University of Groningen Sodium and potassium intake as determinants of cardiovascular and renal health Kieneker, Lyanne Marriët

Sodium and potassium intake as determinants of cardiovascular and renal health

Kieneker, Lyanne Marriët

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CHAPTER 5

Low potassium excretion but not high

sodium excretion is associated with

increased risk of developing chronic

kidney disease

ABSTRACT

Background: It is unclear whether sodium and potassium intake is relevant to

the development of chronic kidney disease (CKD) in the general population. Our aim was to examine the associations of urinary sodium and potassium excretion, as estimates of intake, with risk of developing CKD in a population-based cohort.

Methods: We studied 5,315 individuals free of CKD at baseline of the Prevention

of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 28 to 75 years. Urinary sodium and potassium excretion were measured in 2 24-hour urine specimens at baseline (1997-1998) and midway during follow-up (2001-2003). CKD was defined as de novo development of eGFR under 60 ml/min/1.73 m2 _{or albuminuria over}

30 mg/24h.

Results: Baseline urinary sodium and potassium excretion were 135 mmol/24h

(interquartile range, 106-169 mmol/24h) and 70 mmol/24h (interquartile range, 57-85 mmol/24h), respectively. During a median follow-up of 10.3 years, 872 subjects developed CKD. After multivariable adjustment for important covariables, no association was observed between urinary sodium excretion and risk of CKD (hazard ratio per 50 mmol/24h [1 SD] increment, 0.97; 95% confidence interval, 0.89-1.06). Each 21 mmol/24h (1 SD) decrement in urinary potassium excretion was significantly associated with a 16% higher risk of developing CKD (multivariable-adjusted hazard ratio, 1.16; 95% confidence interval, 1.06-1.28).

Conclusions: Low urinary potassium excretion, and not high urinary sodium

excretion, was associated with an increased risk of developing CKD in a population-based cohort with normal kidney function.

INTRODUCTION

Chronic kidney disease (CKD) is a major public health problem, with adverse outcomes of kidney failure, cardiovascular disease, and premature death (1). The increasing prevalence and incidence of CKD is mostly due to increasing prevalence of obesity, type II diabetes, and hypertension (1). Particularly, reduction of elevated blood pressure is fundamental in preventing and slowing the progression of CKD.

High dietary sodium and low dietary potassium intake is associated with higher blood pressure levels (2-4) and with the risk of hypertension (5, 6). Whether high dietary sodium, or low dietary potassium, or both may also affect the risk of initiation or progression of CKD is uncertain. Some (7, 8), but not all (9-11), studies among patients with CKD have shown that high dietary sodium may increase the risk of CKD progression.

Longitudinal studies in populations with a relatively preserved kidney function, however, have generally observed null associations of sodium intake (12, 13) and inverse associations with potassium intake (12-14) with risk of renal outcomes (i.e., incident CKD, changes in estimated glomerular filtration rate [eGFR] or albuminuria, or end-stage renal disease). Importantly, all these cohorts included high-risk populations, that is, subjects with established CKD, vascular disease, or diabetes mellitus. Furthermore, almost all these studies assessed sodium and potassium intake with either a food frequency questionnaire (12), a spot urine (13), or a single 24-hour urine sample (14). These tools are less objective and precise to estimate dietary sodium and potassium compared with multiple 24-hour urine samples, which is considered to be the criterion standard (15-18).

Therefore, the aim of our study was to prospectively examine the associations between urinary sodium and potassium excretion —measured in multiple 24-hour urine samples— and the risk of developing CKD among participants free of CKD at baseline in a population-based cohort study.

MATERIALS AND METHODS

Study design and population

The PREVEND study is designed to prospectively investigate the natural course of increased levels of urinary albumin excretion (UAE) and its relation with renal and cardiovascular outcomes in a large cohort drawn from the general population. Details of this study have been described elsewhere (29). A flow chart of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study is shown in Supplemental Figure 1. In brief, from 1997 to 1998, all inhabitants of Groningen, the Netherlands, aged 28 to 75 years (N=85,421), were sent a short questionnaire on demographic characteristics and renal and cardiovascular morbidity and a vial to collect a first morning void urine sample. Altogether, 40,856 people (48%) responded and their urinary albumin concentration was assessed. Two subgroups were derived from this population. First, we identified 9,966 individuals who had a urinary albumin concentration of ≥10 mg/L, and after exclusion of pregnant women and subjects with type I diabetes mellitus, 7,768 subjects were invited to participate, of whom 6,000 were enrolled. Second, we identified 30,890 people with a urinary albumin concentration <10 mg/L and after exclusion of pregnant women and subjects with type I diabetes mellitus, a randomly selected group was invited to participate in the cohort, of whom 2,592 were enrolled. These 8,592 individuals form the PREVEND cohort and completed an extensive examination in 1997 and 1998 (baseline).

For the present analyses, we excluded subjects with CKD at baseline or unknown CKD status (n=1,921), with renal disease requiring dialysis (n=11), with missing values of urinary analytes (n=5), with no follow-up data available for CKD (n=1,207), and with missing values of body measurements at baseline (n=133), leaving 5,315 participants for the analyses. All these participants completed a second examination between 2001 and 2003.

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 (30). 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 characteristics, 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 (31). During the first visit, participants’ height and weight were assessed. During each examination and during each visit, blood pressure was measured on the right arm, every minute for 10 and 8 minutes, respectively, by an automatic Dinamap XL Model 9300 series device (Johnson-Johnson Medical, Tampa, FL). The mean of the last 2 recordings from each of the 2 visits was used. In the last week before the second visit, subjects collected 2 consecutive 24-hour specimens after thorough oral and written instruction. In this instruction, the participants were asked to avoid heavy exercise as much as possible during the urine collection and 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 handing in the urine collections, whereafter aliquots of these urine specimens were stored at -20°C. Furthermore, fasting blood samples were provided and stored at -80°C.

Assessment of urinary sodium and potassium excretion

Urine sodium and potassium concentrations were determined on the 2 24-hour urine specimens of the first (baseline) and on the 2 24-hour urine specimens on the second examination by indirect potentiometry with a MEGA clinical chemistry analyzer (Merck, Darmstadt, Germany) (32). The sodium and potassium concentrations in mmol/L were multiplied by the urine volume in L/24-hour to obtain values in mmol per 24 hours. For each of the 2 examinations, the average value of the paired 24-hour collections was calculated.

Ascertainment of CKD

The primary outcome of CKD was defined as a combination of reaching an eGFR <60 ml/min per 1.73 m2 _{or an UAE >30 mg per 24h de novo, or both (33).}

We estimated glomerular filtration rate with the combined creatinine cystatin C-based Chronic Kidney Disease Epidemiology Collaboration equation from 2012, taking into account age, sex, and race (34). UAE was multiplied by urine volume to obtain a value in mg per 24-hour. The 2 24-hour UAE values of each subject per examination were averaged. Data on both measurements were collected during follow-up every 3 to 5 years.

Measurement of serum creatinine was performed by an isotope dilution mass spectrometry traceable enzymatic method on a Roche Modular analyzer using reagents and calibrators from Roche (Roche Diagnostics, Mannheim, Germany), with intraassay and interassay coefficients of variation of 0.9% and 2.9%, respectively. Serum cystatin C concentrations were measured by Gentian Cystatin C Immunoassay (Gentian AS, Moss, Norway) on a Modular analyzer (Roche Diagnostics). Cystatin C was calibrated directly using the standard supplied by the manufacturer (traceable to the International Federation of Clinical Chemistry Working Group for Standardization of Serum Cystatin C) (35). The intraassay and interassay coefficients of variation were <4.1% and <3.3%, respectively. Urinary albumin concentration was measured by nephelometry with a threshold of 2.3 mg/l, and intraassay and interassay coefficients of variation of 2.2% and 2.6%, respectively (Dade Behring Diagnostic, Marburg, Germany).

Assessment of covariates

Smoking status was defined as self-reported never smoker, former smoker, or current smoker (<6, 6–20, or >20 cigarettes/day). Parental history of CKD was defined as having a first-degree relative who had a renal disease requiring dialysis for >6 weeks. Educational level was defined as low (primary education or intermediate vocational education), middle (higher secondary education), and high (higher vocational education and university). Hypertension was defined as systolic blood pressure of ≥140 mm Hg, a diastolic blood pressure of ≥90 mm Hg, or both, or the use of antihypertensive agents as previously described (6, 36).

Concentrations of total cholesterol, high-density lipoprotein cholesterol, triglycerides and glucose were determined as previously described (19, 37). Type II diabetes was defined as a fasting plasma glucose ≥7.0 mmol/L (>126 mg/dL) or the use of glucose-lowering drugs (38). Plasma N-terminal pro-B-type natriuretic peptide was measured on the Roche Modular E170 (Roche Diagnostics) with commercially available kits as previously described (39).

Statistical analyses

Baseline characteristics are presented according to sex-specific quintiles of urinary potassium and sodium excretion. Continuous data are presented as mean with standard deviation (SD) or as median and interquartile range (IQR) in case of skewed distribution. Categorical data are presented as percentiles.

Twenty-four hour urinary sodium and potassium excretion were analyzed as a continuous term per 1-SD increment (per 50 mmol/24h and per 21 mmol/24h, respectively) and in sex-specific quintiles. To study the prospective association between urinary sodium and potassium excretion and the risk of developing CKD, Cox proportional hazards regression analyses with time-dependent variables were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). For events occurring between baseline and the second examination (i.e., between 1997-2003), the average of the 2 baseline 24-hour urinary excretions of sodium and potassium were used. For events occurring after the second examination (i.e., after 2003), the average 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 (40). 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.

We first calculated HRs adjusted for age and sex. Secondly, we additionally adjusted for established renal risk factors including height, weight, smoking status, alcohol consumption, parental history of CKD, race, diabetes, and urinary potassium excretion (in the urinary sodium excretion analyses) or urinary sodium excretion (in the urinary potassium excretion analyses), and urinary urea,

creatinine, and calcium excretion. Finally, we additionally adjusted for baseline eGFR and UAE to calculate multivariable-adjusted HRs (maHRs). In secondary analyses, CKD incidence was defined by either an eGFR <60 ml/min/1.73 m2 _or

UAE >30mg/24h alone.

In case we found a significant association between urinary potassium or sodium excretion and the risk of developing CKD, we evaluated potential effect modification by sex, age, smoking, hypertension, urinary potassium or sodium excretion, and N-terminal pro-B-type natriuretic peptide by fitting models containing both main effects and their cross-product terms. To further check whether there was a potential interaction of urinary sodium excretion in the association of urinary potassium excretion with the risk of CKD, we created 4 groups using the median urinary potassium and sodium excretion as a cut-off, categorized as low (below median) or high (above median). The 4 groups consisted of subjects with low urinary sodium excretion and low urinary potassium excretion, low urinary sodium excretion and high urinary potassium excretion (reference), high urinary sodium excretion and low urinary potassium excretion, and high urinary sodium excretion and high urinary potassium excretion.

Several sensitivity analyses were performed to examine the robustness of the associations between urinary sodium and potassium excretion and the risk of CKD. First, we excluded subjects at baseline with an eGFR <66 (instead of <60) ml/min per 1.73 m2_{, or a UAE >25 (instead of >30) mg/24h, or both, for a more}

pronounced decline in kidney function over time to reach the primary outcome of CKD. Second, we analyzed the association of urinary potassium and sodium excretion with the risk of CKD, defined as an eGFR decline ≥30%, without excluding subjects with CKD at baseline. Third, we restricted the analyses of urinary sodium and potassium excretion and the risk of CKD to subjects who were not using antihypertensive drugs at baseline because of the potential mediating effects of blood pressure in the association between urinary sodium and potassium excretion and the risk of CKD. Fourth, we reanalyzed the data excluding subjects with potential inadequate 24-hour urine collections. We defined potential inadequate 24-hour urine collections (i.e., overcollection 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 (41). Fifth, 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. Sixth, we adjusted for body mass index as measure of adiposity instead of for height and weight in the multivariable model. Finally, in addition to the analyses on urinary sodium and urinary excretion, we examined the association between the urinary sodium to potassium excretion ratio and the risk of developing CKD 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 IBM SPSS (version 22; SPSS, Chicago, IL) and Rstudio (version 0.98.1091; Rstudio, Boston, MA).

RESULTS

Baseline median urinary sodium and potassium excretion were 135 mmol/24h (IQR: 106-169 mmol/24h) and 70 mmol/24h (IQR: 57-85 mmol/24h), respectively. Baseline characteristics are presented according to sex-specific quintiles of urinary potassium excretion (Table 1). At baseline, subjects in the highest sex-specific quintile of urinary potassium excretion were younger, had a higher eGFR, and had a higher UAE compared with subjects in the lowest quintile of urinary potassium excretion. Furthermore, subjects who had a higher urinary potassium excretion were more likely than subjects with a low urinary potassium excretion to be white, less likely to smoke and consumed more alcohol and sodium than subjects with a low urinary potassium excretion. Baseline characteristics according to sex-specific quintiles of urinary sodium excretion are presented in Supplemental Table 1. At baseline, subjects in the highest sex-specific quintile of urinary sodium excretion, were younger, had a higher eGFR, and had a higher UAE compared to subjects in the lowest quintile of urinary sodium excretion.

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 p o ta ss ium e xc re ti o n o f 5, 31 5 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. 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 o u r χ 2 o r t -s ta ti sti c* P-va lu e f o r t re n d † Ma le <6 0 60 -7 1 72 -8 2 83 -9 5 >9 5 Fe m al e <5 1 51 -6 0 61 -6 9 70 -8 1 >8 1 P ar ti ci p an ts , N 1, 0 6 5 1, 0 61 1, 0 6 3 1, 0 6 4 1, 0 6 2 W o m e n , % 52 .6 52 .5 52 .5 52 .5 52 .5 A ge , y 4 9. 7 ± 1 2 .4 4 9. 3 ± 1 1 .9 4 8 .4 ± 1 1 .6 47 .9 ± 1 1 .7 4 6 .3 ± 1 0 .7 -6 .9 8 8 <0 .0 0 1 R ac e, w h it e s, % 89 .4 96 .5 96 .6 98 .3 99 .2 96 .9 6 8 <0 .0 0 1 P ar e n ta l h is to ry o f C K D , % 2. 0 2. 1 1. 2 1. 0 1. 0 6. 2 31 0. 0 1 Sm o ki n g s ta tu s, n e ve r, % 29 .7 27 .9 31 .9 32 .7 35 .2 43 .2 8 1 <0 .0 0 1 A lc o h o l c o n su m p ti o n , n o n e, % 29 .4 25 .7 21 .6 21 .1 18 .1 38 .5 0 7 <0 .0 0 1 Ed u ca ti o n , h ig h , % 22 .7 29 .0 34 .9 37 .2 39 .8 111 .9 37 <0 .0 0 1 H e ig h t, c m 17 1 ± 1 0 17 2 ± 9 17 3 ± 1 0 17 4 ± 9 17 5 ± 9 12 .0 6 6 <0 .0 0 1 W e ig h t, k g 74 .8 ± 1 3 .3 7 5 .9 ± 1 3 .1 7 7. 0 ± 1 3 .1 7 7. 6 ± 1 3 .6 8 0 .4 ± 1 4 .0 10 .1 6 7 <0 .0 0 1 Sy st o lic b lo o d p re ss u re , m m H g 1 27 ± 2 0 1 2 6 ± 1 8 1 2 5 ± 1 7 1 2 5 ± 1 8 1 2 5 ± 1 7 -2 .1 5 4 0. 0 3 D ia st o lic b lo o d p re ss u re , m m H g 7 3 ± 1 0 7 3 ± 9 7 2 ± 9 7 2 ± 9 7 3 ± 9 -2 .3 4 4 0. 0 2 A n ti h yp e rt e n si ve d ru gs , % 15 .2 12 .4 12 .3 9. 4 9. 7 20 .20 9 <0 .0 0 1 A C EI s/ A R B s, % 4. 0 3. 5 4. 1 2. 5 2. 7 6. 4 5 3 0. 0 1 T h ia zi d e d iu re ti cs , % 2. 7 2. 1 2. 4 1. 0 2. 6 0. 7 9 7 0. 37 Lo o p d iu re ti cs , % 0.9 0. 4 0. 4 0. 4 0. 3 2. 0 2 5 0. 16 Po ta ss iu m -s p ar in g d iu re ti cs , % 1. 0 1. 1 0.9 1. 5 0. 2 1. 27 8 0. 26 To ta l c h o le st e ro l, m m o l/ L 5 .7 ± 1 .2 5 .6 ± 1 .1 5 .6 ± 1 .1 5 .5 ± 1 .1 5 .5 ± 1 .1 -4 .9 1 9 <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 .4 ± 0 .4 1 .4 ± 0 .4 1 .4 ± 0 .4 3.6 6 3 <0 .0 0 1 Tr ig ly ce ri d e s, m m o l/ L 1. 2 ( 0.9 -1. 7 ) 1 .1 ( 0 .8 -1 .6 ) 1 .1 ( 0 .8 -1 .6 ) 1 .1 ( 0 .8 -1 .5 ) 1 .1 ( 0 .8 -1 .6 ) -5 .2 8 9 <0 .0 0 1

Ta b le 1 . Co n ti n u e d 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 o u r χ 2 o r t -s ta ti sti c* P-va lu e f o r t re n d † Ma le <6 0 60 -7 1 72 -8 2 83 -9 5 >9 5 Fe m al e <5 1 51 -6 0 61 -6 9 70 -8 1 >8 1 Li p id -l o w e ri n g d ru gs , % 6. 4 5. 6 5. 9 4. 5 3. 5 10 .1 7 0 0. 0 0 1 D ia b e te s, % 1. 7 1. 7 1. 2 1. 2 1. 3 1. 1 2 0 0. 2 9 Glu co se , m m o l/ L 4 .8 ± 0 .9 4 .7 ± 0 .9 4 .7 ± 0 .8 4 .7 ± 0 .8 4 .7 ± 1 .0 -0 .6 61 <0 .0 0 1 G lu co se -l o w e ri n g d ru gs , % 0.9 0. 7 1. 2 0. 8 0. 8 <0 .0 0 1 0.9 3 HOM A -I R 1 .5 8 ( 1 .0 7-2 .5 9) 1 .5 6 ( 1 .0 8 -2 .3 9) 1 .5 9 ( 1 .1 1-2 .4 2) 1 .5 4 ( 1 .0 3 -2 .3 2) 1 .5 8 ( 1 .0 6 -2 .4 0 ) -2 .1 76 0. 0 3 e G FR , m L/ m in /1 .7 3 m ² 9 7 ( 8 3 -1 0 7 ) 9 7 ( 8 6 -1 0 7 ) 9 8 ( 8 7-1 0 9) 9 9 ( 8 8 -1 0 9) 10 0 ( 8 9 -10 9) 6. 1 2 9 <0 .0 0 1 P la sm a p o ta ss iu m , m m o l/ L‡ 4 .3 ± 0 .4 4 .4 ± 0 .7 4 .4 ± 0 .9 4 .4 ± 0 .9 4 .4 ± 0 .7 3. 0 9 4 0. 0 0 2 P la sm a so d iu m , m m o l/ L‡ 14 2 ± 3 14 2 ± 2 14 2 ± 2 14 2 ± 2 14 2 ± 2 -1 .7 41 0. 0 8 P la sm a N T-p ro B N P, p g /m L 3 8 .0 (1 7. 1-74 .8 ) 3 6 .7 ( 17 .0 -6 9. 1) 3 2 .6 ( 14 .8 -6 3 .9 ) 3 4 .2 ( 1 5 .9 -6 5 .1 ) 3 2 .1 ( 14 .6 -5 7. 9) -4 .8 5 7 <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 o u r 47 ( 4 0 -5 1) 6 0 ( 5 6 -6 6) 6 9 ( 6 5 -7 7 ) 8 1 ( 74 -8 8) 9 9 ( 9 0 -1 0 8) 14 7. 3 5 7 <0 .0 0 1 So d iu m , m m o l/ 24 -h o u r 11 0 ( 8 4 -1 4 0 ) 12 7 (1 0 2-1 5 8) 1 37 ( 1 0 8 -1 7 1) 14 4 (1 17 -1 76 ) 16 1 ( 1 2 9 -1 9 8) 26 .0 6 3 <0 .0 0 1 So d iu m t o p o ta ss iu m r ati o 2. 45 (1 .9 4 -3 .0 4) 2. 1 0 (1 .7 1-2. 5 7 ) 1.9 7 (1. 5 8 -2 .4 1) 1 .8 1 ( 1 .4 5 -2 .1 9) 1. 5 8 (1. 3 0 -1.9 6) -3 1 .4 9 1 <0 .0 0 1 C al ci u m , m m o l/ 24 -h o u r 3. 1 ( 2 .1 -4 .3 ) 3.6 ( 2 .5 -5 .0 ) 4 .0 ( 2 .8 -5 .2 ) 4 .1 ( 2 .8 -5 .4 ) 4. 3 ( 3 .1 -5 .7 ) 13 .8 4 6 <0 .0 0 1 Ma gn es ium , m m o l/2 4 -h o ur 3. 1 ( 2 .4 -3. 8) 3 .6 ( 2 .9 -4 .4 ) 4 .0 ( 3 .1 -4 .9 ) 4. 1 ( 3 .2 -5 .1 ) 4.4 ( 3 .4 -5 .5 ) 21 .7 1 8 <0 .0 0 1 U re a m m o l/ 24 -h o u r 27 2 ( 2 2 1-3 24 ) 31 9 ( 27 0 -3 8 1) 3 5 4 ( 3 0 0 -4 16 ) 37 2 ( 31 7-4 3 2) 42 4 ( 3 61 -4 9 7 ) 42 .1 7 2 <0 .0 0 1 Cr e atin ine , m mo l/ 24 -hou r 1 0 .0 ( 8 .4 -1 2 .5 ) 1 1 .3 ( 9. 3 -1 3 .8 ) 1 2 .1 ( 1 0 .0 -1 4 .5 ) 1 2 .4 ( 1 0 .1 -1 5 .3 ) 1 3 .4 ( 1 1 .0 -1 6 .6 ) 25 .0 63 <0 .0 0 1 Al b u m in , m g /2 4 -h o u r 7. 3 ( 5 .3 -1 1 .3 ) 8. 0 ( 5 .7 -1 1 .8 ) 8 .3 ( 6 .1 -1 1 .9 ) 8 .5 ( 6 .3 -1 3 .0 ) 8 .7 ( 6 .5 -1 3 .1 ) 9. 0 1 6 <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 ( 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 C EI , a n gi o te n si n -c o n ve rti n g-e n zy m e i n h ib it o r; A R B , a n gi o te n si n r e ce p to r b lo ck e r; C K D , c h ro n ic k id n e y 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; H D L, h ig h -d e n si ty l ip o p ro te in ; H O M A -I R , h o m e o st ati c m o d e l a ss e ss m e n t i n su lin r e si st an ce ; N T-p ro B N P, N -t e rm in al p ro -B -t yp e n at ri u re ti c p e p ti d e. * χ 2 s ta ti sti c p re se n te d f o r c at e go ri ca l v ar ia b le s an d t -s ta ti sti c f o r c o n ti n u o u s v ar ia b le s ( tr ig ly ce ri d e s, g lu co se , H O M A -I R , p la sm a p o ta ss iu m , p la sm a s o d iu m , p la sm a N T-p ro B N P, s o d iu m t o p o ta ss iu m r ati o , a n d u ri n ar y a lb u m in e xc re ti o n w e re l o g-tr an sf o rm e d t o c al cu la te t -s ta ti sti cs a n d P -v al u e s f o r t re n d ). † 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 (c o n ti n u o u s v ar ia b le s) . ‡ Av ai la b le i n 4 ,9 6 7 s u b je ct s.

5

Both eGFR and UAE were regularly measured at baseline and at several follow-up screening waves, of which the first took place at a median follow-up of 4.1 years (IQR: 4.0-4.4 years), the second at 6.4 years (IQR: 6.1-6.8 years), the third at 9.2 years (IQR: 8.9-9.6 years), and the fourth at 11.6 years (IQR: 11.2-12.6 years).

During a median follow-up of 10.3 years (IQR: 6.2-11.4 years), 872 subjects developed CKD. No significant deviations from linearity were detected for the associations between urinary sodium excretion and the risk of developing CKD (Figure 1A, C, and E). There was no association between urinary sodium excretion and the risk of developing CKD after adjustment for age and sex (HR per 50 mmol/24h increment [1-SD]), 1.01; 95% CI, 0.94-1.09; Table 2), or after additional adjustment for weight, height, smoking, alcohol consumption, family history of CKD, race, diabetes, and 24-hour urinary potassium, calcium, urea, and creatinine excretion, and baseline eGFR and UAE (maHR, 0.97; 95% CI, 0.89-1.07). Secondary analyses, in which CKD incidence was defined as development of either eGFR <60 ml/min/1.73 m2 _{or UAE >30 mg/24h alone, rendered essentially similar}

results (Table 2).

Figure 1 (on next page). Associations of urinary sodium and potassium excretion with the risk of chronic

kidney disease in 5,315 participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. Data were fit by time-dependent Cox proportional hazards regression models based on restricted cubic splines with 3 knots and adjusted for age, sex, height, weight, smoking status, alcohol consumption, parental history of CKD, race, education, and urinary sodium (in the potassium analyses), potassium (in the sodium analyses), calcium, urea, and creatinine excretion, and baseline eGFR and UAE. Left panels represent the associations of urinary sodium excretion with risk of CKD, defined as eGFR_{creatinine-cystatin C} <60 ml/min/1.73 m2_{, or UAE >30 mg/24h, or both (A), eGFR}

creatinine-cystatin C <60 ml/min/1.73 m

2 _{(C), and UAE >30 mg/24h (E). Right}

panels represent the associations of urinary potassium excretion with risk of CKD, defined as eGFR_{creatinine-cystatin}

C <60 ml/min/1.73 m

2_{, or UAE >30 mg/24h, or both (B), eGFR}

creatinine-cystatin C <60 ml/min/1.73 m

2 _{(D), and UAE >30}

mg/24h (F). The gray areas indicate the 95% confidence intervals (CIs). The spline curve is truncated at the 0.5th _{and 99.5}th _{percentile of the distribution curve. Reference standard for sodium was 135 mmol/24h and}

for potassium 70 mmol/24h. P-values for nonlinear association are P=0.72 for part A, P=0.93 for B, P=0.99 for C, P=0.99 for D, P=0.87 for E, and P=0.91 for F. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; maHR, multivariable adjusted hazard ratio; UAE, urinary albumin excretion.

Figure 1. Figure legend on previous page.

Ta b le 2 . A ss o ci ati o n o f u ri na ry s o di um e xc re ti o n w it h t he r is k o f c hr o ni c k id ne y d is ea se in 5 ,3 15 s ub je ct s o f t he P re ve nti o n o f R en al a nd V as cu la r En d -S ta ge D is ea se (P R EV EN D ) s tu d y. C o n ti n u o u s u ri n a ry s o d iu m ex cr e 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 u ri n a ry s o d iu m e xc re ti o n , m m o l/ 24 h Ma le <1 14 11 4 -1 4 0 14 1-1 6 5 16 6 -1 9 9 > 1 9 9 Fe m al e <9 0 90 -1 1 0 111 -1 31 13 2-1 5 9 > 1 5 9 eG FR cr e a ti n in e -c ys ta ti n C o f < 6 0 m l/ m in /1 .7 3 m 2 o r U A E o f > 3 0 m g /2 4 h Pe rs o n -y e ar s 47 ,1 52 9, 0 37 9, 2 8 6 9, 5 4 6 9, 5 0 9 9, 7 7 3 N u m b e r o f e ve n ts 87 2 19 8 17 4 16 8 17 3 15 9 A ge - a n d s e x-ad ju st e d H R 1. 0 1 ( 0 .9 4 -1. 0 9) 1 .0 9 ( 0 .8 8 -1 .3 4) 1. 1 6 ( 0 .9 4 -1. 4 3) 1 .0 0 ( re f) 1. 1 3 ( 0.9 1-1. 4 0 ) 1. 1 5 ( 0 .9 2-1. 4 2) Mul ti va ria b le HR † 0 .9 8 ( 0 .8 9 -1 .0 7 ) 1 .0 7 ( 0 .8 5 -1 .3 4) 1. 1 8 ( 0 .9 5 -1. 4 6) 1 .0 0 ( re f) 1. 14 ( 0 .9 2-1. 4 2) 1 .0 6 ( 0 .8 3 -1 .3 4) Mul ti va ria b le HR ‡ 0 .9 7 ( 0 .8 9 -1 .0 6) 1. 1 3 ( 0.9 0 -1. 4 2) 1. 27 (1. 0 2-1. 5 7 ) 1 .0 0 ( re f) 1. 2 0 ( 0 .9 6 -1. 5 0 ) 1. 1 0 ( 0 .8 7-1. 4 0 ) eG FR cr e a ti n in e -c ys ta ti n C o f < 6 0 m l/ m in /1 .7 3 m 2 Pe rs o n -y e ar s 50 ,3 5 8 9, 6 4 2 9, 9 4 0 10 ,1 26 10 ,1 8 7 10 ,4 6 4 N u m b e r o f e ve n ts 29 1 83 62 64 47 35 A ge - a n d s e x-ad ju st e d H R 0. 8 8 ( 0. 7 7-1 .0 1) 1 .4 3 (1 .0 0 -2 .0 3) 1. 3 8 ( 0 .9 6 -1.9 8) 1 .0 0 ( re f) 1. 1 5 ( 0 .7 6 -1. 7 2) 1. 16 ( 0 .7 6 -1. 76 ) Mul ti va ria b le HR † 0 .9 8 ( 0 .8 2-1 .1 7 ) 1 .2 6 ( 0 .8 6 -1 .8 4) 1. 3 6 ( 0 .9 4 -1.9 7 ) 1 .0 0 ( re f) 1. 3 0 ( 0 .8 6 -1.9 8) 1. 2 3 ( 0. 7 7-1.9 6) Mul ti va ria b le HR ‡ 0 .9 7 ( 0 .8 0 -1 .1 7 ) 1 .3 6 ( 0 .9 1-2 .0 2) 1 .5 6 ( 1 .0 7-2 .2 8) 1 .0 0 ( re f) 1 .3 8 ( 0 .9 1-2 .1 1) 1 .4 5 ( 0 .9 1-2 .3 3) U A E o f > 3 0 m g /2 4 h Pe rs o n -y e ar s 50 ,6 17 9, 7 5 7 9, 9 5 2 10 ,3 1 5 10 ,1 9 0 10 ,4 0 3 N u m b e r o f e ve n ts 67 2 13 5 13 2 12 1 14 7 13 7 A ge - a n d s e x-ad ju st e d H R 1. 1 1 (1. 0 2-1. 2 0 ) 0 .8 8 ( 0 .6 8 -1 .1 2) 1 .0 4 ( 0 .8 2-1 .3 2) 1 .0 0 ( re f) 1. 1 9 ( 0 .9 4 -1. 51 ) 1. 1 8 ( 0 .9 3 -1. 51 )

Ta b le 2 . C o n ti nu ed . C o n ti n u o u s u ri n a ry s o d iu m ex cr e 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 u ri n a ry s o d iu m e xc re ti o n , m m o l/ 24 h Ma le <1 14 11 4 -1 4 0 14 1-1 6 5 16 6 -1 9 9 > 1 9 9 Fe m al e <9 0 90 -1 1 0 111 -1 31 13 2-1 5 9 > 1 5 9 Mul ti va ria b le HR † 1. 0 1 ( 0 .9 1-1. 1 1) 0 .9 4 ( 0 .7 2-1 .2 3) 1 .0 9 ( 0 .8 6 -1 .4 0 ) 1 .0 0 ( re f) 1 .1 7 ( 0 .9 2-1 .4 8) 1 .0 4 ( 0 .8 0 -1 .3 5) Mul ti va ria b le HR ‡ 0 .9 8 ( 0 .8 9 -1 .0 8) 0 .9 6 ( 0 .7 4 -1 .2 6) 1. 1 5 ( 0 .9 0 -1. 4 6) 1 .0 0 ( re f) 1. 1 5 ( 0 .9 0 -1. 4 6) 1 .01 ( 0 .7 8 -1 .3 1) H az ar d r ati o s a n d 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 r e gr e ss io n m o d e ls . A b b re vi ati o n s: C K D , c h ro n ic k id n e y 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; H R , h az ar d r ati o ; U A E, u ri n ar y a lb u m in e xc re ti o n . * 5 0 m m o l= 1 S D . † M o d e l a d ju st e d f o r a ge , s e x, h e ig h t, w e ig h t, s m o ki n g st at u s, a lc o h o l c o n su m p ti o n , p ar e n ta l h is to ry o f C K D , r ac e, d ia b e te s, a n d u ri n ar y p o ta ss iu m , c al ci u m , u re a a n d c re ati n in e e xc re ti o n . ‡ M o d e l f u rt h e r a d ju st e d f o r b as e lin e e G FR a n d U A E.

5

No significant deviations from linearity were detected for the associations between urinary potassium excretion and risk of developing CKD (Figure 1B, D, and F). Each 21 mmol/24h (1-SD) decrement in urinary potassium excretion was significantly associated with a higher risk of developing CKD (HR, 1.11; 95% CI, 1.03-1.19; Table 3), independent of age and sex. After additional adjustment for baseline eGFR, UAE, weight, height, smoking, alcohol consumption, family history of CKD, race, diabetes, and 24-hour urinary excretion of sodium, calcium, urea, and creatinine, each 21 mmol/24h decrement in urinary potassium excretion remained independently associated with a 16% higher risk of developing CKD (maHR, 1.16; 95% CI, 1.06-1.28; Figure 1). There were no material changes in the inverse association between urinary potassium excretion and risk of CKD after additional adjustment for potential intermediate variables of this association, including systolic blood pressure and antihypertensive drugs (maHR, 1.15; 95% CI, 1.05-1.27), or plasma potassium (maHR, 1.16; 95% CI, 1.05-1.28). Secondary analyses, in which CKD incidence was defined as development of either eGFR <60 ml/min/1.73 m2 _{or UAE}

>30 mg/24h alone, rendered essentially similar results (Table 3).

The association of urinary potassium excretion with CKD risk was modified by baseline hypertension status (P_interaction=0.03): urinary potassium excretion had a stronger association with development of CKD in subjects with hypertension (maHR, 1.25; 95% CI, 1.09-1.43) than in subjects without hypertension (maHR, 1.08; 95% CI, 0.95-1.24). In addition, when further examining the possibility of modification of the effect of urinary potassium excretion on the risk of developing CKD by urinary sodium excretion, we observed no indication of this when examined as a cross-product term of urinary sodium and potassium excretion as continuous variables (P_interaction=0.14), or when grouped as low or high on the basis of median (P_interaction =0.91; Supplemental Table 2). We also did not find evidence for effect modification by sex, age, smoking and N-terminal pro-B-type natriuretic peptide (all P_interaction>0.4).

Ta b le 3 . A ss o cia ti o n o f ur in ar y p o ta ss ium e xc re ti o n w it h th e ri sk o f chr o n ic ki dn ey di se as e in 5, 31 5 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. C o n ti n u o u s u ri n a ry p o ta ss iu m ex cr e ti o n , p e r 2 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 p o ta ss iu m e xc re ti o n , m m o l/ 24 h Ma le <6 0 60 -7 1 72 -8 2 83 -9 5 >9 5 C K D d e fi n iti o n Fe m al e <5 1 51 -6 0 61 -6 9 70 -8 1 >8 1 eG FR cr e a ti n in e -c ys ta ti n C o f < 6 0 m l/ m in /1 .7 3 m 2 o r U A E o f > 3 0 m g /2 4 h Pe rs o n -y e ar s 47 ,1 52 8, 8 8 5 9, 3 3 0 9, 4 47 9, 5 0 9 9, 9 8 1 N u m b e r o f e ve n ts 87 2 21 4 17 1 17 1 16 8 14 8 A ge - a n d s e x-ad ju st e d H R 1. 1 1 (1. 0 3 -1. 1 9) 1. 17 ( 0 .9 6 -1. 4 2) 0 .8 4 ( 0 .6 8 -1 .0 4) 1 .0 0 ( re f) 0.9 3 ( 0. 76 -1 .1 5) 0 .8 6 ( 0 .6 9 -1 .0 7 ) Mul ti va ria b le HR † 1. 1 2 (1. 0 2-1. 2 3) 1. 14 ( 0 .9 2-1. 4 2) 0 .8 5 ( 0 .6 9 -1 .0 5) 1 .0 0 ( re f) 0.9 4 ( 0. 76 -1 .1 6) 0 .8 4 ( 0 .6 7-1 .0 7 ) Mul ti va ria b le HR ‡ 1. 1 6 (1. 0 6 -1. 2 8) 1. 2 2 ( 0.9 8 -1. 5 2) 0 .8 5 ( 0 .6 8 -1 .0 5) 1 .0 0 ( re f) 0.9 5 ( 0 .7 7-1. 1 8) 0. 8 2 ( 0. 6 4 -1 .0 3) eG FR cr e a ti n in e -c ys ta ti n C o f < 6 0 m l/ m in /1 .7 3 m 2 Pe rs o n -y e ar s 50 ,3 5 8 9, 5 8 5 9, 8 9 6 10 ,0 9 9 10 ,2 0 1 10 ,5 7 8 N u m b e r o f e ve n ts 29 1 87 73 46 49 36 A ge - a n d s e x-ad ju st e d H R 1. 3 0 (1. 1 3 -1. 4 9) 1. 3 8 (1. 0 0 -1.9 1) 0 .8 9 ( 0 .6 3 -1 .2 8) 1 .0 0 ( re f) 0 .9 3 ( 0 .6 5 -1 .3 4) 0 .5 8 ( 0 .3 7-0 .9 1) Mul ti va ria b le HR † 1. 2 0 (1. 0 1-1. 4 2) 1 .2 0 ( 0 .8 3 -1 .7 3) 0 .8 7 ( 0 .6 0 -1 .2 5) 1 .0 0 ( re f) 0 .9 9 ( 0 .6 8 -1 .4 3) 0 .6 1 ( 0 .3 8 -0 .9 8) Mul ti va ria b le HR ‡ 1. 1 5 ( 0 .9 6 -1. 3 8) 1. 3 2 ( 0 .9 0 -1.9 3) 1 .0 9 ( 0 .7 5 -1 .5 8) 1 .0 0 ( re f) 1 .2 6 ( 0 .8 6 -1 .8 5) 0. 8 2 ( 0. 51 -1 .3 4) U A E o f > 3 0 m g /2 4 h Pe rs o n -y e ar s 50 ,6 17 9, 6 0 0 10 ,0 14 10 ,1 14 10 ,2 2 3 10 ,6 6 6 N u m b e r o f e ve n ts 67 2 15 1 12 1 14 2 13 6 122 A ge - a n d s e x-ad ju st e d H R 1. 0 4 ( 0.9 6 -1. 1 3) 0 .9 9 ( 0 .7 9 -1 .2 4) 0 .7 9 ( 0 .6 2-1 .01 ) 1 .0 0 ( re f) 0 .8 6 ( 0 .6 8 -1 .0 9) 0 .8 8 ( 0 .7 0 -1 .1 2) Mul ti va ria b le HR † 1. 1 1 (1. 0 0 -1. 2 3) 1 .0 6 ( 0 .8 3 -1 .3 7 ) 0 .8 3 ( 0 .6 5 -1 .0 5) 1 .0 0 ( re f) 0 .8 4 ( 0 .6 6 -1 .0 6) 0 .8 4 ( 0 .6 5 -1 .0 8) Mul ti va ria b le HR ‡ 1. 1 5 (1. 0 4 -1. 2 8) 1 .1 2 ( 0 .8 7-1 .4 3) 0 .8 0 ( 0 .6 2-1 .0 2) 1 .0 0 ( re f) 0 .8 2 ( 0 .6 5 -1 .0 4) 0. 7 7 ( 0. 5 9 -0.9 9) H az ar d r ati o s a n d 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 r e gr e ss io n m o d e ls . A b b re vi ati o n s: C K D , c h ro n ic k id n e y 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; H R , h az ar d r ati o ; U A E, u ri n ar y a lb u m in e xc re ti o n . * 2 1 m m o l= 1 S D . † M o d e l a d ju st e d f o r a ge , s e x, h e ig h t, w e ig h t, s m o ki n g st at u s, a lc o h o l c o n su m p ti o n , p ar e n ta l h is to ry o f C K D , r ac e, d ia b e te s, a n d u ri n ar y s o d iu m , c al ci u m , u re a a n d c re ati n in e e xc re ti o n . ‡ M o d e l f u rt h e r a d ju st e d f o r b as e lin e e G FR a n d U A E.

5

Sensitivity analyses

Results were essentially the same when we excluded subjects with an eGFR <66 (instead of <60) ml/min/1.73m2_{, or a UAE <25 (instead of <30) mg/24h at baseline}

(N=5,066, n=703) for a more pronounced decline in kidney function during follow-up before reaching the CKD end point for urinary sodium excretion (maHR, 0.95; 95% CI, 0.85-1.05) and urinary potassium excretion (maHR, 1.17; 95% CI, 1.05-1.30). Second, we analyzed the association of urinary potassium and sodium excretion with the risk of CKD, defined as a decline ≥30% in eGFR and without excluding subjects with CKD at baseline (N=6,217, n=311, see Supplemental Table 3 for baseline characteristics). Results were not essentially different (urinary sodium excretion: maHR, 0.98; 95% CI, 0.84-1.15; urinary potassium excretion: maHR, 1.21; 95% CI, 1.03-1.43). Third, when we restricted the analyses to subjects who were not using antihypertensive drugs at baseline (N=4,687, n=626), results for the risk of CKD did not materially change (urinary sodium excretion: maHR, 1.06; 95% CI, 0.95, 1.18; urinary potassium excretion: maHR, 1.16 95% CI, 1.04-1.30). Also, when we restricted the analyses to subjects with no potential overcollection or undercollection of 24-hour urine samples based on differences in expected and observed 24-hour urinary creatinine excretions (N=5,051, n=821), generally similar results were found for the risk of CKD (urinary sodium excretion: maHR, 0.99; 95% CI, 0.90-1.09; urinary potassium excretion: maHR, 1.17; 95% CI, 1.06-1.29). In weighted analyses that accounted for the sampling design of the study, results were not essentially different (urinary sodium excretion: maHR, 0.90; 95% CI, 0.75-1.09, urinary potassium excretion: maHR, 1.35; 95% CI, 1.10-1.65). When adjusting for body mass index instead of adjusting for height and weight, similar results were observed for risk of CKD for urinary sodium excretion (maHR, 0.97; 95% CI, 0.89-1.06) and urinary potassium excretion (maHR, 1.16; 95% CI, 1.06-1.28). Finally, the urinary sodium to potassium excretion ratio was not associated with the risk of CKD (maHR per 1-unit increment, 1.01; 95% CI, 0.95-1.08; Supplemental Table 4).

DISCUSSION

In this prospective population-based cohort study, low urinary potassium excretion, as an estimate of low potassium intake, was associated with a higher risk of developing CKD. The inverse association of urinary potassium excretion with the risk of developing CKD remained after adjustment for confounders, CKD risk factors, and potential mediators of the association such as systolic blood pressure, antihypertensive medication, and plasma potassium. We did not observe an association of urinary sodium excretion, as an estimate of sodium intake, with the risk of developing CKD.

The inverse association between repeated 24-hour urinary potassium excretion with the risk of developing CKD —based on eGFR <60 ml/min/1.73 m2_,

microalbuminuria, or both— confirm and extend previous data of prospective cohort studies on potassium intake, based on a single (estimated) 24-hour urine sample or food frequency questionnaire (12-14). Also, the few prospective observational studies that have investigated the association between potassium intake and the risk of renal outcomes (i.e., incident CKD, end-stage renal disease, or changes in eGFR or proteinuria) were all performed among high-risk populations, that is, subjects with established CKD, vascular diseases, or diabetes mellitus, or all (8, 12-14) instead of a more population-based cohort.

Although, as previously reported (19), there was a significant cross-sectional association of urinary sodium excretion with albuminuria, we did not find a prospective association between repeated 24-hour urinary sodium excretion and the risk of CKD, based on de novo eGFR <60 ml/min/1.73 m2 _{and microalbuminuria,}

or one of both variables alone. Our present findings are in line with other data of longitudinal cohort studies examining the association of sodium intake — based on a spot urine or food frequency questionnaire— with the risk of renal outcomes among subjects with a relatively preserved kidney function(12-14). Although studies among subjects with established CKD observed a positive association between repeated 24-hour urinary sodium excretion and the risk of CKD progression (7, 8) other studies —based on a single baseline 24-hour urinary sodium excretion— reported null associations (10, 11). The inconsistency between studies among patients with CKD using multiple 24-hour urinary sodium excretion

versus a single 24-hour urinary sodium excretion to assess dietary sodium may underscore the importance of using repeated 24-hour urinary sodium excretion. Less-frequent measurements introduce mainly random error and reduce statistical precision and are more likely to bias relationships toward the null.

Baseline median urinary potassium excretion in this study was 70 mmol/24h, which corresponds to a potassium intake of approximately 90 mmol/day when accounting for a gastrointestinal potassium absorption of 77% (20, 21). The 2002 Joint World Health Organization/Food and Agriculture Organization Expert Consultation recommends a potassium intake of >3,500 mg/day (20). Despite the fact that approximately 50% of the subjects of the PREVEND study would have been classified as having a potassium intake below this recommendation, subjects of the PREVEND study have a relatively high intake of potassium compared with subjects of other cohort studies (13, 14, 22). Our data are in line with the recommendation for a potassium intake of 3,500 mg/d, as subjects with a urinary potassium excretion lower than 70 mmol/24h (intake of ~90 mmol/24h or ~3,500 mg/day) had a higher risk of developing CKD.

The mechanisms by which urinary potassium excretion may influence the risk of developing CKD remain unclear. A high potassium intake may increase plasma potassium, which is reported to reduce renal vascular resistance and increase glomerular filtration rate (23). As another possible mechanism, low potassium intake could increase blood pressure (2, 4, 6), which, in turn, might increase the risk of developing CKD. However, when we additionally adjusted for plasma potassium, or systolic blood pressure, the association of urinary potassium excretion with CKD remained similar, suggesting that other mechanisms are responsible for the inverse associations of urinary potassium excretion with the risk of CKD. A mechanism that has been proposed involves induction of tubulointerstitial injury by ammoniagenesis caused by potassium deficiency, which has been observed in animal experimental models (24, 25). Furthermore, urinary potassium excretion itself might be renoprotective by upregulating renal kinins, such as kallikrein (26). Data on urinary ammonia excretion and plasma kallikrein were not available in the PREVEND study, so we could not investigate these possible mechanisms. Alternatively, high urinary potassium excretion may simply be a marker of healthy dietary patterns that are rich in potassium (e.g., high consumption of fruit and

vegetables). A possible biological explanation for the finding of an association of urinary potassium excretion with the risk of CKD in subjects with hypertension and the absence of an association in subjects without hypertension might be that hypertensive subjects have an increased risk of developing CKD due to the longer exposure to hypertension-induced renal damage, including endothelial dysfunction and oxidative stress (27). Hypertensive subjects may therefore be more prone to the renal consequences of a low potassium intake.

Some limitations of this study should be noted. 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, which may have weakened the associations that were observed. Second, in the PREVEND study, information on diet was obtained from 24-hour urine collections. This is a reductionist approach with the ability to only account for one or a few nutrients. A more comprehensive diet assessment could have considered the entire dietary pattern, which may be associated with urinary potassium excretion. Also, we did not have information on total calorie intake, which may be a confounder. Third, information on potassium supplements was not available, so we could not distinguish between dietary and supplemental potassium intake. Fourth, as with any observational study, there may be unmeasured or residual confounding. Finally, we could not investigate all previously proposed mechanisms potentially explaining the association of urinary potassium excretion with the risk of incident CKD because data on urinary ammonia excretion and plasma kallikrein were not available in the PREVEND study.

A major strength of our study is that, to our knowledge, this study is the first to prospectively investigate the association of urinary sodium and potassium excretion with the risk of CKD in a population-based cohort. A second strength of this 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). A third strength of this study is the combined CKD end point consisting of a creatinine-cystatin C-based eGFR and 2 consecutive 24-hour UAE at each screening to ascertain CKD events. 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 including dietary factors.

In conclusion, low urinary potassium excretion was associated with a higher risk of developing CKD in this prospective population-based cohort. This association appeared to be independent of dietary and nondietary factors and was more pronounced in subjects with hypertension. A higher consumption of potassium, while concurrently not exceeding dietary recommendations on sodium intake, may be a promising approach for the primary prevention of CKD in subjects with normal kidney function. Despite its effect on blood pressure, it remains to be established whether higher sodium intake may increase the risk of developing CKD.

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Su p p le m e n ta l T ab 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 5, 31 5 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. 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 s o d iu m e xc re ti o n , m m o l/ 24 -h o u r χ 2 o r t-st a ti sti c* P -va lu e fo r tre n d † Ma le <1 14 11 4 -1 4 0 14 1-1 6 5 16 6 -1 9 9 >1 9 9 Fe m al e <9 0 90 -1 1 0 111 -1 32 13 3 -1 5 9 >1 5 9 P ar ti ci p an ts , N 1, 0 6 2 1, 0 6 4 1, 0 6 2 1, 0 6 5 1, 0 6 2 W o m e n , % 52 .5 52 .5 52 .4 52 .6 52 .2 A ge , y 5 0 .0 ± 1 2 .5 4 9. 1 ± 1 2 .1 4 8 .6 ± 1 1 .8 47 .7 ± 1 1 .3 4 6 .2 ± 1 0 .5 -8 .0 1 6 <0 .0 0 1 R ac e, w h it e s, % 94 .9 95 .7 96 .4 97 .1 95 .9 1. 6 3 2 0. 2 0 P ar e n ta l h is to ry o f C K D , % 1. 5 1. 6 0. 5 1.9 1.9 0. 7 8 5 0. 3 8 Sm o ki n g s ta tu s, c u rr e n t, % 38 .2 29 .5 32 .8 28 .8 29 .8 14 .8 9 2 0. 0 0 3 A lc o h o l c o n su m p ti o n , n o n e, % 25 .5 23 .6 22 .8 22 .8 21 .2 1. 61 7 0. 2 0 Ed u ca ti o n , h ig h , % 33 .5 35 .7 33 .1 33 .4 28 .0 6. 6 3 0 0. 0 1 H e ig h t, c m 17 2 ± 1 0 17 3 ± 9 17 3 ± 9 17 4 ± 9 17 5 ± 9 7. 0 9 3 <0 .0 0 1 W e ig h t, k g 7 3 ± 1 3 74 ± 1 2 7 7 ± 1 3 7 8 ± 1 3 8 3 ± 1 5 18 .18 2 <0 .0 0 1 Sy st o lic b lo o d p re ss u re , m m H g 1 2 6 ± 2 0 1 2 6 ± 1 8 1 2 6 ± 1 8 1 2 6 ± 1 7 1 2 6 ± 2 74 -0 .6 8 1 0. 5 0 D ia st o lic b lo o d p re ss u re , m m H g 7 3 ± 9 7 3 ± 9 7 3 ± 9 7 3 ± 9 7 3 ± 9 -0 .4 0 8 0. 6 8 A n ti h yp e rt e n si ve d ru gs , % 14 .3 11 .6 11 .6 10 .8 10 .8 6.0 9 0 0. 0 1 A C Ei /A R B , % 3.6 2. 2 3. 5 4. 2 3. 3 1. 24 6 0. 26 T h ia zi d e d iu re ti cs , % 2. 0 2. 2 1. 6 2. 3 2. 7 0. 7 76 0. 3 8 Lo o p d iu re ti cs , % 0. 5 0. 1 0. 4 0. 8 0. 7 1. 4 9 1 0. 2 2 Po ta ss iu m -s p ar in g d iu re ti cs , % 0. 5 1. 0 1. 3 0.9 0.9 0. 3 6 3 0. 5 5 To ta l c h o le st e ro l, m m o l/ L 5 .6 ± 1 .1 5 .5 ± 1 .1 5 .6 ± 1 .1 5 .6 ± 1 .1 5 .6 ± 1 .1 0. 3 5 5 0. 7 2 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 .3 ± 0 .4 -0 .2 61 0. 7 9 Tr ig ly ce ri d e s, m m o l/ L 1 .1 1 ( 0 .8 2-1 .5 6) 1 .0 8 ( 0 .7 9 -1 .5 9) 1 .1 0 ( 0 .8 0 -1 .5 8) 1 .0 9 ( 0 .7 9 -1 .6 0 ) 1 .1 5 ( 0 .8 5 -1 .6 6) 2. 1 1 9 0. 0 3

Su p p le m e n ta l T ab le 1 . Co n ti n u e d 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 s o d iu m e xc re ti o n , m m o l/ 24 -h o u r χ 2 o r t-st a ti sti c* P -va lu e fo r tre n d † Ma le <1 14 11 4 -1 4 0 14 1-1 6 5 16 6 -1 9 9 >1 9 9 Fe m al e <9 0 90 -1 1 0 111 -1 32 13 3 -1 5 9 >1 5 9 Li p id -l o w e ri n g d ru gs , % 5. 6 5. 9 5. 0 5. 2 4. 2 2. 4 9 3 0. 1 1 D ia b e te s, % 1. 1 0. 8 1.9 2. 0 1. 3 1. 7 0 6 0. 1 9 Glu co se , m m o l/ L 4 .7 ± 0 .7 4 .7 ± 0 .8 4 .7 ± 1 .0 4 .8 ± 1 .1 4 .8 ± 0 .8 4. 3 0 0 <0 .0 0 1 G lu co se -l o w e ri n g d ru gs , % 0. 8 0. 8 0.9 0.9 0.9 0. 0 9 4 0. 76 HOM A -I R 1 .4 1 ( 0 .9 6 -2 .1 1) 1 .5 1 ( 1 .0 6 -2 .2 9) 1 .5 5 ( 1 .0 8 -2 .3 8) 1 .6 1 (1 .1 1-2 .4 8) 1. 76 (1. 17 -2 .7 7 ) 9. 0 8 0 <0 .0 0 1 e G FR , m L/ m in /1 .7 3 m ² 9 6 ( 8 4 -1 0 7 ) 9 7 ( 8 7-1 0 7 ) 9 8 ( 8 6 -1 0 8) 9 9 ( 8 8 -1 0 9) 10 1 ( 9 0 -10 9) 8. 14 3 <0 .0 0 1 P la sm a p o ta ss iu m , m m o l/ L‡ 4 .4 ± 0 .8 4 .4 ± 0 .7 4 .4 ± 1 .1 4 .3 ± 0 .3 4 .4 ± 0 .5 0. 4 6 8 0. 6 4 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 -3. 4 8 2 0. 0 0 1 P la sm a N T-p ro B N P, p g /m L 39 .7 (1 7. 5 -7 8 .6 ) 3 4 .9 ( 1 6 .6 -6 5 .8 ) 3 5 .1 (1 6 .3 -6 6 .8 ) 3 2 .5 ( 14 .3 -6 2 .3 ) 31 .5 ( 14 .6 -5 8 .5 ) -5 .4 9 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 o u r 5 9 ( 47 -7 3) 6 6 ( 5 5 -8 1) 7 0 ( 5 9 -8 4) 7 5 ( 6 3 -8 8) 8 1 ( 6 6 -9 5) 25 .7 6 7 <0 .0 0 1 So d iu m , m m o l/ 24 -h o u r 8 3 ( 7 1-9 7 ) 11 0 (1 0 0 -1 2 8) 1 31 ( 1 2 1-1 5 3) 1 5 7 ( 14 3 -1 7 8) 20 8 (1 7 9 -2 3 3) 13 4 .5 24 <0 .0 0 1 So d iu m t o p o ta ss iu m r ati o 1. 4 (1. 1-1. 7 ) 1 .7 ( 1 .4 -2 .1 ) 1.9 (1. 7-2 .3 ) 2 .2 ( 1 .8 -2 .5 ) 2. 6 ( 2. 2-3 .1 ) 38 .6 38 <0 .0 0 1 C al ci u m , m m o l/ 24 -h o u r 2. 9 (1 .9 -3 .9 ) 3.6 ( 2 .5 -4 .6 ) 3 .9 ( 2 .8 -5 .0 ) 4. 3 ( 3 .0 -5 .6 ) 4 .7 ( 3 .4 -6 .2 ) 26 .0 1 5 <0 .0 0 1 Ma gn es ium , m m o l/2 4 -h o ur 3 .3 ( 2 .4 -4 .1 ) 3.6 ( 2 .8 -4 .6 ) 3 .9 ( 3 .0 -4 .9 ) 4 .1 ( 3 .3 -5 .0 ) 4 .3 ( 3 .2 -5 .3 ) 16 .9 17 <0 .0 0 1 U re a m m o l/ 24 -h o u r 27 6 ( 2 2 1-3 3 4) 31 4 ( 27 0 -3 8 2) 34 8 ( 2 9 8 -4 0 9) 37 7 ( 3 2 2-4 4 0 ) 42 2 ( 3 6 0 -4 9 1) 41 .1 3 3 <0 .0 0 1 Cr e atin ine , m mo l/ 24 -hou r 9. 9 (8 .3 -1 2 .7 ) 11 .1 ( 9. 3 -1 3 .6 ) 1 1 .8 ( 9. 9 -1 4 .4 ) 1 2 .4 ( 1 0 .3 -1 5 .5 ) 1 3 .5 ( 1 1 .2 -1 6 .6 ) 26 .6 5 0 <0 .0 0 1 Al b u m in , m g /2 4 -h o u r 7. 2 ( 5 .3 -1 1 .1 ) 7. 9 ( 5 .8 -1 2 .0 ) 8. 0 ( 6 .0 -1 1 .7 ) 8 .5 ( 6 .3 -1 2 .3 ) 9. 1 ( 6 .6 -1 3 .3 ) 7. 1 2 0 <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 ( 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: AC Ei , an gi o te n si n -c o n ve rti n g-e n zy m e i n h ib it o r; A R B , a n gi o te n si n r e ce p to r b lo ck e r; C K D , c h ro n ic k id n e y 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; H D L, h ig h -d e n si ty l ip o p ro te in ; H O M A -I R , h o m e o st ati c m o d e l a ss e ss m e n t i n su lin r e si st an ce ; 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. * χ 2 s ta ti sti c p re se n te d f o r c at e go ri ca l v ar ia b le s a n d t -s ta ti sti c f o r c o n ti n u o u s v ar ia b le s ( tr ig ly ce ri d e s, g lu co se , H O M A -I R , p la sm a p o ta ss iu m , p la sm a N T-p ro B N P, a n d s o d iu m t o p o ta ss iu m r ati o w e re l o g-tr an sf o rm e d t o c al cu la te t -s ta ti sti cs a n d P -v al u e s f o r t re n d ). † 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 va ri ab le s) . ‡ A va ila b le i n 4 ,9 6 7 s u b je ct s.

5

Supplemental Table 2. Association of urinary sodium and urinary potassium grouped

as low or high based on the median with risk chronic kidney disease in 5,315 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study.

Group Urinary sodium excretion/ urinary potassium excretion

N/n maHR (95% CI)*†

Low urinary sodium excretion/

Low urinary potassium excretion

<135 mmol/24h/

<70 mmol/24h 1,702/297 1.21 (0.98-1.50)

Low urinary sodium excretion/

High urinary potassium excretion

<135 mmol/24h/

≥70 mmol/24h 940/139 1.00 (ref)

High urinary sodium excretion/

Low urinary potassium excretion

≥135 mmol/24h/

<70 mmol/24h) 901/150 1.15 (0.91-1.46)

High urinary sodium excretion/

High urinary potassium excretion

≥135 mmol/24h/

≥70 mmol/24h 1,767/285 0.98 (0.79-1.21)

Multivariable adjusted hazard ratios (maHRs) and 95% confidence intervals (CIs) were derived from Cox proportional hazards regression models. Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; UAE, urinary albumin excretion. * maHR for risk of CKD (eGFRcreatinine-cystatin C

<60 ml/min/1.73m2 _{or UAE >30 mg/24h) per 21 mmol/24h increment of urinary potassium excretion. †}

Model adjusted for age, sex, height, weight, smoking status, alcohol consumption, parental history of chronic kidney disease, race, diabetes, urinary calcium, urea and creatinine excretion, and baseline eGFR and UAE.

Sup p le m e n ta l T ab le 3. Ba se lin e ch ara ct er is ti cs a cc o rd in g to q u in ti le s o f u ri n ar y po ta ss iu m e xc re ti o n o f 6 ,2 17 s u b je ct s o f th e P re ve n 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 in clu di n g s ub je ct s w it h C K D at b as eli n e. 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 s o d iu m e xc re ti o n , m m o l/ 24 -h o u r χ 2 o r t -s ta ti sti c* P -v a lu e f o r tr e n d * Ma le <6 0 60 -7 2 73 -82 83 -9 5 >9 5 Fe m al e <5 1 51 -6 0 61 -6 9 70 -8 1 >8 1 P ar ti ci p an ts , N 1, 24 5 1, 24 4 1, 24 1 1, 24 4 1, 24 3 W o m e n , % 50 .0 50 .1 50 .0 50 .0 50 .0 A ge , y 51 .2 ± 1 2 .7 5 0 .7 ± 1 2 .3 4 9. 7 ± 1 2 .1 4 8 .9 ± 1 2 .0 47 .3 ± 1 1 .1 -7 .7 0 0 <0 .0 0 1 R ac e, w h it e s, % 89 .7 96 .4 96 .9 98 .1 99 .3 11 0 .0 2 2 <0 .0 0 1 P ar e n ta l h is to ry o f C K D , % 2. 2 2. 2 1. 4 1. 2 1. 5 3. 7 7 7 0. 0 5 Sm o ki n g s ta tu s, c u rr e n t, % 37 .5 34 .5 32 .2 29 .3 27 .7 35 .2 9 3 <0 .0 0 1 A lc o h o l c o n su m p ti o n , n o n e, % 30 .7 25 .6 22 .0 21 .1 18 .7 48 .6 0 0 <0 .0 0 1 Ed u ca ti o n , h ig h , % 21 .8 26 .2 32 .6 35 .7 37 .8 11 6 .7 5 9 <0 .0 0 1 H e ig h t, c m 17 1 ± 1 0 17 2 ± 9 17 3 ± 1 0 17 4 ± 9 17 6 ± 9 13 .4 8 0 <0 .0 0 1 W e ig h t, k g 7 5 .4 ± 1 3 .4 76 .9 ± 1 3 .6 7 8 .1 ± 1 3 .6 7 8 .8 ± 1 4 .1 8 1 .5 ± 1 4 .3 11 .6 2 6 <0 .0 0 1 Sy st o lic b lo o d p re ss u re , m m H g 1 3 0 ± 2 1 1 2 8 ± 2 0 1 2 8 ± 1 9 1 2 8 ± 1 9 12 7 ± 1 8 -3. 2 5 9 0. 0 0 1 D ia st o lic b lo o d p re ss u re , m m H g 7 5 ± 1 0 74 ± 9 74 ± 1 0 7 3 ± 9 74 ± 9 -3. 1 3 4 0. 0 0 2 A n ti h yp e rt e n si ve d ru gs , % 18 .5 16 .3 15 .3 12 .0 11 .3 34 .3 5 4 <0 .0 0 1 A C Ei /A R B , % 5. 2 4. 7 4. 7 3. 3 3.6 8. 3 9 2 0. 0 0 4 T h ia zi d e d iu re ti cs , % 3. 1 2. 6 2. 4 1. 4 3. 3 0. 4 2 3 0. 52 Lo o p d iu re ti cs , % 1. 2 0. 5 0. 5 0.9 0. 6 1. 1 5 7 0. 2 8 Po ta ss iu m -s p ar in g d iu re ti cs , % 1. 3 1. 4 1. 3 1. 3 0. 4 3. 3 0 7 0. 0 7 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 .1 5 .6 ± 1 .1 5 .5 ± 1 .1 -4 .9 61 <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 3. 0 7 5 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 .8 -1 .7 ) 1 .1 ( 0 .8 -1 .6 ) 1 .1 ( 0 .8 -1 .7 ) -0 .4 47 <0 .0 0 1

5