HTN: Magnesium (2015)


Kesteloot H, Tzoulaki I, Brown IJ, Chan Q, Wijeyesekera A, Ueshima H, Zhao L, Dyer AR, Unwin RJ, Stamler J, Elliott P. Relation of urinary calcium and magnesium excretion to blood pressure. Am J Epidemiol. 2011; 174 (1): 44-51.

PubMed ID: 21624957
Study Design:
Cross-Sectional Study
D - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To investigate associations between blood pressure and timed 24-hour urinary calcium and magnesium excretion in the cross-sectional population-based INTERMAP and INTERSALT studies.
Inclusion Criteria:
Participants in INTERMAP and INTERSALT studies.
Exclusion Criteria:
INTERMAP participants:
  • Non-participation in all four clinic visits
  • Dietary data unreliable
  • Energy intake less than 500kcal or more than 5,000kcal (females) or 8,000kcal (males)
  • Two urine specimens not available
  • Other data incomplete.
INTERSALT participants:
  • Urine specimens incomplete
  • Blood pressure measurements incomplete.
Description of Study Protocol:


Participants randomly selected from population lists and stratified by age and gender; both general population and workforce samples were included.


Re-analysis of data from cross-sectional studies, INTERMAP and INTERSALT.

Blinding Used

Implied with measurements.

Statistical Analysis

  • Primary analysis performed with INTERMAP data
  • Reproducibility of results performed with INTERSALT data
    • Nutrient and blood pressure data averaged across four visits
    • Urine excretion levels averaged across two 24-hour urine studies
    • Reliability of excretion data: Ratio of intra-individual variance divided by inter-individual variance estimated for eight gender/country strata then pooled
    • Multiple linear regression analysis: To assess associations of calcium and magnesium excretion with blood pressure; adjustment for confounders were done sequentially
      • Regression models fit by country and coefficients pooled across countries and weighted by inverse of variance
      • Done for all, and for males and females separately
      • Sensitivity analysis of non-hypertensive participants and of non-intervened participants
      • Censored regression analysis to adjust for potential anti-hypertensive treatment bias.
    • Two blood pressure measurements were averaged
    • Multiple linear regression analyses  to assess associations between urinary calcium and magnesium and blood pressure with non-dietary confounders
    • Regression analyses done for all; males and females, 20 to 39 years old and 40 to 59 years old
    • Censored regression analysis to adjust for potential anti-hypertensive treatment bias and limiting to non-hypertensives only.

Data Collection Summary:

Timing of Measurements

    • Two visits on consecutive days, a three-week gap, then two visits on consecutive days
    • Two BP measurements at each visit
    • 24-hour multiple pass dietary recall at each visit
    • Two 24-hour urine collections.
    • One clinic visit
    • A 24-hour urine collection returned the following day.

Dependent Variables

Blood pressure.

Independent Variables

  • Urinary calcium
  • Urinary magnesium.

Control Variables

  • Age
  • Gender
  • Weight
  • Height
  • Special diet
  • Physical activity
  • Doctor-diagnosed heart attack or stroke
  • Family history of hypertension
  • Alcohol intake
  • A 24-hour urinary test on sodium and potassium levels
  • Dietary intake of cholesterol, saturated fat, total polyunsaturated fat, calcium, magnesium and animal protein.
Description of Actual Data Sample:

Initial N

  • INTERMAP:  N=4,680
  • INTERSALT: N=10,079.

Attrition (Final N)

  • INTERMAP:  N=4,679
  • INTERSALT:  N=10,067.


  • INTERMAP: Ages 40 years to 59 years
  • INTERSALT:  Ages 20 years to 59 years.


  • Mean SBP: 117.2mm Hg to 121.3mm Hg
  • Mean DBP: 73.2mm Hg to 77.3mm Hg
  • Mean urinary Ca: 4.0mmol to 4.5mmol
  • Mean urinary Mg: 3.2mmol to 4.2mmol
  • Mean dietary Ca intake: 149mg to 445mg per 1,000kcal
  • Mean dietary Mg intake: 134mg to 155mg per 1,000kcal.


  • INTERMAP: Japan, China, UK, US
  • INTERSALT: Worldwide.
Summary of Results:

Key Findings

  • Reliability of urinary Ca and Mg excretion data (mean of two 24-hour urine): Ca=81.3%; Mg=72.6%
  • Urinary Ca showed consistent significant associations with BP across all analyses (controlling for all confounders):
    • In model adjusting for age, gender, sample weight, height, special diet, physical activity, history of heart attack or stroke, family history of HTN, smoking and alcohol intake past seven days: A difference of two SD in urinary Ca excretion (4.1mmol per 24 hours; equivalent to 163.1mg per 24 hours) was associated with a difference in SBP of 1.9mm Hg (P<0.001) and in DBP of 0.9mm Hg (P<0.001)
    • Associations remained after adjustment for dietary Ca, Mg or animal protein intakes.
  • Urinary Mg showed weak, mostly inverse and non-significant associations with BP:
    • In models adjusting for age, gender, sample weight, height, special diet, physical activity, history of heart attack or stroke, family history of HTN, smoking: A difference of two SD in urinary Mg excretion was associated with a difference in  SBP of 0.98mm Hg (P<0.05) and in DBP of 1.04mm Hg (P<0.001)
    • Differences did not remain after adjusting for alcohol intake past seven days, dietary Ca, Mg or animal protein intake.
  • Results from INTERSALT were qualitatively similar.
Author Conclusion:
Data suggest that altered calcium homeostasis, as exhibited by increased calcium excretion, is associated with higher BP levels.
Funding Source:
WHO; International Society of Hypertension; other health societies
Other non-profit:
Reviewer Comments:
Authors note the following limitations:
  • The data are cross-sectional, and thus the long-term influences of mineral excretion on BP may be underestimated and that causality cannot be inferred.
  • Despite adjustment for multiple confounders, the possibility of residual confounding by dietary or other variables remains; such misclassification would probably reduce observed associations between urinary cations and BP
  • Associations were larger in the INTERMAP population than in the INTERSALT population. This could be explained at least in part by reduced regression dilution bias in INTERMAP analyses, which had two 24-hour urine collections for each individual vs. the one collection in INTERSALT, as well as the eight BP measurements in INTERMAP compared with two in INTERSALT.
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) Yes
  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) Yes
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? Yes
  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? Yes
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) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  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? Yes
  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? N/A
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? N/A
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? N/A
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  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? N/A
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? N/A
  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? Yes
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? Yes
  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