Sodium and potassium intake as determinants of cardiovascular and renal health
Kieneker, Lyanne Marriët
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Kieneker, L. M. (2019). Sodium and potassium intake as determinants of cardiovascular and renal health. Rijksuniversiteit Groningen.
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CHAPTER 4
Urinary potassium excretion and risk of
cardiovascular events
Lyanne M. Kieneker Ron T. Gansevoort Rudolf A. de Boer Frank P. Brouwers Edith J.M. Feskens Johanna M. Geleijnse Gerjan Navis Stephan J.L. Bakker Michel M. Joosten Am J Clin Nutr 2016; 103: 1204-1412ABSTRACT
Background: Observational studies on dietary potassium and risk of cardiovascular
disease (CVD) have reported weak-to-modest inverse associations. Long-term prospective studies with multiple 24-hour urinary samples for accurate estimation of habitual potassium intake, however, are scarce. We examined the association between urinary potassium excretion and risk of blood pressure-related cardiovascular outcomes.
Methods: We studied 7,795 subjects free of cardiovascular events at baseline
of the Prevention of Renal and Vascular End-Stage Disease study, a prospective, observational cohort with oversampling of subjects with albuminuria at baseline. Main cardiovascular outcomes were CVD (including ischemic heart disease [IHD], stroke, and vascular interventions), IHD, stroke, and new-onset heart failure (HF). Potassium excretion was measured in 2 24-hour urine specimens at start of the study (1997-1998) and midway through follow-up (2001-2003).
Results: Baseline median urinary potassium excretion was 70 mmol/24h (IQR:
56-84 mmol/24h). During a median follow-up of 10.5 years (IQR: 9.9-10.8 years), a total of 641 CVD, 465 IHD, 172 stroke, and 265 HF events occurred. After adjustment for age and sex, inverse associations were observed between potassium excretion and risk (HR per each 26-mmol/24h [1-g/day] increase; 95% CI) of CVD (0.87; 0.78, 0.97) and IHD (0.86; 0.75, 0.97), as well as nonsignificant inverse associations for risk of stroke (0.85; 0.68, 1.06) and HF (0.94; 0.80, 1.10). After further adjustment for body mass index, smoking, alcohol consumption, education, and urinary sodium and magnesium excretion, urinary potassium excretion was not statistically significantly associated with risk (multivariable-adjusted HR per 1-g/day increment; 95% CI) of CVD (0.96; 0.85, 1.09), IHD (0.90; 0.81, 1.04), stroke (1.09; 0.86, 1.39), or HF (0.99; 0.83, 1.18). No associations were observed between the sodium-to-potassium excretion ratio and risk of CVD, IHD, stroke, or HF.
Conclusions: In this cohort with oversampling of subjects with albuminuria at
baseline, urinary potassium excretion was not independently associated with a lower risk of cardiovascular events.
INTRODUCTION
Potassium supplementation has consistently been shown to lower blood pressure in short-term randomized controlled trials, particularly among subjects with (pre)hypertension (1). Moreover, low dietary potassium uptake has been associated with the risk of developing hypertension in normotensive subjects (2). Because elevated blood pressure is an important and modifiable risk factor for cardiovascular morbidity and mortality (3-7), higher potassium intake may favorably affect risk of cardiovascular disease (CVD) and new-onset heart failure (HF).
Meta-analyses of the few observational studies on dietary potassium have reported nonsignificant inverse associations with risks of CVD and ischemic heart disease (IHD) (1, 8). Besides these inverse trends, a larger body of epidemiological evidence supports an association between potassium intake and lower risk of stroke, specifically ischemic stroke (9, 10), with substantial heterogeneity among studies (1, 8). Importantly, nearly all cohort studies relied on food-frequency questionnaires or 24-hour recalls to assess potassium intake. These self-reported dietary methods, however, may be less objective and precise for the assessment of minerals such as potassium (11), compared with potassium measured in a 24-hour urine sample, which is considered to be the gold standard (12-15). So far, only 2 studies have assessed potassium intake in 24-hour urine collections with respect to cardiovascular events, of which one observed a nonsignificant inverse association with cardiovascular risk after controlling for potential confounders (16), and the other observed a significant inverse association with risk of IHD in men and a nonsignificant inverse association in women, while only adjusting for age (17).
Therefore, the aim of this study was to prospectively examine the association between 24-hour urinary potassium excretion, measured on multiple occasions, and risk of blood pressure-related cardiovascular events (i.e., CVD, IHD, stroke, and HF) in a cohort with oversampling of subjects with albuminuria at baseline.
MATERIALS AND METHODS
Study design and populationThe Prevention of Renal and Vascular End-stage Disease (PREVEND) study is a prospective investigation of albuminuria and renal and cardiovascular disease in a large cohort with oversampling of persons with albuminuria at baseline. Details of this study are described elsewhere (18, 19). In total, 8,592 individuals (6,000 individuals with a urinary albumin concentration of ≥10 mg/L and 2,592 individuals with a urinary albumin concentration <10 mg/L) were recruited between 1997 and 1998 and constitute the PREVEND cohort. All participants completed an extensive examination between 1997 and 1998 (baseline).
For the present analyses, we excluded subjects with history of cardiovascular events (n=458), subjects with renal disease requiring dialysis (n=18), and subjects with missing values of urinary analytes at baseline (n=321), leaving 7,795 participants for the analyses. Of these, 6,313 participants completed a second examination between 2001 and 2003 (Supplemental Figure 1).
The PREVEND study has been approved by the medical ethics committee of the University Medical Center Groningen. 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 (20). In brief, each examination included 2 visits to an outpatient clinic separated by 3 weeks. Before the first visit, all participants completed a self-administered questionnaire regarding demographics, cardiovascular and renal disease history, smoking habits, alcohol consumption, and medication use. Medication use, including antihypertensive drugs, was complemented by information garnered from community pharmacies. During the first visit, participants’ height and weight were assessed. Height was measured to the nearest 0.5 cm. Weight was measured to the nearest 0.5 kg after removing shoes and heavy clothing with a Seca balance scale (Vogel and Halke, Hamburg, Germany). In the last week before the second visit, subjects had to collect 2 consecutive 24-hour specimens after thorough oral and written instruction.
During the urine collection, the participants were asked to avoid heavy exercise as much as possible. Subjects were also instructed to postpone the urine collection in case of urinary tract infection, menstruation, or fever. The collected urine was stored cold (4°C) for a maximum of 4 days before the second visit. After handing in the urine collections, the urine specimens were stored at -20°C. Furthermore, fasting blood samples were provided and stored at -80°C.
Assessment of urinary potassium excretion
Determination of urine potassium concentration was performed on the 24-hour urine specimens of the first (baseline) and second examinations by indirect potentiometry with a MEGA clinical chemistry analyzer (Merck) (21). The potassium concentration in mmol/L was multiplied by the urine volume in liters per 24h to obtain a value in mmol/24h. For each of the 2 examinations, the mean value of the paired 24-hour collections was calculated.
Ascertainment of cardiovascular events
Incident CVD was coded according to the International Classification of Diseases, Ninth Revision, and consisted of the combined incidence of fatal and nonfatal events of IHD, stroke, and vascular interventions such as percutaneous transluminal angioplasty or bypass grafting of aorta and peripheral vessels. IHD events were defined as acute myocardial infarction (code 410), acute and subacute ischemic heart disease (code 411), coronary artery bypass grafting (code 414) or percutaneous transluminal coronary angioplasty. Stroke events were defined as subarachnoid hemorrhage (code 430), intracerebral hemorrhage (code 431), other intracranial hemorrhage (code 432), or occlusion or stenosis of the precerebral (code 433) or cerebral (code 434) arteries. In addition, stroke was subclassified into hemorrhagic strokes (codes 430-431), ischemic strokes (codes 433-434), and unspecified strokes (code 432). Data on fatal CVD were received through the municipal register. Cause of death was obtained by linking the number of the death certificate to the primary cause of death as coded by the Dutch Central Bureau of Statistics. Information on hospitalization for nonfatal CVD was obtained from PRISMANT, the Dutch national registry of hospital discharge diagnoses. The
validity of this database has been shown to be high, with 84% of the primary diagnoses matching the diagnoses found in patient charts (22).
HF was identified using criteria described in the Heart Failure Guidelines of the European Society of Cardiology, and an endpoint adjudication committee ascertained the diagnosis of HF as described elsewhere (23). In addition, HF was subclassified as either HF with a reduced ejection fraction (HFrEF) or HF with a preserved ejection fraction (HFpEF) based on
the left ventricular ejection fraction at the time of diagnosis (left ventricular ejection fraction ≤40 or >50%, respectively) in accordance with the most recent HF guidelines for HFpEF (24). Cardiovascular events were defined as the combined incidence of CVD and heart failure.
Assessment of variables
BMI was calculated as weight (kg) divided by height squared (m2). Smoking status
was categorized as never, former, current (<6, 6-20, or >20 cigarettes/day) and alcohol intake as no/rarely, 1-4 drinks/month, 2-7 drinks/week, 1-3 drinks/day, and ≥4 drinks/day. Education was categorized into low (primary education up to those completing intermediate vocational education), average (higher secondary education), and high (higher vocational education and university). Sodium, magnesium, creatinine and albumin in urine and circulating potassium, sodium, total cholesterol, HDL cholesterol, triglycerides and glucose were determined as previously described (21, 25). During both visits of each examination, blood pressure was assessed on the right arm in supine position every minute for 10 and 8 minutes, respectively, with an automatic Dinamap XL Model 9300 series device (Johnson-Johnson Medical, Tampa, FL). The mean of the last 2 recordings from each visit was used. Type 2 diabetes was defined as a fasting plasma glucose ≥7.0 mmol/L (>126 mg/dL) or the use of glucose-lowering medication (26). Estimated glomerular filtration rate was calculated from the Chronic Kidney Disease Epidemiology Collaboration equation (27).
Statistical analyses
Baseline characteristics are presented according to sex-specific quintiles of urinary potassium excretion. Continuous data are presented as mean with SDs or
as median and IQRs in case of skewed distribution. Categorical data are presented as percentages. Pearson’s product-moment correlation coefficient was calculated for the paired 24-hour urine specimens at the first and second examinations and, for the averaged potassium excretions of the first and the second examinations, as estimates of the intraclass correlation coefficient of reliability R (28).
We analyzed 24-hour urinary potassium excretion as a continuous term (per 26-mmol/24h increase; equivalent to 1 g potassium/day) and in sex-specific quintiles. To study the association between urinary potassium excretion and risk of CVD, IHD, stroke, and HF, we used Cox proportional hazards regression analyses with time-dependent covariates. For events occurring between baseline and the second examination (i.e., between 1997 and 2003), the mean of the 2 baseline 24-hour urinary excretions of potassium (and sodium alike) was used. For events occurring after the second examination (i.e., after 2003), the mean of the 2 baseline and 2 follow-up 24-hour urinary excretions was used, because using cumulative averages of dietary factors yield stronger associations than either only baseline or most recent dietary factors (29). The other covariates in the model were also updated by time-dependent covariates, when available, during follow-up. Nonlinearity was tested by using the likelihood ratio test, comparing nested models with linear or linear and cubic spline terms. Survival time was defined from baseline until the date of last examination that participants attended, the incidence of the cardiovascular event, death, relocation to an unknown destination or 1 January 2009 (end of follow-up). HRs are reported with 95% CIs.
We included covariables in our models as linear variables if appropriate or as categorical if discrete or if their association with cardiovascular events was nonlinear. We first calculated HRs adjusted for age and sex. Second, we calculated multivariable-adjusted HRs (maHRs) which were also adjusted for lifestyle and dietary factors including BMI, smoking, alcohol consumption, education, and 24-hour urinary sodium and magnesium excretion. In addition, in an extra model, we calculated HRs further adjusted for miscellaneous risk factors, including parental history of CVD, lipid-lowering drugs, presence of type 2 diabetes, and biochemical measures, including total to HDL cholesterol ratio, and 24-hour urinary creatinine excretion. In secondary analyses, stroke was subdivided into ischemic, hemorrhagic, and unspecified stroke, whereas HF was subdivided into
HFrEF and HFpEF. We evaluated potential effect modification by age, sex, BMI, smoking, hypertension, and 24-hour urinary sodium and albumin excretion in the analyses of risk of cardiovascular outcomes by fitting models containing both main effects and their cross-product terms. We also tested whether the association of 24-hour urinary potassium excretion with outcomes differed between subjects with low and high potassium excretion (low [<70 mmol/24h] compared with high [ ≥70 mmol/24h]).
To examine the robustness of the findings of the analyses for the association between urinary potassium excretion and risk of CVD, IHD, stroke, and HF, we performed several sensitivity analyses. First, we restricted the analysis of urinary potassium excretion and risk of cardiovascular events to subjects who were not taking antihypertensive drugs at baseline because of the potential mediating effects of blood pressure in the association between urinary potassium excretion and risk of cardiovascular events. Second, we reanalyzed the data excluding subjects with potential inadequate 24-hour urine collections. We defined potential inadequate 24-hour urine collections (i.e., over- or undercollection) as the upper and lower 2.5% of the difference between the estimated and measured volume of a subject’s 24-hour urine sample. The estimated 24-hour urine volume was derived from the formula: creatinine clearance = ([urine creatinine] × 24-hour urine volume)/(serum creatinine), where creatinine clearance was estimated using the Cockcroft-Gault formula (30). 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. Fourth, we performed analyses adjusted for height, weight, or height and weight instead of adjusting for BMI. Finally, in addition to the analyses on urinary potassium excretion and our previous analyses on urinary sodium excretion and risk of IHD (31), we also examined the association between the urinary sodium to potassium excretion ratio and risk of cardiovascular events with time-dependent Cox proportional hazards regression analyses.
All P values are 2-tailed. A P-value <0.05 was considered statistically significant. All analyses were conducted with the use of the statistical package SPSS (version 22.0.1; SPSS Inc.) and RStudio (version 0.98.1091; RStudio).
RESULTS
Median urinary potassium excretion at baseline was 70 mmol/24h (IQR: 56-84 mmol/24h), with a higher value in men (76 mmol/24h; IQR: 63-91 mmol/24h) than in women (65 mmol/24h; IQR: 52-77 mmol/24h). Baseline characteristics are shown according to sex-specific quintiles of urinary potassium excretion (Table 1). At baseline, subjects who had a higher urinary potassium excretion were more likely to be younger, were less likely to smoke, consumed more alcohol, were more highly educated, had a higher BMI, and had a higher 24-hour urinary sodium and magnesium excretion than did subject with a low urinary potassium excretion. The within-subject correlations for potassium excretion between the paired 24-hour urine specimens at the first and second examination were r=0.60 (P<0.0001; n=7,761) and r=0.65 (P<0.0001; N=6,150), respectively. The within-subject correlation between the averaged potassium excretions of the first and the second examinations (separated by a median of 4.3 years; IQR: 4.0-4.9 years) was r=0.51 (P<0.0001; N=6,173).
By January 2009, a total of 1,459 subjects (19%) had been lost to follow-up. Compared with the subjects who remained in the study, those who were lost to follow-up were younger (42.3 ± 11.1 compared with 50.6 ± 12.2 y; P<0.001), had a lower BMI (25.2 ± 4.0 compared with 26.2 ± 4.3 kg/m2; P<0.001), had a
slightly higher urinary excretion of potassium (71 [IQR: 57-85] compared with 70 [IQR: 56-84] mmol/24h; P=0.04), and were less likely to have a urinary albumin concentration ≥10 mg/L (16% compared with 20%; P<0.001). A complete overview of the baseline characteristics of the participants who were lost to follow-up is shown in Supplemental Table 1.
Ta b le 1 . B as el in e ch ar ac te ri sti cs ac co rd in g to se x-sp ec ifi c q u in ti le s o f u ri n ar y p o ta ss iu m ex cr e ti o n in 7, 7 95 p ar ti ci p an ts in th e P R E V EN D s tud y. Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , mm o l/ 24 h P-va lu e f o r tr e n d * Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 P ar ti ci p an ts , N 1, 5 5 8 1, 5 61 1, 5 5 8 1, 5 61 1, 5 5 7 W o m e n , % 51 .3 51 .4 51 .3 51 .4 51 .3 A ge , y 5 0 .6 ± 1 3 .3 5 0 .3 ± 1 2 .6 4 9. 5 ± 1 2 .2 4 8 .4 ± 1 2 .2 4 6 .7 ± 1 1 .2 <0 .0 0 1 P ar e n ta l h is to ry o f C V D , % 34 .3 34 .0 35 .9 35 .4 34 .7 0. 5 6 Sm o ki n g s ta tu s, n e ve r, % 28 .9 27 .4 30 .0 31 .6 32 .7 <0 .0 0 1 A lc o h o l c o n su m p ti o n , n o n e, % 32 .6 25 .8 22 .8 21 .9 19 .3 <0 .0 0 1 Ed u ca ti o n , h ig h , % 21 .1 25 .2 32 .2 35 .2 38 .5 <0 .0 0 1 B M I, k g /m 2 2 5 .8 ± 4 .3 2 5 .9 ± 4 .1 26 .0 ± 4 .0 26 .0 ± 4 .2 26 .5 ± 4 .5 <0 .0 0 1 B lo o d p re ss u re , m m H g Sy st o lic 1 3 0 ± 2 2 1 2 9 ± 2 0 1 2 8 ± 2 0 1 2 8 ± 1 9 1 27 ± 1 8 <0 .0 0 1 Di as to lic 7 5 ± 1 0 74 ± 1 0 74 ± 1 0 7 3 ± 9 7 3 ± 9 <0 .0 0 1 B lo o d p re ss u re -l o w e ri n g d ru gs , % 16 .2 14 .7 13 .4 10 .6 10 .1 <0 .0 0 1 To ta l c h o le st e ro l, m m o l/ L 5 .7 ± 1 .2 5 .7 ± 1 .1 5 .7 ± 1 .2 5 .6 ± 1 .1 5 .5 ± 1 .1 <0 .0 0 1 H D L c h o le st e ro l, m m o l/ L 1 .3 ± 0 .4 1 .3 ± 0 .4 1 .3 ± 0 .4 1 .3 ± 0 .4 1 .3 ± 0 .4 0. 0 0 2 Tr ig ly ce ri d e s, m m o l/ L 1. 2 ( 0.9 -1. 8) 1 .2 ( 0 .8 -1 .7 ) 1. 2 ( 0.9 -1. 7 ) 1 .1 ( 0 .8 -1 .6 ) 1 .1 ( 0 .8 -1 .6 ) <0 .0 0 1 Li p id -l o w e ri n g d ru gs , % 5. 3 4. 5 5. 1 4.4 3. 9 0. 0 8 Glu co se , m m o l/ L 4 .9 ± 1 .1 4 .9 ± 1 .1 4 .9 ± 1 .1 4 .8 ± 1 .0 4 .8 ± 1 .2 0. 2 0 B lo o d g lu co se -l o w e ri n g d ru gs , % 1. 7 1. 2 1. 4 1. 3 1. 3 0. 6 3 eG FR , m L/ m in /1 .7 3 m 2 8 4 ( 7 3 -9 5) 8 4 ( 7 3 -9 4) 8 4 ( 74 -9 6) 8 5 ( 7 5 -9 5) 8 6 ( 76 -9 6) 0. 0 0 6
4
Ta b le 1 . C o n ti n u ed Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , mm o l/ 24 h P-va lu e f o r tr e n d * Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 P la sm a p o ta ss iu m †, m m o l/ L 4 .4 ± 0 .4 4 .4 ± 0 .9 4 .4 ± 0 .8 4 .4 ± 0 .5 4 .4 ± 0 .7 0. 5 5 P la sm a so d iu m †, m m o l/ L 14 2 ± 2 14 2 ± 2 14 2 ± 2 14 2 ± 2 14 2 ± 2 0. 2 9 P la sm a r e n in ‡, µ IU /m L 1 8 ( 1 0 -2 9) 1 8 ( 1 1-2 9) 1 8 ( 1 1-2 9) 1 8 ( 1 1-2 8) 1 8 ( 1 2-27 ) 0. 3 3 P la sm a al d o st e ro n e §, p g /m L 1 1 5 ( 8 9 -1 4 8) 1 1 9 ( 9 5 -1 51 ) 1 1 8 ( 9 3 -1 52 ) 1 17 ( 9 3 -1 5 7 ) 1 2 3 ( 9 6 -1 5 6) 0. 0 0 1 U ri n ar y e xc re ti o n o f Po ta ss iu m , m m o l/ 24 h 4 6 ( 3 9 -5 0 ) 6 0 ( 5 5 -6 5) 6 9 ( 6 4 -7 6) 8 1 ( 74 -8 7 ) 10 0 ( 9 0 -10 9) <0 .0 0 1 So d iu m , m m o l/ 24 h 10 9 ( 8 3 -1 4 0) 12 8 (1 0 2-1 5 8) 14 0 ( 1 1 0 -1 7 2) 14 6 (1 17 -1 7 8) 16 3 ( 1 3 0 -2 0 2) <0 .0 0 1 So d iu m t o p o ta ss iu m r ati o 2 .5 ( 2 .0 -3 .1 ) 2. 1 (1 .7 -2. 6) 2 .0 ( 1 .6 -2 .5 ) 1 .8 ( 1 .5 -2 .2 ) 1 .6 ( 1 .3 -2 .0 ) <0 .0 0 1 C al ci u m , m m o l/ 24 h 3 .0 ( 2 .0 -4 .2 ) 3 .6 ( 2 .4 -4 .9 ) 3. 9 ( 2 .7 -5 .2 ) 4 .1 ( 2 .8 -5 .4 ) 4. 3 ( 3 .1 -5 .8 ) <0 .0 0 1 Ma gn es ium , m m o l/2 4 h 3. 1 ( 2 .3 -3. 8) 3 .6 ( 2 .8 -4 .3 ) 3. 9 ( 3. 1-4 .8 ) 4 .2 ( 3 .3 -5 .1 ) 4 .5 ( 3 .4 -5 .7 ) <0 .0 0 1 Cr e atin ine , m mo l/ 24h 1 0 .0 ( 8 .2 -1 2 .4 ) 1 1 .3 ( 9. 3 -1 3 .7 ) 1 2 .1 ( 1 0 .0 -1 4 .6 ) 1 2 .6 ( 1 0 .2 -1 5 .3 ) 1 3 .6 (1 1 .1 -1 6 .8 ) <0 .0 0 1 Al b u m in , m g /2 4 h 8 .3 ( 5 .5 -1 6 .6 ) 9. 0 ( 6 .0 -1 5 .9 ) 9. 3 ( 6 .5 -1 6 .3 ) 9. 4 ( 6 .5 -1 6 .9 ) 1 0 .1 ( 6 .9 -1 8 .4 ) <0 .0 0 1 C 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: C V D , c ar d io va sc u la r d is e as e; e G FR , e sti m at e d g lo m e ru la r fi lt ra ti o n r at e; P R E V EN D , P re ve n ti o n o f R e n al a n d V as cu la r E n d -s ta ge D is e as e; Q , q u in ti le . * P -t re n d w as d e te rm in e d b y l in e ar -b y-lin e ar as so ci ati o n χ 2 t e st ( ca te go ri ca l v ar ia b le s) o r 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 la b le i n 6 ,6 9 9 s u b je ct s. ‡ Av ai la b le i n 7 ,5 9 6 s u b je ct s. § A va ila b le i n 6 ,9 1 0 su b je ct s.
Ta b le 2 . Ri sk o f ca rd io va sc u la r d is ea se , is ch e m ic h ea rt d is ea se , str o ke , an d n ew -o n se t h ea rt f ai lu re a cc o rd in g to u ri n ar y p o ta ss iu m e xc re ti o n i n 7 ,7 9 5 p ar ti ci p an ts i n t h e P R E V EN D s tu d y. C o n ti n u o u s p o ta ss iu m ex cr e ti o n , p e r 2 6 -m m o l/ 24 h in cr e as e* Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , m m o l/ 2 4 h Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 C a rd io va sc u la r d is e a se Pe rs o n -y e ar s 73 ,1 8 7 14 ,3 4 5 14 ,6 9 0 14 ,6 6 7 14 ,7 3 4 14 ,7 51 Ev e n ts , n 64 1 16 5 14 6 11 6 122 92 A ge - a n d s e x-ad ju st e d H R 0 .8 7 ( 0 .7 8 -0 .9 7 ) 1. 1 9 ( 0 .9 4 -1. 5 0 ) 1. 1 5 ( 0 .9 1-1. 4 6) 1 .0 0 ( re f) 0.9 7 ( 0. 7 5 -1 .2 5) 0. 8 8 ( 0. 6 7-1 .1 5) + L if e st yl e & d ie ta ry f ac to rs -a d ju st e d H R† 0 .9 6 ( 0 .8 5 -1 .0 9) 1 .0 3 ( 0 .8 1-1 .3 1) 1 .0 9 ( 0 .8 6 -1 .3 8) 1 .0 0 ( re f) 0 .9 8 ( 0 .7 6 -1 .2 7 ) 0 .9 2 ( 0 .7 0 -1 .2 2) + A d d iti o n al c ar d io va sc u la r d is e as e r is k f ac to rs -ad ju st e d H R‡ 0.9 6 ( 0. 8 5 -1 .1 0 ) 0.9 9 ( 0. 7 7-1 .2 7 ) 1 .0 7 ( 0 .8 4 -1 .3 6) 1 .0 0 ( re f) 0 .9 6 ( 0 .7 4 -1 .2 3) 0.9 2 ( 0. 6 9 -1 .2 1) Is ch e m ic h e a rt d is e a se Pe rs o n -y e ar s 73 ,82 4 14 ,5 2 8 14 ,8 31 14 ,7 9 5 14 ,8 51 14 ,8 1 9 Ev e n ts , n 46 5 11 7 10 3 88 88 69 A ge - a n d s e x-ad ju st e d H R 0 .8 6 ( 0 .7 5 -0 .9 7 ) 1. 1 9 ( 0 .9 1-1. 5 6) 1 .0 8 ( 0 .8 2-1 .4 2) 1 .0 0 ( re f) 0.9 0 ( 0 .67 -1. 2 1) 0 .8 6 ( 0 .6 2-1 .1 8) + L if e st yl e & d ie ta ry f ac to rs -a d ju st e d H R† 0 .9 0 ( 0 .7 8 -1 .0 4) 1 .0 8 ( 0 .8 1-1 .4 3) 1 .0 4 ( 0 .7 9 -1 .3 7 ) 1 .0 0 ( re f) 0 .8 9 ( 0 .6 6 -1 .2 1) 0 .8 6 ( 0 .6 2-1 .1 9) + A d d iti o n al c ar d io va sc u la r d is e as e r is k f ac to rs ‡ 0.9 0 ( 0. 7 7-1 .0 4) 1 .0 3 ( 0 .7 9 -1 .3 4) 0 .9 7 ( 0 .7 4 -1 .2 8) 1 .0 0 ( re f) 0 .8 4 ( 0 .6 2-1 .1 3) 0 .8 3 ( 0 .5 9 -1 .1 5) St ro ke Pe rs o n -y e ar s 75 ,1 4 0 14 ,8 2 8 15 ,0 8 1 15 ,0 4 3 15 ,0 8 8 15 ,0 9 9 Ev e n ts , n 17 2 48 39 31 32 22 A ge - a n d s e x-ad ju st e d H R 0 .8 5 ( 0 .6 8 -1 .0 6) 1. 3 2 ( 0 .8 3 -2 .1 1) 1 .3 9 ( 0 .8 7-2 .2 1) 1 .0 0 ( re f) 1 .2 2 ( 0 .7 4 -2 .01 ) 1 .0 2 ( 0 .5 9 -1 .7 8)
4
Ta b le 2 . Co n ti n u e d C o n ti n u o u s p o ta ss iu m ex cr e ti o n , p e r 2 6 -m m o l/ 24 h in cr e as e* Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , m m o l/ 2 4 h Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 + L if e st yl e & d ie ta ry f ac to rs -ad ju st e d H R† 1 .0 9 ( 0 .8 6 -1 .3 9) 0 .9 8 ( 0 .6 0 -1 .6 0 ) 1. 2 5 ( 0 .7 8 -1.9 9) 1 .0 0 ( re f) 1 .3 2 ( 0 .8 0 -2 .1 8) 1 .2 2 ( 0 .7 0 -2 .1 4) + A d d iti o n al c ar d io va sc u la r d is e as e r is k f ac to rs -a d ju st e d H R‡ 1 .1 3 ( 0 .8 8 -1 .4 6) 0 .7 6 ( 0 .4 9 -1 .1 8) 0 .8 2 ( 0 .6 7-1 .7 2) 1 .0 0 ( re f) 1. 0 7 ( 0 .67 -1. 7 2) 1 .01 ( 0 .5 9 -1 .7 3) N e w -o n se t h e a rt f a il u re Pe rs o n -y e ar s 75 ,1 8 0 14 ,8 3 0 15 ,0 6 2 15 ,0 7 7 15 ,1 1 1 15 ,1 0 0 Ev e n ts , n 26 5 70 64 44 42 45 A ge -a n d s e x-ad ju st e d H R 0.9 4 ( 0. 8 0 -1 .1 0 ) 1. 3 0 ( 0 .8 8 -1.9 0 ) 1 .4 9 ( 1 .01 -2 .1 9) 1 .0 0 ( re f) 0 .9 4 ( 0 .6 2-1 .4 4) 1. 31 ( 0 .8 6 -2 .0 0 ) + L if e st yl e & d ie ta ry f ac to rs -a d ju st e d H R† 0 .9 7 ( 0 .7 9 -1 .1 8) 1 .5 2 ( 1 .0 0 -2 .3 0 ) 1.9 1 (1. 2 8 -2 .8 6) 1 .0 0 ( re f) 1 .5 1 ( 0 .9 8 -2 .3 1) 1 .4 1 ( 0 .8 9 -2 .2 3) + A d d iti o n al c ar d io va sc u la r d is e as e r is k f ac to rs -a d ju st e d H R‡ 1 .01 ( 0 .8 2-1 .2 5) 1 .4 6 ( 0 .9 6 -2 .2 3) 1 .8 8 ( 1 .2 5 -2 .8 2) 1 .0 0 ( re f) 1 .5 5 ( 1 .01 -2 .3 8) 1 .4 5 ( 0 .9 1-2 .3 0 ) H az ar d r ati o s ( 9 5 % c o n fi d e n ce i n te rv al s) 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 m o d e ls . A b b re vi ati o n s: P R E V EN D , P re ve n ti o n o f R e n al a n d V as cu la r E n d -st ag e D is e as e; Q , q u in ti le . * 2 6 m m o l/ 24 h = 1 g /d ay . † Fu rt h e r a d ju st e d f o r l if e st yl e a n d d ie ta ry f ac to rs , i n cl u d in g B M I, s m o ki n g s ta tu s, a lc o h o l c o n su m p ti o n , e d u ca ti o n , a n d 2 4 -h o u r u ri n ar y s o d iu m a n d m ag n e si u m e xc re ti o n . ‡ Fu rt h e r a d ju st e d f o r a d d iti o n al c ar d io va sc u la r d is e as e r is k f ac to rs , i n cl u d in g p ar e n ta l h is to ry o f ca rd io va sc u la r d is e as e, u se o f l ip id -l o w e ri n g d ru gs , p re se n ce o f t yp e 2 d ia b e te s, t o ta l t o H D L c h o le st e ro l r ati o , a n d u ri n ar y c re ati n in e e xc re ti o n .
Figure 1. Associations between urinary potassium excretion and risk of CVD, IHD, stroke, and new-onset HF
in 7,795 participants in the Prevention of Renal and Vascular End-stage Disease study. Data were fit by a Cox proportional hazards regression model based on restricted cubic splines with 3 knots and adjusted for age, sex, BMI, smoking status, alcohol consumption, education, and 24-hour urinary sodium and magnesium excretion. The figure indicates the multivariable-adjusted associations for risk of CVD (A), IHD (B), stroke (C), and HF (D), respectively. 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 70 mmol/24h. P-values for nonlinear association are P=0.28 for CVD risk, P=0.33 for IHD risk, P=0.99 for risk of stroke, and P=0.46 for risk of HF. HR, hazard ratio.
During a median follow-up of 10.5 years (IQR: 9.9-10.8 years), 641 CVD cases (112 fatal), 465 IHD cases, 172 stroke cases, and 265 HF cases occurred. After adjustment for age and sex, each 1-g/day increment in urinary potassium excretion was associated with a 13% lower risk of CVD (HR, 0.87; 95% CI, 0.78, 0.97; Table 2) and a 14% lower risk of IHD (HR, 0.86; 95% CI, 0.75, 0.97). However, these associations lost significance after multivariable adjustment for age, sex, BMI, smoking status, alcohol consumption, education, and urinary sodium and magnesium excretion for risk of CVD (maHR, 0.96; 95% CI, 0.85, 1.09; Figure 1) and IHD (maHR, 0.90; 95% CI, 0.78, 1.04). No single dietary or lifestyle confounder in particular was responsible for the loss of significance. No statistically significant association of urinary potassium excretion with risk (maHR per 1-g/day increment; 95% CI) of total stroke was observed (1.09; 0.86, 1.39; Figure 1), or with risk of ischemic (1.14; 0.86, 1.51; n=124) or hemorrhagic stroke (1.04; 0.60, 1.83; n=32). Also, no association of urinary potassium excretion with risk (maHR per 1-g/day increment; 95% CI) of HF was observed (0.99; 0.83, 1.18), or with risk of HFrEF (0.95; 0.76, 1.19; n=161) or HFpEF (1.06; 0.79, 1.42; n=104).
There was no evidence of effect modification by age, sex, BMI, smoking behavior, hypertension, 24-hour urinary sodium, albumin, and potassium (low compared with high) excretion in the association between potassium and all 4 cardiovascular outcomes (P-interaction >0.05 for all).
Results of the analyses of urinary potassium and sodium excretion and risk of cardiovascular events, all-cause mortality, and cardiovascular events or all-cause mortality are shown in Supplemental Tables 2-3 and Supplemental Figures 2-3.
When we restricted the analyses to subjects who were not taking antihypertensive drugs at baseline (N=6,781), results for risk (maHR per 1-g/ day increment; 95% CI) of CVD (0.99; 0.86, 1.15; n=431), IHD (0.95; 0.80, 1.13; n=314), stroke (1.02; 0.76, 1.36; n=115), and HF (1.02; 0.81, 1.27; n=159) did not materially change. Also, when we restricted the analyses to subjects with no potential over- or undercollections of 24-hour urine samples (N=7,411), generally similar results were found for risk of CVD (maHR per 1-g/day increment, 0.96; 95% CI, 0.85, 1.00; n=602), IHD (0.89; 0.77, 1.04; n=436), stroke (1.12; 0.88, 1.43; n=166), and HF (1.00; 0.83, 1.20; n=253). 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 potassium excretion and risk (maHR per 1-g/day increment; 95% CI) of CVD (1.10; 0.89, 1.37), IHD (0.92; 0.72, 1.19), stroke (1.56; 0.95, 2.58), and HF (0.93; 0.67, 1.29). When we adjusted the analyses for height, weight, or height and weight as proxy variables to control for variation in food intake instead of BMI, results for the association of urinary potassium excretion with risk of CVD, IHD, stroke, and HF did not materially change (Supplemental Table 4). Finally, the sodium to potassium excretion ratio was not statistically significantly associated with risk of CVD, IHD, stroke, and HF, with maHRs (95% CIs) per 1-unit increment in the ratio of 0.99 (0.90, 1.09), 1.04 (0.95, 1.15), 0.82 (0.65, 1.03), and 1.05 (0.94, 1.16), respectively (Supplemental Table 5 and Supplemental Figures 4-5).
DISCUSSION
In this prospective population-based cohort study with multiple 24-hour urinary collections, urinary potassium excretion was inversely associated with risk of total CVD, and more specifically with risk of IHD, independent of age and sex. These associations were no longer statistically significant after further adjustment for important dietary and lifestyle risk factors. No associations were found between urinary potassium excretion and risk of stroke and HF or specific subtypes of these 2 outcomes.
So far, only one observational study (16) has used multiple 24-hour urine collections — considered the gold standard (12-15)— to assess dietary potassium with risk of cardiovascular events. Similar to our findings, this study found an inverse trend between urinary potassium excretion and risk of CVD (including myocardial infarction, stroke, and revascularizations) among 2974 prehypertensive subjects of the Trials of Hypertension Prevention study (RR per 50-mmol/24h increment in urinary potassium excretion=0.67; 95% CI, 0.41, 1.10), while adjusting for important cardiovascular disease risk factors (16). Furthermore, a study in which potassium excretion was assessed in one 24-hour urine collection found a statistically significant inverse association with risk of IHD in men and a nonsignificant inverse association in women, while only adjusting for age (17).
Moreover, our results of nonsignificant inverse associations between potassium and risk of CVD and IHD are also consistent with the results from 2 meta-analyses (1, 8).
There were no statistically significant associations between urinary potassium excretion and risk of total stroke or specific subtypes of stroke such as ischemic and hemorrhagic stroke, although we had limited power to detect an association with stroke because we had relatively few stroke cases. Meta-analyses of prospective epidemiological studies have shown that potassium intake is associated with a lower risk of stroke (1, 8, 9) particularly ischemic stroke (9, 10), although with substantial heterogeneity between studies (1, 8). Importantly, the few studies that relied on 24-hour urinary potassium excretion to estimate potassium intake either did not separately report on the association of urinary potassium excretion with stroke (17), or reported to not find an inverse association of urinary potassium excretion with stroke, remaining unclear whether the association was positive or absent (16). Furthermore, only a few studies have simultaneously adjusted for intakes of other, highly correlated dietary minerals and observed, similar to our findings, no independent association between dietary potassium and stroke risk after adjustment for magnesium (32) or calcium intake (33).
Dietary potassium may reduce the risk of cardiovascular events through its effects on blood pressure (1, 2). In a meta-analysis of randomized trials, increased potassium intake reduced systolic blood pressure by 3.5 mm Hg among hypertensive subjects (1), and suboptimal dietary potassium appeared to be responsible for some 7% of all incident hypertension cases in our study (2). Elevated blood pressure may explain ~60% of strokes (34), ~50% of HF cases (6, 7), and ~25% of IHD cases (35). Perhaps the role of potassium on elevated blood pressure may have been too small to translate into a subsequent association with risk of cardiovascular events in this study because we may not have had enough power to detect such an association. Alternatively, low potassium excretion may, independent of the established effect on blood pressure (36-38), simply be a marker of a poor dietary quality (39). This may partially explain why the inverse association with risk of CVD was no longer significant after controlling for dietary and lifestyle factors.
It can be hypothesized that the lack of association with cardiovascular events may be due to the on average relatively high potassium intake in our study population, as reflected by the high 24-hour urinary potassium excretion. The median urinary potassium excretion was 70 mmol/24h, which corresponds to a potassium intake of ~90 mmol/day when accounting for a gastrointestinal potassium absorption of 77% (40, 41). This is higher than the intake in 8 out of 9 studies based on dietary recall methods (8) with mean potassium intakes between 45 and 85 mmol/day except for one with an intake of 125 mmol/day (42). Studies specifically using (estimated) 24-hour urinary potassium excretion also reported lower mean amounts ranging from 54 to 60 mmol/24h (16, 43, 44). The latter 2 studies showed increased risks of stroke (43) or death (44) among subjects with an estimated 24-hour potassium excretion <38.5 mmol/24h (1.5 g/day). The relatively high potassium intake observed in the PREVEND study is likely a reflection of habitually high potassium intake in the Netherlands (45). The higher consumption of potassium in the Netherlands compared with the United States, for example, might be explained by a higher consumption of potassium-rich foods, such as milk products, potatoes, and vegetables (45, 46).
Furthermore, next to the relatively high potassium intake, the PREVEND study is oversampled with subject with albuminuria. We tried to eliminate bias that might have been caused by the oversampling of albuminuria by using design-based Cox proportional hazards regression models that took into account the selection by statistical weighing. Results of these sensitivity analyses were materially the same for risk of CVD, IHD, stroke, and HF, indicating that the oversampling of albuminuria does not materially influence the results of our study.
Despite stronger associations with CVD in cross-sectional analyses than sodium or potassium excretion alone (16), we and others (47) did not find a prospective association between the urinary sodium to potassium excretion ratio and risk of CVD. This difference might be explained by the notable higher excretion of urinary sodium and/or lower excretion of urinary potassium in the other studies compared to our study.
Some limitations warrant consideration. First, 4 24-hour urinary collections may not be representative of a participant’s long-term dietary potassium intake. This may have resulted in misclassification of habitual potassium consumption
at the individual level (48) and tends to bias an association toward the null. Second, there might be variation in dietary potassium absorption. In carefully performed balance studies, the mean ± SEM potassium absorption was 77.0% ± 1.7%, consistent with a 95% CI of absorption of 73.7-80.3%, with most extreme values in this report ranging from 64% to 95% (41). Also, ageing of the intestine may have influenced potassium absorption. Third, 19% of the subjects who participated in the first examination did not participate until the end of the study, in large part because of refusal or death. Any survival bias that was introduced might have led to a misclassification of the true association between potassium excretion and risk of cardiovascular events. Fourth, the use of medication (e.g., antihypertensive drugs), could have changed during follow-up, which might have led to bias toward the null. Fifth, like with any observational study, we cannot exclude the possibility of residual confounding. In the PREVEND study, no data on energy intake were available. To control for variation in food intake and to limit residual confounding, we not only adjusted for BMI but also performed secondary analyses in which we included adjustment for height and weight as proxies of variation in food intake. These analyses did not materially influence the results. Finally, our results of no association between urinary potassium excretion and risk of cardiovascular events may not be readily generalizable to different demographic populations because >95% of the individuals of the PREVEND study are white. Blacks, for instance, typically show a lower urinary excretion rate of potassium than do whites (49, 50) due to a higher loss of potassium via other routes, a slower rate of disposal as a result of slower skeletal muscle uptake of potassium, or genetic differences in renal potassium handling (50). Other factors that limit the generalizability of our results are the relatively high potassium intake in the PREVEND study compared with other studies and the oversampling of participants with elevated concentrations of urinary albumin.
A major strength of the study is the use of multiple 24-hour urine collections updated over time to estimate habitual dietary potassium intake. Potassium uptake measured in urine collections tends to have higher repeatability than those based on 24-hour dietary recall (28). The within-subject correlations for the paired 24-hour urine assessments for potassium in this study were similar to or higher than those observed in the International Cooperative Study on Salt, Other
Factors, and Blood Pressure study (51); the Trials of Hypertension Prevention (52); and the Trial of Nonpharmacological Interventions in the Elderly trial (28).
In conclusion, urinary potassium excretion was not independently associated with risk of cardiovascular events in this prospective Dutch cohort, oversampled with subjects with albuminuria and with a relatively high dietary potassium uptake. Despite its effect on blood pressure and its association with risk of stroke observed in previous studies, it remains to be established whether dietary potassium may reduce the risk of other cardiovascular events.
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SUPPLEMENTAL DATA: MATERIALS AND METHODS
Data collectionIn 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. Medication use, including antihypertensive drugs, was complemented by information garnered from community pharmacies. During the first visit, participants’ height and weight were assessed. Height was measured to the nearest 0.5 cm. Weight was measured to the nearest 0.5 kg after removing shoes and heavy clothing, with a Seca balance scale (Vogel and Halke, Hamburg, Germany). In the last week before the second visit, subjects had to collect 2 consecutive 24-hour specimens after thorough oral and written instruction. During the urine collection, the participants were asked to avoid heavy exercise as much as possible. Subjects were also instructed to postpone the urine collection in case of urinary tract infection, menstruation or fever. The collected urine was stored cold (4°C) for a maximum of four days before the second visit. After handing in the urine collections, the urine specimens were stored at -20°C. Furthermore, fasting blood samples were provided and stored at -80°C.
Su p p le m e n ta l Ta b le 1 . Ba se lin e ch ara ct er is ti cs ac co rd in g to se x-sp ec ifi c q u in ti le s o f u ri n ar y p o ta ss iu m ex cr e ti o n in 1, 45 9 p ar ti ci p an ts o f t h e P R E V EN D s tud y w ho w er e lo st t o f o llo w -u p . Va ri a b le s Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , m m o l/ 24 h P-va lu e f o r tr e n d * Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 P ar ti ci p an ts , N 27 8 26 8 30 1 19 9 31 3 W o m e n , % 49 .3 48 .1 54 .2 47 .2 51 .8 A ge , y 4 3 .9 ± 1 2 .2 4 3 .7 ± 1 2 .4 4 2 .6 ± 1 0 .8 41 .7 ± 1 0 .5 4 0 .0 ± 9 .3 <0 .0 0 1 P ar e n ta l h is to ry o f C V D , % 33 .5 31 .7 33 .2 33 .4 30 .7 0. 6 4 Sm o ki n g s ta tu s, n e ve r, % 28 .4 38 .4 36 .9 36 .5 39 .9 <0 .0 0 1 A lc o h o l c o n su m p ti o n , n o n e, % 28 .4 25 .4 15 .6 17 .1 18 .2 <0 .0 0 1 Ed u ca ti o n , h ig h , % 31 .3 39 .2 49 .5 54 .5 51 .4 <0 .0 0 1 B M I, k g /m 2 2 5 .3 ± 4 .3 24 .9 ± 3 .9 2 5 .4 ± 4 .3 24 .8 ± 3 .6 2 5 .5 ± 4 .0 0. 4 3 B lo o d p re ss u re Sy st o lic , m m H g 1 2 6 ± 1 9 1 2 5 ± 1 8 1 24 ± 1 8 1 2 3 ± 1 6 1 24 ± 17 0. 1 8 D ia st o lic , m m H g 7 3 ± 1 0 7 2 ± 1 0 7 1 ± 1 0 7 2 ± 9 7 2 ± 9 0. 1 2 B lo o d p re ss u re -l o w e ri n g d ru gs , % 8. 6 10 .1 11 .6 5. 0 3. 5 0. 0 0 1 To ta l c h o le st e ro l, m m o l/ L 5 .5 ± 1 .2 5 .4 ± 1 .1 5 .4 ± 1 .0 5 .3 ± 1 .0 5 .3 ± 1 .0 0. 0 1 H D L c h o le st e ro l, m m o l/ L 1 .3 ± 0 .4 1. 4 ± 0 .4 1 .3 ± 0 .4 1. 4 ± 0 .4 1. 4 ± 0 .4 0. 0 5 Tr ig ly ce ri d e s, m m o l/ L 1 .1 ( 0 .8 -1 .6 ) 1 .1 ( 0 .8 -1 .5 ) 1 .1 ( 0 .8 -1 .6 ) 1 .1 ( 0 .8 -1 .5 ) 1 .0 ( 0 .8 -1 .4 ) 0. 2 5 Li p id -l o w e ri n g d ru gs , % 2. 5 2. 6 5. 0 1. 0 1. 0 0. 0 8 Glu co se , m m o l/ L 4 .7 ± 0 .9 4 .6 ± 0 .7 4 .6 ± 0 .7 4 .6 ± 0 .8 4 .7 ± 1 .1 0. 8 3 B lo o d g lu co se -l o w e ri n g d ru gs , % 1. 4 0. 0 1. 0 0. 7 0. 6 0. 5 6 eG FR , m L/ m in /1 .7 3 m 2 8 9 ( 7 8 -9 7 ) 8 8 ( 7 8 -9 9) 89 ( 7 7-1 0 0 ) 89 ( 8 0 -1 0 0 ) 9 0 ( 8 0 -1 01 ) 0. 0 2
4
Su p p le m e n ta l T ab le 1 . Co n ti n u ed Va ri a b le s Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , m m o l/ 24 h P-va lu e f o r tr e n d * Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 P la sm a p o ta ss iu m , m m o l/ L † 4.4 ± 0 .6 4.4 ± 0 .4 4 .5 ± 1 .6 4.4 ± 0 .3 4 .5 ± 1 .5 0.9 6 P la sm a s o d iu m , m m o l/ L † 14 2 ± 2 14 2 ± 2 14 2 ± 2 14 2 ± 2 14 2 ± 2 0. 3 8 P la sm a r e n in , µ IU /m L ‡ 1 8 ( 1 1-31 ) 2 0 ( 1 2-31 ) 1 9 ( 1 2-2 9) 1 8 ( 1 2-26 ) 1 8 ( 1 2-27 ) 0. 7 1 P la sm a a ld o st e ro n e, p g /m L § 1 1 8 ( 9 0 -1 47 ) 1 1 8 ( 9 4 -1 5 5) 1 2 2 ( 9 9 -1 5 6) 11 6 ( 92 -1 51 ) 1 2 3 ( 9 7-1 6 2) 0. 2 0 U ri n ar y e xc re ti o n o f: Po ta ss iu m , m m o l/ 24 h 4 6 ( 3 9 -5 1) 6 0 ( 5 5 -6 5) 6 8 ( 6 4 -7 6) 8 2 ( 7 5 -8 7 ) 10 1 ( 9 0 -1 1 0) <0 .0 0 1 So d iu m , m m o l/ 24 h 1 1 0 ( 8 0 -1 4 2) 1 2 6 ( 9 9 -1 5 7 ) 14 1 ( 1 1 0 -1 6 8) 14 7 ( 1 2 1-1 8 1) 16 4 ( 1 27 -1 9 9) <0 .0 0 1 So d iu m t o p o ta ss iu m r ati o 2 .5 ( 1 .9 -3 .1 ) 2. 1 (1 .7 -2. 7 ) 2 .0 ( 1 .6 -2 .4 ) 1 .8 ( 1 .5 -2 .2 ) 1. 6 (1. 3 -1.9 ) <0 .0 0 1 C al ci u m , m m o l/ 24 h 3 .0 ( 2 .0 -4 .2 ) 3 .6 ( 2 .5 -1 .9 ) 3. 9 ( 2 .6 -5 .2 ) 3. 9 ( 2 .7 -5 .2 ) 4. 3 ( 3 .1 -5 .6 ) <0 .0 0 1 Ma gn es ium , m m o l/2 4 h 3. 1 ( 2 .4 -3. 7 ) 3.6 ( 3. 0 -4 .4 ) 3 .9 ( 3 .0 -4 .8 ) 4 .3 ( 3 .3 -5 .1 ) 4. 5 ( 3 .5 -5 .6 ) <0 .0 0 1 Cr e atin ine , m mo l/ 24h 1 0 .3 ( 8 .6 -1 2 .8 ) 1 1 .6 ( 9. 5 -1 4 .0 ) 1 2 .3 (1 0 .4 -1 4 .8 ) 1 2 .8 ( 1 0 .6 -1 5 .9 ) 1 3 .7 ( 1 1 .3 -1 7. 0 ) <0 .0 0 1 Al b u m in , m g /2 4 h 7. 0 ( 5 .2 -1 4 .6 ) 8 .5 ( 6 .0 -1 3 .7 ) 8 .6 ( 6 .4 -1 4 .0 ) 7. 9 ( 6 .1 -1 2 .9 ) 9. 0 ( 6 .6 -1 4 .5 ) <0 .0 0 1 C 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 ± SD o r m e d ia n ( in te rq u ar ti le r an ge ) 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: P R E V EN D , P re ve n ti o n o f R e n al a n d V as cu la r E n d -s ta ge D is e as e; C V D , c ar d io va sc u la r d is e as e; e G FR , e sti m at e d g lo m e ru la r fi lt ra ti o n r at e. * D e te rm in e d b y l in e ar -b y-lin e ar as so ci ati o n c h i-sq u ar e 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 la b le i n 1 ,0 47 s u b je ct s. ‡ Av ai la b le i n 1 ,4 2 5 s u b je ct s. § A va ila b le i n 1 ,2 7 2 s u b je ct s.
Su p p le me n ta l Ta b le 2 . Ha za rd ra ti o s (9 5% co n fi d en ce in te rv al s) fo r ri sk o f co mp o si te o u tc o m es an d all -c au se m o rt ali ty ac co rdi n g to ur in ar y p o ta ss ium e xc re ti o n i n 7 ,7 9 5 p ar ti ci p an ts o f t h 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. C o n ti n u o u s po ta ss iu m ex cr e ti o n , p e r 2 6 m m o l/ 24 h in cr e as e* Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , mm o l/ 24 h Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 C o m p o si te c a rd io va sc u la r o u tc o m e† Pe rs o n -y e ar s 72 ,8 0 3 14 ,2 2 0 14 ,5 9 4 14 ,6 1 5 14 ,6 6 8 14 ,7 0 6 N u m b e r o f e ve n ts 78 5 20 3 17 9 14 4 14 3 11 6 A ge - a n d s e x-ad ju st e d H R 0 .8 8 ( 0 .7 9 -0 .9 8) 1. 2 6 (1. 0 0 -1. 5 6) 1. 1 8 ( 0 .9 4 -1. 47 ) 1 .0 0 ( re f) 1 .0 4 ( 0 .8 2-1 .3 3) 0 .9 7 ( 0 .7 5 -1 .2 6) + L if e st yl e & d ie ta ry f ac to rs -ad ju st e d H R‡ 0.9 5 ( 0 .8 5 -1. 0 7 ) 1. 1 5 ( 0 .9 1-1. 4 5) 1. 14 ( 0 .9 1-1. 4 3) 1 .0 0 ( re f) 1 .0 5 ( 0 .8 3 -1 .3 4) 1. 0 1 ( 0 .7 7-1. 31 ) + A d d iti o n al c ar d io va sc u la r ri sk fa ct o rs -a d ju st e d H R § 0 .9 9 ( 0 .8 8 -1 .1 3) 1 .0 6 ( 0 .8 3 -1 .3 5) 1 .0 9 ( 0 .8 6 -1 .3 7 ) 1 .0 0 ( re f) 1 .0 0 ( 0 .7 8 -1 .2 8) 1 .0 4 ( 0 .8 0 -1 .3 7 ) A ll -c a u se m o rt a li ty Pe rs o n -y e ar s 75 ,7 2 5 14 ,9 9 1 15 ,2 0 9 15 ,15 0 15 ,2 0 9 15 ,1 6 5 N u m b e r o f e ve n ts 493 13 9 10 7 97 82 68 A ge - a n d s e x-ad ju st e d H R 0 .8 0 ( 0 .7 0 -0 .9 1) 1. 4 6 (1. 1 2-1. 8 9) 1 .0 8 ( 0 .8 2-1 .4 3) 1 .0 0 ( re f) 1. 0 4 ( 0 .7 7-1. 4 0 ) 0 .9 6 ( 0 .7 0 -1 .3 3) + L if e st yl e & d ie ta ry f ac to rs -ad ju st e d H R‡ 0 .9 1 ( 0 .7 9 -1 .0 6) 1. 2 1 ( 0 .9 2-1. 5 9) 1. 0 2 ( 0 .7 7-1. 3 5) 1 .0 0 ( re f) 1 .0 6 ( 0 .7 9 -1 .4 3) 1 .0 5 ( 0 .7 5 -1 .4 6) + A d d iti o n al c ar d io va sc u la r ri sk fa ct o rs -a d ju st e d H R § 1 .0 2 ( 0 .8 8 -1 .1 9) 1. 0 7 ( 0 .8 1-1. 42 ) 0 .9 7 ( 0 .7 3 -1 .2 9) 1 .0 0 ( re f) 1 .0 8 ( 0 .8 0 -1 .4 6) 1 .1 4 ( 0 .8 2-1 .5 9) C o m p o si te o u tc o m e ¶ Pe rs o n -y e ar s 72 ,8 0 3 14 ,2 2 0 14 ,5 9 4 14 ,6 1 5 14 ,6 6 8 14 ,7 0 6
4
Su p p le m e n ta l T ab le 2 . C o n ti n u e d C o n ti n u o u s po ta ss iu m ex cr e ti o n , p e r 2 6 m m o l/ 24 h in cr e as e* Se x-sp e ci fi c q u in ti le s o f u ri n a ry p o ta ss iu m e xc re ti o n , mm o l/ 24 h Ma le <5 9 59 -71 72 -8 1 82 -9 5 >9 5 Fe m al e <5 0 50 -6 0 61 -6 9 70 -8 1 >8 1 N u m b e r o f e ve n ts 1, 0 9 9 29 5 23 7 21 0 19 4 16 3 A ge - a n d s e x-ad ju st e d H R 0 .8 6 ( 0 .7 9 -0 .9 4) 1. 27 (1. 0 5 -1. 5 3) 1. 1 3 ( 0.9 3 -1. 37 ) 1 .0 0 ( re f) 0 .9 9 ( 0 .8 1-1 .2 2) 0.9 7 ( 0. 7 7-1 .2 0 ) + L if es ty le & d ie ta ry f ac to rs -a dj u st ed HR ‡ 0.9 5 ( 0 .8 6 -1. 0 5) 1. 1 3 ( 0.9 3 -1. 3 8) 1. 0 9 ( 0.9 0 -1. 3 2) 1 .0 0 ( re f) 1 .01 ( 0 .8 2-1 .2 4) 1 .0 2 ( 0 .8 1-1 .2 7 ) + A d d iti o n al c ar d io va sc u la r ri sk fa ct o rs -a d ju st e d H R § 0 .9 9 ( 0 .8 9 -1 .1 1) 1 .0 4 ( 0 .8 5 -1 .2 7 ) 1 .0 4 ( 0 .8 5 -1 .2 7 ) 1 .0 0 ( re f) 0 .9 7 ( 0 .7 9 -1 .2 0 ) 1 .0 4 ( 0 .8 3 -1 .3 2) H az ar d r ati o s ( 9 5 % c o n fi d e n ce i n te rv al s) 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 m o d e ls . * 2 6 m m o l/ 24 h =1 g /d ay . † C o m p o si te c ar d io va sc u la r o u tc o m e co m p ri se s c ar d io va sc u la r d is e as e ( in cl u d in g i sc h e m ic h e ar t d is e as e a n d s tr o ke ), a n d h e ar t f ai lu re . ‡ Fu rt h e r a d ju st e d f o r l if e st yl e a n d d ie ta ry f ac to rs i n cl u d in g B M I, sm o ki n g s ta tu s, a lc o h o l c o n su m p ti o n , e d u ca ti o n , a n d 2 4 -h o u r u ri n ar y s o d iu m a n d m ag n e si u m e xc re ti o n . § Fu rt h e r a d ju st e d f o r a d d iti o n al c ar d io va sc u la r r is k f ac to rs in cl u d in g p ar e n ta l h is to ry o f c ar d io va sc u la r d is e as e, u se o f l ip id -l o w e ri n g d ru gs , p re se n ce o f t yp e 2 d ia b e te s, t o ta l t o H D L c h o le st e ro l r ati o , a n d u ri n ar y c re ati n in e ex cr e ti on . ¶ C o m p o si te o u tc o m e c o m p ri se s c ar d io va sc u la r d is e as e ( in cl u d in g i sc h e m ic h e ar t d is e as e a n d s tr o ke ), h e ar t f ai lu re , a n d a ll-ca u se m o rt al it y. Su p p le me n ta l Ta b le 3 . Ha za rd ra ti o s (9 5% co n fi d en ce in te rv al s) fo r ri sk o f an d co m p o si te o u tc o m es all -c au se m o rt ali ty ac co rdi n g to ur in ar y s o di um e xc re ti o n i n 7 ,7 9 5 p ar ti ci p an ts o f t h 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. C o n ti n u o u s sod iu m e xc re ti o n , p e r 5 0 m m o l/ 24 h in cr e as e* Se x-sp e ci fi c q u in ti le s o f s o d iu m e xc re ti o n , mm o l/ 24 h Ma le <1 1 5 11 5 -1 41 14 2-1 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 C o m p o si te c a rd io va sc u la r o u tc o m e† Pe rs o n -y e ar s 72 ,8 0 3 14 ,27 8 14 ,5 3 5 14 ,5 41 14 ,6 8 9 14 ,7 6 0 N u m b e r o f e ve n ts 78 5 18 6 15 8 16 5 14 0 13 6 A ge - a n d s e x-ad ju st e d H R 0.9 9 ( 0 .9 1-1. 0 7 ) 1 .0 6 ( 0 .8 5 -1 .3 2) 0 .8 3 ( 0 .6 6 -1 .0 5) 1 .0 0 ( re f) 1 .0 5 ( 0 .8 3 -1 .3 2) 0.9 9 ( 0. 7 7-1 .2 6) + L if e st yl e & d ie ta ry f ac to rs -a d ju st e d H R‡ 0 .9 6 ( 0 .8 7-1 .0 6) 1 .0 2 ( 0 .8 1-1 .2 8) 0 .8 5 ( 0 .6 7-1 .0 7 ) 1 .0 0 ( re f) 1 .0 4 ( 0 .8 2-1 .3 1) 0 .9 0 ( 0 .7 0 -1 .1 6)
