A journal club presentation on Urinary sodium and potassium excretion, mortality and cardiovascular events

1. Urinary Sodium and
Potassium Excretion,
Mortality and
Cardiovascular Events
Dr. Rikka Banayat
Dr. Joana Thomas
Dr. Aasems Jacob

2. Sodium intake - to restrict or not?

3. Global Sodium Intake
◎ Mean global sodium intake is 3.95 grams/day
◎ WHO recommended limit: 2 grams/day
◎ Intake in men ~10% higher
◎ Highest in East Asia, Central Asia, Eastern Europe (mean >4.2
grams/day)
◎ North America, Western Europe, Australia/New Zealand = 3.4
to 3.8 grams/day
◎ Sub-Saharan Africa and Latin America = <3.3 grams/day
John Powles Saman Fahimi, et al. Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of
24 h urinary sodium excretion and dietary surveys worldwide. BMJ Open 2013;3:e003733

4. Global Sodium Intake
◎ European and North American countries - 75% of
sodium intake is from manufactured foods
◎ UK and US - Cereals and baked goods were the
single largest contributor to dietary sodium intake
◎ Japan and China - salt added at home and soy sauce
were the largest sources
Brown IJ, Tzoulaki I, Candeias V, Elliott P. Salt intakes around the world: implications for public health.
Int J Epidemiol. 2009 Jun;38(3):791-813.

5. How much sodium is in
table salt???
◎Sodium chloride or
table salt is
approximately 40%
sodium
◎ 1 tsp salt (6
grams)= 2300 mg
sodium
http://sodiumbreakup.heart.org/

6. How much sodium should
I eat per day?
◎AHA recommendations:Lower sodium intake (Level I)
○ Consume no more than 2,400 mg/day of sodium (Level IIa)
○ Further reduction of sodium intake to 1,500 mg/day is desirable
since it is associated with an even greater reduction in BP (Level IIa)
○ Reduce sodium intake by at least 1,000 mg/day since that will lower
BP, even if the desired daily sodium intake is not yet achieved (Level
IIa)

7. Sodium intake and Hypertension
Effect of longer-term modest salt reduction on blood pressure.
He FJ1, Li J, Macgregor GA. Cochrane Database Syst Rev. 2013 Apr 30;(4):CD004937
◎ A modest reduction in salt intake for 4 or more weeks causes significant
and, from a population viewpoint, important falls in BP in both hypertensive
and normotensive individuals, irrespective of sex and ethnic group.
◎ Significant association between the reduction in 24-h urinary sodium and
the fall in systolic BP, indicating the greater the reduction in salt intake, the
greater the fall in systolic BP.
◎ The current recommendations to reduce salt intake from 9-12 to 5-6 g/d
will have a major effect on BP, but are not ideal. A further reduction to 3 g/d
will have a greater effect and should become the long term target for
population salt intake.

8. Sodium intake and Hypertension
Effect of lower sodium intake on health: systematic review
and meta-analyses.
Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP. BMJ 2013;346:f1326.
◎ Reduced sodium intake reduces blood pressure and has no adverse effect
on blood lipids, catecholamine levels or renal function
◎ There were insufficient randomized controlled trials to assess the effects
of reduced sodium intake on mortality and morbidity.
◎The associations in cohort studies between sodium intake and all cause
mortality, incident fatal and non-fatal cardiovascular disease, and coronary
heart disease were non-significant

9. Sodium Intake and
Cardiovascular Disease
Compared with usual sodium intake, low- and excessive-sodium
diets are associated with increased mortality: a meta-analysis.
Graudal N, Jürgens G, Baslund B, Alderman MH. Am J Hypertens. 2014 Sep;27(9):1129-37.
◎ The objective was to investigate the incidence of all-cause mortality
(ACM) and cardiovascular disease events (CVDEs) in populations exposed
to dietary intakes of low sodium (<115 mmol), usual sodium (low usual
sodium: 115-165 mmol; high usual sodium: 166-215 mmol), and high
sodium (>215 mmol).
◎ Data from 23 cohort studies and 2 follow-up studies of RCTs (n =
274,683) showed that the risks of ACM and CVDEs were decreased in usual
sodium vs. low sodium intake and increased in high sodium vs. usual
sodium intake
◎Within the usual sodium intake range, the number of events was stable
◎Both low sodium intakes and high sodium intakes are associated with
increased mortality

10. Sodium Intake and
Cardiovascular Disease
Sodium excretion and risk of developing coronary heart disease.
Joosten MM1, Gansevoort RT, Mukamal KJ, Circulation. 2014 Mar 11;129(10):1121-8.
◎In the overall population, there was no
association between sodium excretion and
risk of CHD.
◎Higher sodium excretion was associated
with an increased CHD risk among subjects
with increased NT-proBNP concentrations
or with hypertension.

11. Sodium Intake and
Cardiovascular Disease
Fatal and Nonfatal Outcomes, Incidence of Hypertension, and
Blood Pressure Changes in Relation to Urinary Sodium Excretion
Katarzyna Stolarz-Skrzypek, MD, PhD; Tatiana Kuznetsova, MD, et al.
JAMA. 2011;305(17):1777-1785.
◎In this population-based cohort, systolic blood pressure, but not
diastolic pressure, changes over time aligned with change in sodium
excretion, but this association did not translate into a higher risk of
hypertension or CVD complications.
◎Lower sodium excretion was associated with higher CVD mortality.

12. Sodium Consumption and Mortality
Global Sodium Consumption and Death from Cardiovascular Causes
Dariush Mozaffarian, M.D., Dr.P.H., et al. N Engl J Med 2014
◎1.65 million deaths from cardiovascular
causes that occurred in 2010 were attributed
to sodium consumption above a reference
level of 2.0 g per day.

13. Sodium, Potassium and
Cardiovascular Disease
Urinary Sodium and Potassium Excretion and Risk of
Cardiovascular Events
Martin J. O'Donnell, MB, PhD; Salim Yusuf, et al. JAMA. 2011;306(20):2229-2238.
◎In patients with established CV disease or DM, compared
with baseline sodium excretion of 4 to 5.99 g per day, sodium
excretion of greater than 7 g per day was associated with an
increased risk of all CV events, and a sodium excretion of less
than 3 g per day was associated with increased risk of CV
mortality and hospitalization for CHF.
◎Higher estimated potassium excretion was associated with a
reduced risk of stroke.

14. Potassium and
Cardiovascular Disease
Effect of increased potassium intake on cardiovascular risk factors
and disease: systematic review and meta-analyses.
Aburto NJ, Hanson S, Gutierrez H. BMJ. 2013 Apr 3;346
◎Increased potassium intake reduced systolic blood pressure by 3.49 mm Hg and
diastolic blood pressure by 1.96 mm Hg in adults, an effect seen in people with
hypertension but not in those without hypertension.
◎Systolic blood pressure was reduced by 7.16 mm Hg when the higher potassium
intake was 90-120 mmol/day, without any dose response.
◎Higher potassium intake was associated with a 24% lower risk of stroke (moderate
quality evidence). These results suggest that increased potassium intake is
potentially beneficial to most people without impaired renal handling of potassium
for the prevention and control of elevated blood pressure and stroke.
156,424

15. Prospective Urban
Rural Epidemiology
(PURE) study

16. Study design
Participants: 156,424 (101,945)
Age: 35 to 70 years
628 Communities
in 17, low (4), middle
(10) and high income
countries (3)
Period
Jan 2003 to 2013 (first
data), continued
Coordinated by Population Health Research Institute,
Hamilton Health Sciences and McMaster University, Canada.
Funding: Sponsored by nonprofit, government and industry sponsors. Funders
had no role in analyses, or design or conduct of the study or writing manuscripts

17. Maps
our office

18. Procedures
◎ Initial questionnaire
◎ Fasting morning midstream urine sample collection
◎ 24-hour urinary sodium and potassium excretion
estimated using Kawasaki formula
◎ Considered surrogate for intake
Kawasaki T, Itoh K, Uezono K, Sasaki H. A simple method for estimating 24 h urinary sodium and potassium excretion from
second morning voiding urine specimen in adults. Clin Exp Pharmacol Physiol 1993;20:7-14. [Erratum, Clin Exp Pharmacol
Physiol 1993;20:199.] 25.
Mente A, O’Donnell MJ, Dagenais G, et al. Validation and comparison of three formulae to estimate sodium and potassium
excretion from a single morning fasting urine compared to 24-h measures in 11 countries. J Hypertens 2014;32:1005- 14. 26.

19. Urine analyses
◎ Frozen at -20C to -70C
◎ Shipped to Clinical Research labs in Canada, India, China and
Turkey
◎ Indirect potentiometry
◎ 0.1% had implausible urine concentrations and excluded
◎ All labs were within analytical range as compared to Central
Laboratory, Hamilton, Canada

20. Follow up
o Follow up started in 2008, completed by 2013
o Information on events: participants/family
o Verbal autopsies/Review of medical records

21. Statistical
analysis
Primary outcome measures
◎Death from any cause
◎Death from major cardiovascular events
(stroke, MI, heart failure)

22. Multivariable logistic regression analysis performed to determine
association between urinary sodium and potassium excretion and
outcome measure using 3 sequential models
Model 1
Adjusted for age,
sex, educational
level, ancestry,
alcohol use,
diabetes mellitus,
BMI, history of
cardiovascular
events, smoking,
LDL:HDL ratio
Model 2
Model 1 + Caloric
intake, fruit/
vegetable intake
Model 3
Model 1 + 2 +
systolic blood
pressure,
hypertension,
antihypertensive
therapy

23. Exclusion criteria
Cardiovascular disease
Cancer (at baseline or follow-up)
Events in the first 2 year of follow-up
Tested for interactions
of age, hypertension,
sex, ancestry, history
of cardiovascular
disease, diabetes, BMI
and estimated sodium
and potassium
excretion
Potential influence
of unmeasured
confounders on our
estimates of risk
using array-
approach sensitivity
Potential influence of
imbalanced
confounders:
propensity score
matched sensitivity
analyses

24. 4.93 grams
Mean estimated 24-hour sodium excretion
Mean systolic and diastolic blood pressure
higher among those with higher sodium
excretion (p<0.001)
2.12 gramsMean estimated 24-hour potassium excretion
Results

25. Baseline characteristics
◎Proportion of participants (%)
○ <3.00 g/day : 10.6
○ 3.00–3.99 g/day : 20.7
○ 4.00–5.99 g/day : 45.8
○ 6.00–6.99 g/day : 12.1
○ 7.00 g/day : 10.8

26. 3.3% (3317 subects)
857 MI
872 stroke
261 heart failure
1976 deaths
◉ 650 from cardiovascular causes
Primary composite outcome of death
or major CVE

27. Urinary sodium excretion >7.00g per day
◎ Increased risk of primary composite outcome
(Odds Ratio: 1.15; 95% CI: 1.02 to 1.30)
◎ Death from any cause
(Odds Ratio: 1.25; 95%CI: 1.07 to 1.48)
◎ Major CVE (OR:1.16; 95%CI: 1.01 to 1.34)
◎ Death from CVE (OR:1.54; 95% CI: 1.21 to 1.95)
◎ Stroke (OR: 1.29; 95%CI: 1.02 to 1.63)
Not significant after adjustment for blood pressure and history of
hypertension except death from any cause

28. Urinary sodium excretion <3.00g per day
◎ Increased risk of primary composite outcome
(OR:1.27; 95% CI:1.12 to 1.44)
◎ Death from any cause
(OR:1.38; 95% CI:1.15 to 1.66)
◎ Major CVE (OR:1.30; 95% CI:1.13 to 1.50)
◎ Death from CVE (OR:1.77; 95% CI:1.36 to 2.31)
◎ Stroke (OR: 1.37; 95% CI:1.07 to 1.76)
Significant after adjustment for blood pressure or
history of hypertension

29. Potassium excretion >1.50g per day
◎ Reduction in the risks of death and CVEs
◎ Reduction in the risk of death
◎ No evidence of an interaction between estimated
potassium and sodium excretion with respect to
the primary composite outcome

30. Maps
our office

31. Maps
our office

32. Maps
our office

34. Association between Estimated Sodium Excretion
and Composite Outcome (All-cause Mortality and
CVD) in Subgroups

35. Association between Estimated Sodium Excretion
and Composite Outcome (All-cause Mortality and
CVD) in Subgroups

37. “
An estimated sodium excretion between 3g
and 6g per day was associated with a lower
risk of death and cardiovascular events than
either a higher or lower estimated level of
sodium intake.

38. “
As compared with an estimated
potassium excretion of less than
1.50 g per day, higher potassium
excretion was associated with a
reduction in the risk of the
composite outcome.

40. Discussion
Current guidelines recommend maximum
intake of 1.5 to 2.4 g per day (derived from BP
trials that assume a linear relationship)
Na intake = blood pressure
blood pressure = CV events

42. Discussion
◎ higher risk of CV disease and death only in
individuals with HTN consuming >6g/day
(representing only 10% of the population)
◎ increased risk of CV disease and death in
low sodium intake (compared with
moderate intake) irrespective of HTN status

43. Discussion
◎ A very small proportion of the worldwide
proportion consumes a low Na diet; Na
intake not related to BP in these people
◎? Lower Na best targeted at those
individuals with HTN who also consume high
Na

44. ◎ Previous studies has shown a J-shaped
association between Na intake and CV disease
or death
◎ Some of theses studies included participants
at high CV risk and were vulnerable to biases
from reverse causation (e.g. people with CV
disease or increased CV risk reduce their Na
intake due illness or recommendations)
Discussion

45. Discussion
◎ PURE study: vast majority did not have a
history of cardiovascular disease
◎ DM and history of CV disease were more
common in those with low Na excretion, they had
a similar overall mean INTERHEART Modifiable
Risk Score
◎ exclusion criteria did not alter findings
◎ reverse causation still cannot be ruled out, may
account for the increased risk in low Na excretion
group

46. Discussion
◎ interaction between Na excretion and K
excretion: higher Na strongly associated
with increased BP in people with lower K
excretion
◎ alternative approach to BP management?
Recommend K-high diets to achieve greater
health benefits, including BP reduction, than
aggressive Na reduction alone

47. ◎ Higher K excretion was associated with a lower
CV risk or deaths
◎ A small, cluster-randomized, controlled trial
which showed participants increased K consumption
and reduced high Na consumption reduced CV
mortality
◎ High K - effect on BP or maker of diet high in
fruits and vegetables
◎ Large definitive trials needed

48. Study limitations
◎ Method of estimating Na and K intake was a
formula-derived estimate of 24-hour urinary
excretion and not actual 24-hour urinary
collection
◎ True probability - sampling approach was
not undertaken – issues with practical
constraints of studying Na excretion in a wide
range of countries and settings

49. Study limitations
◎ epidemiologic comparison of groups that
consume different levels of Na, does not
provide information on the effect on clinical
outcomes of reducing Na intake
◎ lack of intervention component to assess
the direct effects of altering Na and K intake
on BP and cardiovascular-disease outcomes,
impossible to establish causality

50. Should we take these results
with a grain of salt?
◎ estimated Na intake between 3-6g per day was
associated with a lower risk of death and
cardiovascular events than either a higher or
lower estimated level of sodium intake
◎ higher K excretion (1.5 g /day) was associated
with a reduction in the risk of the composite
outcome

51. Thank you