Sodium and potassium intake as determinants of cardiovascular and renal health
Kieneker, Lyanne Marriët
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Kieneker, L. M. (2019). Sodium and potassium intake as determinants of cardiovascular and renal health. Rijksuniversiteit Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
CHAPTER 3
Association of low urinary sodium
excretion with increased risk of stroke
Lyanne M. Kieneker Michele F. Eisenga Ron T. Gansevoort Rudolf A. de Boer Gerjan Navis Robin P.F. Dullaart Michel M. Joosten Stephan J.L. Bakker
ABSTRACT
Background: The positive relationship between sodium intake and blood pressure
is well established. However, results of observational studies on dietary sodium intake and risk of stroke are inconsistent. Moreover, prospective studies with multiple 24-hour urine samples for accurate estimation of habitual sodium intake are scarce.We examined the association of urinary sodium excretion as an accurate estimate of intake with risk of stroke.
Methods: We studied 7,330 individuals free of cardiovascular events at baseline
in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women. Urinary sodium excretion was measured in 2 24-hour urine specimens at baseline (1997-1998) and 2 specimens during follow-up (2001-2003).
Results: Baseline median urinary sodium excretion was 137 mmol/24h (IQR:
106-171 mmol/24h). During a median follow-up of 12.5 years (IQR: 11.9-12.9 years), a total of 183 stroke events occurred. An inverse association between urinary sodium excretion and risk of stroke was observed after adjustment for age and sex (HR per 1 SD [51 mmol/24h] decrement,1.36; 95% CI, 1.11-1.65), which remained independent of additional adjustment for anthropometric, dietary, lifestyle, and other potential confounding factors (HR,1.44; 95% CI, 1.14-1.82). After adjustment for potential mediators (systolic blood pressure and antihypertensive medication, plasma renin, plasma aldosterone, and sodium levels), the association of urinary sodium excretion with risk of stroke remained unchanged, with HRs (95% CIs) of 1.44 (1.14-1.82), 1.50 (1.18-1.90), 1.54 (1.21-1.97), and 1.49 (1.17-1.90), respectively.
Conclusions: This prospective study revealed an association of low urinary sodium
INTRODUCTION
The positive relationship between sodium intake and blood pressure is well established (1). There is strong and convincing evidence that high sodium intake (>8 g/day) is associated with an increased risk of cardiovascular disease (CVD) morbidity and mortality, and that reduction of such excess sodium intake to moderate intake lowers the risk of CVD, including ischemic heart disease and stroke (1-4). However, there have been a number of studies reporting that intakes of sodium below 3 g/day may also be associated with an increased risk of CVD morbidity and mortality (3-8). These studies, and the absence of high quality randomized controlled trials indicating that reducing sodium intake to low levels will decrease CVD risk, have led to the assumption that there might be a J-shaped association between sodium intake and CVD morbidity and mortality.
Since high blood pressure has a prominent role in stroke risk, it may be anticipated that an increased sodium intake confers a higher incidence of stroke. The evidence for the association of sodium intake with risk of stroke is, however, even less consistent than for CVD, with overall positive associations (3, 9-11), positive associations only present in subgroups (12, 13), null associations (14-18), and, recently, a prospective cohort study which included 101,945 persons from 17 countries, reporting a J-shaped association (4). This inconsistency of the evidence might lie in methodological limitations of the studies, i.e. all studies, except one (18), relied on dietary questionnaires or spot urine samples, which are less reliable measures of sodium intake compared to measurement in 24-hour urine collections, which is considered the gold standard (19, 20).
Our aim was to examine the association of urinary sodium excretion, measured in multiple 24-hour urine collections as accurate estimate of intake, with risk of stroke in a population-based cohort.
METHODS
Study design and population
We analyzed data of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 25-75 years. In total, 8,592 subjects constitute the PREVEND study at baseline (1997-1998). For the present analyses, we excluded subjects with cardiovascular disease at baseline (n=456), renal disease requiring dialysis (n=18), missing values of urinary analytes (n=93), and with missing values of covariates at baseline (n=695), leaving 7,330 participants for the analyses. The study has been approved by the local medical ethics committee and written informed consent was obtained from all participants.
Data collection
The procedures at each examination in the PREVEND study have been described in detail previously (21-23). In brief, each examination included 2 visits to an outpatient clinic separated by 3 weeks. Prior to the first visit, all participants completed a self-administered questionnaire regarding demographics, cardiovascular and renal disease history, smoking habits, alcohol consumption and medication use. Information on medication use was combined with information from the IADB.nl database, containing pharmacy-dispensing data from community pharmacies in the Netherlands (24).
Urinary sodium excretion was measured in 2 24-hour urine specimens collected at baseline and in 2 24-hour urine specimens collected during follow-up (2001-2003) by indirect potentiometry with a MEGA clinical chemistry analyzer (Merck, Darmstadt, Germany). Incident stroke consisted of combined incidence of fatal and nonfatal hemorrhagic strokes (codes 430-431), ischemic strokes (codes 433-434), and unspecified strokes (code 432), with follow-up until December 31, 2010. Data on fatal stroke events were received through the municipal register. Information on hospitalization for nonfatal stroke events was obtained from the Dutch national registry of hospital discharge diagnoses (“Landelijke Medische Registratie”).
Statistical analyses
The Pearson product–moment correlation coefficient was calculated for the paired 24-hour urine specimens at the first and second examination, and for the averaged potassium excretions of the first and the second examination, as estimates of the intra-class correlation coefficient of reliability R (25). Cox proportional hazards regression analyses with time-dependent variables were used to calculate HRs (95% CIs). The first multivariable model is adjusted for age and sex. The second multivariable model is additionally adjusted for height, weight, race, smoking status, alcohol consumption, education, type 2 diabetes, total-to-high density lipoprotein cholesterol ratio. The third multivariable model is further adjusted for 24-hour urinary excretion of potassium, magnesium, creatinine, and albumin, and estimated glomerular filtration rate. For events occurring between baseline and the second examination, the average of the 2 baseline 24-hour urinary excretions of sodium was used. For events occurring after the second examination, the average of the 2 baseline and 2 follow-up 24-hour urinary excretions were used, since using cumulative averages of dietary factors yield stronger associations than either only baseline or most recent dietary factors (26).
In additional secondary analyses, we additionally adjusted multivariable model 3 for systolic blood pressure and antihypertensive medication, plasma renin, plasma aldosterone, and plasma sodium, one at the time to investigate whether the association of urinary sodium excretion with risk of stroke is independent of these potential mediators. We evaluated potential effect modification by age, sex, BMI, smoking status, hypertension, and urinary potassium excretion in the analyses of risk of stroke by fitting models adjusted according to multivariable model 3 containing both main effects and their cross-product terms.
To examine the robustness of the findings of the analyses for the association between urinary sodium excretion and risk of stroke, we performed several sensitivity analyses. First, we restricted the analysis of urinary sodium excretion and risk of stroke to subjects who were not taking antihypertensive drugs at baseline because of the potential mediating effects of blood pressure in the association between urinary sodium excretion and risk of stroke. Second, we reanalyzed the data excluding subjects with malignancies, type 2 diabetes, or
chronic kidney disease at baseline. Third, we addressed the oversampling of subjects with higher urinary albumin concentrations by using design-based Cox proportional hazards regression models that took into account the probability of selection by statistical weighting. A 2-tailed P-value <0.05 was considered statistically significant.
RESULTS
Baseline median urinary sodium excretion was 137 (interquartile range [IQR]: 106-171) mmol/24h. Table 1 presents the baseline characteristics according to sex-stratified quintiles of urinary sodium excretion. At baseline, mean BMI was 26.0 ± 4.2 kg/m2 and 69% (N=4,949) of the PREVEND participants was classified
as normotensive. The within-subject correlations for sodium excretion between the paired 24-hour urine specimens at the first and second examination were r=0.59 (P<.001; N=7,296) and r=0.63 (P<.001; N=5,823), respectively. The within-subject correlation between the averaged sodium excretions of the first and the second examination [separated by a median of 4.3 years (IQR: 4.0-4.9 years)] was r=0.59 (P<.001; N=7,330).
During median follow-up of 12.5 (IQR: 11.9-12.9) years, 183 stroke events occurred. In age- and sex-adjusted analysis, we found a significant inverse association between urinary sodium excretion and stroke risk (HR per 1 SD [51 mmol/24h] decrement, 1.36; 95% CI, 1.11-1.65; Table 2, Figure 1A). Additional adjustment for potential confounding factors, including height, weight, race, smoking status, alcohol consumption, education, type 2 diabetes, total-to-high density lipoprotein cholesterol ratio, did not materially alter the association (HR, 1.36; 95% CI, 1.11-1.67; Table 2). Further adjustment for 24-hour urinary excretion of potassium, magnesium, creatinine, and albumin, and estimated glomerular filtration rate, did also not materially alter the association (HR, 1.44; 95% CI, 1.14-1.82; Table 2, Figure 1B).
Ta b le 1 . B as eli n e ch ar ac te ri sti cs ac co rdi n g to qu in ti le s o f ur in ar y so di um e xc re ti o n o f 7, 3 3 0 sub je ct s o f th e P rev en ti o n o f R en al an d V as cul ar E n d -s ta ge D is ea se ( P R E V EN D ) s tu d y. Se x-sp e ci fi c q u in ti le s o f u ri n a ry s o d iu m e xc re ti o n , mm o l/ 24 -h o u r P -v a lu e f o r t re n d * Ma le <1 1 6 11 6 -1 4 2 14 3 -1 6 7 16 8 -2 0 1 >2 0 1 Fe m al e <8 9 89 -1 1 0 111 -1 32 13 3 -1 6 0 >1 6 0 P ar ti ci p an ts , N 1, 4 6 5 1, 4 6 7 1, 4 6 6 1, 4 6 6 1, 4 6 6 W o m e n , % 51 .4 51 .4 51 .4 51 .4 51 .4 A ge , y 5 0 .5 ± 1 3 .0 5 0 .1 ± 1 2 .9 4 9. 2 ± 1 2 .5 4 8 .2 ± 1 2 .0 47 .0 ± 1 1 .1 <0 .0 0 1 B M I, k g /m 2 2 5 .0 ± 3 .8 2 5 .3 ± 3 .6 2 5 .7 ± 4 .0 26 .3 ± 4 .0 27 . 8 ± 4 .9 <0 .0 0 1 R ac e, w h it e s, % 93 .9 95 .2 96 .5 96 .1 96 .0 0. 0 1 Sm o ki n g s ta tu s, c u rr e n t, % 39 .0 33 .1 33 .9 31 .6 32 .3 <0 .0 0 1 A lc o h o l c o n su m p ti o n , n o n e, % 27 .2 24 .7 23 .5 23 .5 21 .8 0. 1 2 Ed u ca ti o n , h ig h , % 31 .1 32 .9 32 .2 31 .4 26 .5 0. 0 1 Sy st o lic b lo o d p re ss u re , m m H g 1 2 9 ± 2 1 1 2 9 ± 2 0 1 2 8 ± 2 0 1 2 8 ± 2 0 1 2 9 ± 1 8 0.9 7 D ia st o lic b lo o d p re ss u re , m m H g 74 ± 1 0 74 ± 1 0 74 ± 1 0 7 3 ± 1 0 74 ± 9 0.9 9 A n ti h yp e rt e n si ve d ru gs , % 14 .7 12 .0 12 .2 12 .3 13 .0 0. 26 A n ti co ag u la n ts , % 2. 9 3. 0 2. 4 2. 7 2. 3 0. 2 9 To ta l c h o le st e ro l, m m o l/ L 5 .6 ± 1 .2 5 .6 ± 1 .1 5 .6 ± 1 .1 5 .6 ± 1 .1 5 .7 ± 1 .1 0. 2 0 H D L c h o le st e ro l, m m o l/ L 1 .3 4 ± 0 .4 1 1 .3 4 ± 0 .4 0 1 .3 5 ± 0 .3 9 1 .3 3 ± 0 .4 0 1 .3 1 ± 0 .4 1 0. 0 1 Li p id -l o w e ri n g d ru gs , % 4.4 4. 7 4. 2 4. 5 4. 8 0. 6 6 Glu co se , m m o l/ L 4 .7 ± 1 .0 4 .8 ± 1 .0 4 .8 ± 1 .1 4 .9 ± 1 .2 5 .0 ± 1 .3 <0 .0 0 1 G lu co se -l o w e ri n g d ru gs , % 1. 0 1. 5 0.9 1. 4 1. 8 0. 1 5 e G FR , m L/ m in /1 .7 3 m ² 9 4 ± 1 8 9 5 ± 1 7 9 5 ± 1 7 9 7 ± 1 6 9 8 ± 1 5 <0 .0 0 1 P la sm a so d iu m , m m o l/ L† 14 2 .1 ± 2 .4 14 2 .0 ± 2 .5 14 2 .0 ± 2 .3 14 1 .9 ± 2 .3 14 1 .8 ± 2 .1 <0 .0 0 1
3
b le 1 . Co n ti n u e d Se x-sp e ci fi c q u in ti le s o f u ri n a ry s o d iu m e xc re ti o n , mm o l/ 24 -h o u r P -v a lu e f o r t re n d * Ma le <1 1 6 11 6 -1 4 2 14 3 -1 6 7 16 8 -2 0 1 >2 0 1 Fe m al e <8 9 89 -1 1 0 111 -1 32 13 3 -1 6 0 >1 6 0 la sm a r e n in , µI U /mL ‡ 1 9. 6 ( 1 2 .2 -3 0 .0 ) 17 .9 (1 1 .1 -2 7. 6) 1 8 .3 ( 1 1 .6 -2 8 .8 ) 17 .3 (1 0 .8 -2 7. 7 ) 17 .7 (1 0 .7 -2 9. 6) 0. 0 0 4 la sm a a ld o st e ro n e, p g /m L§ 1 2 3 ( 9 6 -1 5 7 ) 1 1 9 ( 9 3 -1 5 3) 11 8 ( 92 -1 51 ) 11 6 ( 9 3 -1 5 2) 11 7 ( 92 -1 4 9) 0. 0 4 ri n ar y e xc re ti o n o f: Po ta ss iu m , m m o l/ 24 h 5 7 ( 4 6 -7 2) 6 6 ( 5 5 -7 9) 7 0 ( 5 8 -8 3) 74 ( 6 2-8 8) 8 1 ( 6 8 -9 6) <0 .0 0 1 So d iu m , m m o l/ 24 h 8 3 ( 7 1-9 7 ) 11 0 (1 0 0 -1 2 9) 13 2 (1 2 1-1 5 4) 1 5 9 ( 14 4 -1 8 0 ) 2 0 9 ( 1 8 0 -2 3 5) <0 .0 0 1 Ma gn es ium , m m o l/2 4 h 3 .3 ( 2 .4 -4 .1 ) 3.6 ( 2 .8 -4 .6 ) 3 .8 ( 3 .0 -4 .8 ) 4 .0 ( 3 .2 -5 .0 ) 4.4 ( 3 .3 -5 .4 ) <0 .0 0 1 Cr e atin ine , m mo l/ 24h 10 .0 ( 8 .3 -1 2 .6 ) 11 .2 ( 9. 3 -1 3 .6 ) 1 1 .8 ( 9. 8 -1 4 .3 ) 1 2 .5 ( 1 0 .3 -1 5 .6 ) 1 3 .8 ( 1 1 .3 -1 6 .8 ) <0 .0 0 1 Al b u m in , m g /2 4 h 8 .0 ( 5 .5 -1 4 .4 ) 8. 9 ( 6 .1 -1 6 .0 ) 9. 1 ( 6 .3 -1 6 .2 ) 9. 5 ( 6 .5 -1 8 .1 ) 1 0 .5 ( 7. 0 -1 9. 9) <0 .0 0 1 o n ti n u o u s v ar ia b le s a re r e p o rt e d a s m e an ± S D o r m e d ia n ( IQ R ), a n d c at e go ri ca l v ar ia b le s a re r e p o rt e d a s p e rc e n ta ge . A b b re vi ati o n s: B M I, b o d y m as s i n d e x; e G FR , sti m at e d g lo m e ru la r fi lt ra ti o n r at e; H D L, h ig h -d e n si ty l ip o p ro te in . * D e te rm in e d b y χ 2 t e st ( ca te go ri ca l v ar ia b le s) , l in e ar r e gr e ss io n ( co n ti n u o u s v ar ia b le s) . † Av ai l-le i n 6 ,7 6 6 s u b je ct s. ‡ Av ai la b le i n 7 ,1 51 s u b je ct s. § A va ila b le i n 6 ,4 8 5 s u b je ct s.
Ta b le 2 . A ss o cia ti o n o f ur in ar y so di um e xc re ti o n w it h ri sk o f st ro ke in 7, 3 3 0 sub je ct s o f th e P rev en ti o n o f R en al an d V as cul ar En d -s ta ge D is ea se ( P R E V EN D ) s tu d y. C o n ti n u o u s s o d iu m e x-cr e ti o n , p e r 5 1 m m o l/ 24 h de cr e as e* Se x-sp e ci fi c q u in ti le s o f u ri n a ry s o d iu m e xc re ti o n , mm o l/ 24 h ♂ : <1 1 6 11 6 -1 4 2 14 3 -1 6 7 16 8 -2 0 1 >2 0 1 ♀ : < 8 9 89 -1 1 0 111 -1 32 13 3 -1 6 0 >1 6 0 Pe rs o n -y e ar s 83 ,1 8 9 16 ,2 7 2 16 ,5 1 5 16 ,7 74 16 ,7 2 0 16 ,9 0 8 N u m b e r o f e ve n ts 18 3 57 49 33 25 19 A ge - a n d s e x-ad ju st e d m o d e l 1 .3 6 ( 1 .1 1-1 .6 5) 1. 4 6 ( 0 .9 5 -2 .2 4) 1 .0 9 ( 0 .6 9 -1 .7 3) 1 .0 0 ( re f) 1 .0 6 ( 0 .6 5 -1 .7 2) 0. 8 7 ( 0. 51 -1 .5 0 ) M u lti va ri ab le a d ju st e d m o d e l 2 † 1. 3 6 (1. 1 1-1. 67 ) 1 .4 5 ( 0 .9 4 -2 .2 3) 1 .1 5 ( 0 .7 3 -1 .8 1) 1 .0 0 ( re f) 1 .1 1 ( 0 .6 8 -1 .8 1) 0 .8 6 ( 0 .4 9 -1 .4 9) M u lti va ri ab le a d ju st e d m o d e l 3 ‡ 1. 4 4 (1. 14 -1. 8 2) 1 .4 5 ( 0 .9 2-2 .2 9) 1. 1 3 ( 0 .7 1-1. 7 9) 1 .0 0 ( re f) 1 .0 4 ( 0 .6 4 -1 .7 1) 0 .8 1 ( 0 .4 6 -1 .4 1) H R s a n d 9 5 % C Is w e re d e ri ve d f ro m C o x p ro p o rti o n al h az ar d s r e gr e ss io n m o d e ls . A b b re vi ati o n s: C I, c o n fi d e n ce i n te rv al ; H R = h az ar d r ati o . * 51 m m o l= 1 SD . † M u lti va ri ab le ad ju st e d m o d e l 2 is ad d iti o n al ly ad ju st e d fo r h e ig h t, w e ig h t, ra ce , s m o ki n g st at u s, al co h o l c o n su m p ti o n , e d u ca ti o n , t yp e 2 d ia b e te s, an d t o ta l-to -h ig h d e n si ty li p o p ro te in c h o le st e ro l r ati o . ‡ M u lti va ri ab le a d ju st e d m o d e l 3 is a d d iti o n al ly a d ju st e d f o r 24 -h o u r u ri n ar y e xc re ti o n o f p o ta ss iu m , m ag n e -si u m ,c re ati n in e, a n d a lb u m in , a n d e sti m at e d g lo m e ru la r fi lt ra ti o n r at e.
3
Figure 1. Association of urinary sodium excretion and risk of stroke in 7,330 participants of the Prevention
of Renal and Vascular End-stage Disease (PREVEND) study. Data were fit by a Cox proportional hazards re-gression model based on restricted cubic splines with 3 knots. Figure 1A is adjusted for age and sex, Figure 1B is additionally adjusted for height, weight, race, smoking status, alcohol consumption, education, type 2 diabetes, total-to-high density lipoprotein cholesterol ratio, 24-hour urinary potassium, magnesium, creat-inine, and albumin excretion, and estimated glomerular filtration rate. The gray areas indicate the 95% CIs.
The spline curve is truncated at the 0.5th and 99.5th percentile of the distribution curve. Reference standard
was 136 mmol/24h.
When additionally accounting for potential mediators (systolic blood pressure and antihypertensive medication, plasma renin, plasma aldosterone, plasma sodium), the association of urinary sodium excretion with risk of stroke remained materially unchanged, with HRs (95% CIs) of 1.44 (1.14-1.82), 1.50 (1.18-1.90), 1.54 (1.21-1.97), and 1.49 (1.17-1.90), respectively. In secondary analyses dividing stroke into ischemic and hemorrhagic stroke events, low urinary sodium excretion was associated with an increased risk of ischemic stroke (n=131, age- and sex adjusted HR, 1.44; 95% CI, 1.13-1.85), but not with hemorrhagic stroke (n=36, age- and sex adjusted HR, 1.09; 95% CI, 0.69-1.72). We did not find evidence for effect-modification by age, sex, body mass index, hypertension, and urinary potassium excretion in the association between urinary sodium excretion and risk of stroke, while adjusting according to multivariable model 3 (all Pinteraction>0.1).
As sensitivity analyses, we excluded subjects who were using antihypertensive drugs at baseline (leaving N=6,388, n=126), and subjects with malignancies, type 2 diabetes, or chronic kidney disease at baseline (leaving N=6,054, n=112). Results remained unchanged, with HRs with adjustment according to multivariable model
2 of 1.47 (1.14-1.89) and 1.45 (1.10-1.92), respectively. In the weighted analyses that accounted for the sampling design of the study, results were not essentially different in the multivariable model for the association between urinary sodium excretion and risk of stroke (HR with adjustment according to multivariable model 3, 1.68; 95% CI, 1.12.-2.50).
DISCUSSION
In this prospective study, low urinary sodium excretion, as estimate of low sodium intake, was associated with an increased risk of stroke. This inverse association of urinary sodium excretion with risk of stroke remained independent of adjustment for potential confounders and potential mediators.
Our finding is in line with a previous study of O’Donnell and colleagues (4), which also observed that a low urinary sodium excretion (<130 mmol/24h) – estimated from spot urine samples– was associated with an increased stroke risk. In contrast with our data, O’Donnell et al. identified a non-linear association, as estimated urinary sodium excretion >304 mmol/24h was also associated with an increased stroke risk. The absence of this phenomenon in the present study might be explained by the relatively low sodium intake of the participants in our study, since <1% of them had a urinary sodium excretion >300 mmol/24h.
Between study differences in the methods of sodium intake make between-study comparisons difficult. For example, there are many variations in methods of measuring sodium intake. In general, dietary questionnaires underestimate sodium intake compared with 24-hour urine measures, which is considered to be the gold standard for measuring sodium intake (19, 20). Other than our study, most of the studies which observed a positive association between sodium intake and risk of stroke, assessed intake of dietary sodium via self-reported questionnaires (9-13). One study that reported a positive association between sodium intake and risk of stroke assessed dietary sodium intake via a spot urine sample. This study was, however, performed in patients with an established or high risk of CVD (3). Variations in the study populations may also lead to different ranges of sodium intake. This could possibly be the cause of the heterogeneity
observed in meta-analyses on sodium intake and risk of stroke (1, 27), since a large part of the heterogeneity appeared to be explained by region, with all studies in Asia –a region known for its high sodium intake (28)– reporting a significant positive association, whereas no association was observed for studies from Europe or North America (27, 29).
Several mechanisms might underlie the association of low sodium intake with increased stroke risk. Sodium restriction is known to lead to increases in circulating concentrations of cholesterol, triglycerides, renin, aldosterone and catecholamines, which might accelerate atherosclerosis and induce vasoconstriction (30, 31). We found the association of sodium intake with risk of stroke to remain materially unchanged after adjustment for available ones of these parameters, leaving the possibility that increased triglycerides or vasoconstriction induced by catecholamines play a role. When we tested for interactions, we observed that the association of urinary sodium excretion with stroke risk was similar among subgroups who might be more salt-sensitive (subjects with hypertension, obesity) and therefore may have an increased risk of stroke.
Some limitations of this study should be noted. First, the results of our study cannot directly be extrapolated to individuals with a high sodium intake, as the average sodium intake in this population was relatively low. Second, the possibility of reverse causation cannot completely be ruled out, despite that the sensitivity analysis excluding ill individuals at baseline rendered similar results. A third limitation of this study, as with all other observational studies, is the possibility of residual confounding for unmeasured or poorly measured variables. For example, diet was obtained from 24-hour urine collections and therefore, we could only account for a few nutrients.
The major strength of this study is the use of multiple 24-hour urine collections updated over time to estimate habitual dietary sodium intake. As approximately 90% of ingested sodium in healthy individuals is excreted in the urine, 24-hour urinary sodium excretion is considered the gold standard for dietary sodium intake (19, 20). Other strengths of this study were the prospective design, the relatively large sample size, and the availability of detailed and updated (midway
through the period of follow-up to reduce potential misclassification) data on potential confounders.
Conclusion
In this population-based cohort predominantly consisting of normotensive subjects with a fairly healthy weight, low urinary sodium excretion was associated with an increased risk of stroke. This association appeared to be independent of confounders and potential mediators. Further investigation is needed to unravel whether the currently identified association can be extrapolated to the notion that an adequate sodium intake could possibly lower risk of stroke.
REFERENCES
1. Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP, Meerpohl JJ. Effect of lower
sodium intake on health: systematic review and meta-analyses. BMJ 2013;346:f1326.
2. Alderman MH, Cohen HW. Dietary sodium intake and cardiovascular mortality: controversy
resolved? Am J Hypertens 2012;25:727-34.
3. O’Donnell MJ, Yusuf S, Mente A, Gao P, Mann JF, Teo K, McQueen M, Sleight P, Sharma AM,
Dans A, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA 2011;306:2229-38.
4. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, Yan H, Lee SF, Mony P,
Devanath A, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 2014;371:612-23.
5. Stolarz-Skrzypek K, Kuznetsova T, Thijs L, Tikhonoff V, Seidlerova J, Richart T, Jin Y,
Olszanecka A, Malyutina S, Casiglia E, et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA 2011;305:1777-85.
6. Graudal N, Jurgens G, Baslund B, Alderman MH. Compared with usual sodium intake, low-
and excessive-sodium diets are associated with increased mortality: a meta-analysis. Am J Hypertens 2014;27:1129-37.
7. Cohen HW, Hailpern SM, Fang J, Alderman MH. Sodium intake and mortality in the NHANES
II follow-up study. Am J Med 2006;119:275.e7,275.14.
8. Mente A, O’Donnell M, Rangarajan S, Dagenais G, Lear S, McQueen M, Diaz R, Avezum
A, Lopez-Jaramillo P, Lanas F, et al. Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies. Lancet 2016;388:465-75.
9. Gardener H, Rundek T, Wright CB, Elkind MS, Sacco RL. Dietary sodium and risk of stroke
in the Northern Manhattan study. Stroke 2012;43:1200-5.
10. Fung TT, Chiuve SE, McCullough ML, Rexrode KM, Logroscino G, Hu FB. Adherence to a
DASH-style diet and risk of coronary heart disease and stroke in women. Arch Intern Med 2008;168:713-20.
11. Umesawa M, Iso H, Date C, Yamamoto A, Toyoshima H, Watanabe Y, Kikuchi S, Koizumi
A, Kondo T, Inaba Y, et al. Relations between dietary sodium and potassium intakes and mortality from cardiovascular disease: the Japan Collaborative Cohort Study for Evaluation of Cancer Risks. Am J Clin Nutr 2008;88:195-202.
12. He J, Ogden LG, Vupputuri S, Bazzano LA, Loria C, Whelton PK. Dietary sodium intake and
subsequent risk of cardiovascular disease in overweight adults. JAMA 1999;282:2027-34.
13. Nagata C, Takatsuka N, Shimizu N, Shimizu H. Sodium intake and risk of death from stroke
in Japanese men and women. Stroke 2004;35:1543-7.
14. Larsson SC, Virtanen MJ, Mars M, Mannisto S, Pietinen P, Albanes D, Virtamo J. Magnesium,
15. Geleijnse JM, Witteman JC, Stijnen T, Kloos MW, Hofman A, Grobbee DE. Sodium and potassium intake and risk of cardiovascular events and all-cause mortality: the Rotterdam Study. Eur J Epidemiol 2007;22:763-70.
16. Lamelas PM, Mente A, Diaz R, Orlandini A, Avezum A, Oliveira G, Lanas F, Seron P,
Lopez-Jaramillo P, Camacho-Lopez P, et al. Association of Urinary Sodium Excretion With Blood Pressure and Cardiovascular Clinical Events in 17,033 Latin Americans. Am J Hypertens 2016;29:796-805.
17. Kagan A, Popper JS, Rhoads GG, Yano K. Dietary and other risk factors for stroke in
Hawaiian Japanese men. Stroke 1985;16:390-6.
18. Tuomilehto J, Jousilahti P, Rastenyte D, Moltchanov V, Tanskanen A, Pietinen P, Nissinen
A. Urinary sodium excretion and cardiovascular mortality in Finland: a prospective study. Lancet 2001;357:848-51.
19. Holbrook JT, Patterson KY, Bodner JE, Douglas LW, Veillon C, Kelsay JL, Mertz W, Smith
JC,Jr. Sodium and potassium intake and balance in adults consuming self-selected diets. Am J Clin Nutr 1984;40:786-93.
20. McLean RM. Measuring population sodium intake: a review of methods. Nutrients
2014;6:4651-62.
21. Verhave JC, Gansevoort RT, Hillege HL, Bakker SJ, De Zeeuw D, de Jong PE, PREVEND
Study Group. An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population. Kidney Int Suppl 2004;(92):S18-21.
22. Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, Van Gilst WH, De Zeeuw
D, De Jong PE, Prevend Study Group. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 2001;249:519-26.
23. Kieneker LM, Gansevoort RT, de Boer RA, Brouwers FP, Feskens EJ, Geleijnse JM, Navis G,
Bakker SJ, Joosten MM, PREVEND Study Group. Urinary potassium excretion and risk of cardiovascular events. Am J Clin Nutr 2016;103:1204-12.
24. Visser ST, Schuiling-Veninga CC, Bos JH, de Jong-van den Berg LT, Postma MJ. The
population-based prescription database IADB.nl: its development, usefulness in outcomes research and challenges. Expert Rev Pharmacoecon Outcomes Res 2013;13:285-92.
25. Espeland MA, Kumanyika S, Wilson AC, Reboussin DM, Easter L, Self M, Robertson J, Brown
WM, McFarlane M, TONE Cooperative Research Group. Statistical issues in analyzing 24-hour dietary recall and 24-24-hour urine collection data for sodium and potassium intakes. Am J Epidemiol 2001;153:996-1006.
26. Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman D, Willett WC. Dietary
fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol 1999;149:531-40.
27. Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular
disease: meta-analysis of prospective studies. BMJ 2009;339:b4567.
28. Powles J, Fahimi S, Micha R, Khatibzadeh S, Shi P, Ezzati M, Engell RE, Lim SS, Danaei G, Mozaffarian D, et al. Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24h urinary sodium excretion and dietary surveys worldwide. BMJ Open 2013;3:e003733,2013-003733.
29. O’Donnell MJ, Mente A, Smyth A, Yusuf S. Salt intake and cardiovascular disease: why are
the data inconsistent? Eur Heart J 2013;34:1034-40.
30. Ma TK, Kam KK, Yan BP, Lam YY. Renin-angiotensin-aldosterone system blockade for
cardiovascular diseases: current status. Br J Pharmacol 2010;160:1273-92.
31. Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium
diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride. Cochrane Database Syst Rev 2011;11:CD004022.
