietary Supplement Company:
Not-for-profit
Heart and Stroke Foundation of Ontario; Population Health Research Institute
Foundation associated with industry:
Other: Various national and local organizations in participating countries
In-Kind support reported by Industry: Yes
Reviewer Comments:
  • Non-validity of a portion of the urine samples, which contributed to non-participation skewed the representative demographic contribution from this study compared to the PURE study (India specifically was under-represented, making the lower income population comparatively under-represented)
  • Funding is provided from multiple sources, including several global pharmaceutical countries. Bias is unlikely because multiple companies were listed, along with other governmental and non-profit agencies. 
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) N/A
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? N/A
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? No
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? Yes
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? N/A
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? N/A
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes