Sodium and potassium intake as determinants of cardiovascular and renal health
Kieneker, Lyanne Marriët
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as determinants of cardiovascular
and renal health
Sodium and potassium intake as determinants of cardiovascular and renal health Thesis, University of Groningen, the Netherlands
Financial support by the University of Groningen, University Medical Center Groningen, Graduate School of Medical Sciences, the Dutch Kidney Foundation, and the Dutch Heart Foundation for publication of this thesis is gratefully acknowledged.
Financial support for printing of this thesis was also kindly provided by:
ERBE Nederland B.V., ChipSoft B.V., Astellas Pharma B.V., Pfizer B.V. en Noord Negentig accountants en belastingadviseurs.
Lay-out: Thomas van der Vlis, persoonlijkproefschrift.nl Printing: Ridderprint BV – www.ridderprint.nl
ISBN (printed): 978-94-6375-212-1 © 2019, L.M. Kieneker, the Netherlands.
as determinants of cardiovascular
and renal health
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op woensdag 13 februari 2019 om 16.15 uur
door
Lyanne Marriët Kieneker geboren op 18 mei 1989
Prof. dr. S.J.L. Bakker Prof. dr. R.A. de Boer Prof. dr. R.T. Gansevoort Copromotor
Dr. M.M. Joosten Beoordelingscommissie Prof. dr. S.A. Reijneveld Prof. dr. J.M. Geleijnse Prof. dr. E.J. Hoorn
L. Lanting-Hidding Drs. A.L. Messchendorp
Chapter 1 General Introduction 9
Chapter 2 Urinary potassium excretion and risk of developing hypertension: Prevention of Renal and Vascular End-stage Disease study.
Hypertension 2014; 4: 769-776.
31
Chapter 3 Association of low urinary sodium excretion with increased risk of stroke.
Mayo Clin Proc 2018; 93(12): 1803-1809.
59
Chapter 4 Urinary potassium excretion and risk of cardiovascular events.
Am J Clin Nutr 2016; 103: 1204-12.
77
Chapter 5 Low potassium excretion but not high sodium excretion is associated with increased risk of developing chronic kidney disease.
Kidney Int 2016; 90; 888-896.
119
Chapter 6 Urinary potassium excretion, renal ammoniagenesis and risk of graft failure and mortality in renal transplant recipients.
Am J Clin Nutr 2016; 104: 1703-11.
153
Chapter 7 Plasma potassium, diuretic use and risk of developing chronic kidney disease in a predominantly white population.
PLoS ONE 2017; 12(3): e0174686.
187
Chapter 8 General Discussion and Conclusions 219
Nederlandse samenvatting/Dutch summary 243
Dankwoord/Acknowledgements 253
Author Affiliations 261
CHAPTER 1
GENERAL INTRODUCTION
Hypertension, defined as a blood pressure of ≥140/90 mm Hg, is a major public health issue and is currently affecting nearly half of all adults globally (1). The World Health Organization (WHO) ranks hypertension the leading global risk factor for disease, specifically for a variety of cardiovascular diseases (CVD), including stroke, ischemic heart disease (IHD), heart failure, atrial fibrillation, and peripheral vascular disease (2-4). Hypertension is also one of the leading causes of chronic kidney disease (CKD) in all developed and many developing countries (5). Underlying mechanisms responsible for these associations include the development of structural vascular changes and atherosclerosis caused by uncontrolled and prolonged elevation of blood pressure (6, 7), resulting in changes in the coronary vasculature, myocardial structure, conduction system of the heart (6, 7), hypertrophy of the renal arterial vessels, and increased renal vascular resistance (8, 9).
Complications of hypertension account for approximately 9.4 million deaths worldwide every year, which is 17% of all global deaths (10, 11). Due to this high number, and the fact that many people are undiagnosed because hypertension rarely causes symptoms in the early stages, hypertension is sometimes referred to as “the silent killer”. Over the last decades, the number of deaths as a result of CVD increased by over 25% and those of CKD nearly doubled (12). As the population ages, the prevalences of hypertension, CVD, and CKD will increase even further. According to projections of the WHO, the total number of deaths from these chronic diseases continues to increase if no actions will be taken at global, regional, and national levels (13).
Treatment and prevention: drugs versus lifestyle
The public health goal of blood pressure lowering therapy is the reduction of cardiovascular and renal morbidity and mortality. Therefore, hypertensive patients are often treated with antihypertensive drugs, including angiotensin converting enzyme inhibitors, calcium channel blockers, angiotensin receptor blockers, beta-blockers, or diuretics (14). Most patients with hypertension will
pressure goals (15, 16). Lifestyle modifications are also critical in the treatment of hypertension and blood pressure-related outcomes. These modifications include, among others, a reduction in weight, an increase in physical activity, abstinence from smoking and alcohol, and particularly, the promotion of a healthy diet (14).
A healthy diet is not only an alternative to, or alongside with, drug therapy in the treatment of hypertension and blood pressure-related outcomes including CVD and CKD, but it is also fundamental in the promotion and maintenance of good health throughout the entire life course, also independent of blood pressure. Therefore, nutrition is one of the key determinants in the prevention of developing chronic diseases. Many studies have investigated the role of diet and specific nutrients with the risk of developing hypertension and chronic diseases. Especially dietary intake of sodium, but also potassium, have been suggested to play a major role in the development of hypertension and blood-pressure related outcomes. Moreover, also associations of dietary intake of sodium and potassium with risk of CVD and renal function decline independent of blood pressure are suggested. Figure 1 represents a schematic illustration of the suggested associations of sodium and potassium intake with hypertension, CVD, and renal function decline.
Figure 1. Schematic illustration of the association between sodium and potassium intake and risk of
developing hypertension and blood pressure related outcomes, including cardiovascular disease and renal function decline.
Sodium and potassium homeostasis
Sodium is the most abundant cation in the extracellular fluid in the human body, whereas potassium is the predominating cation in the intracellular fluid (17, 18). These concentration differences are maintained by the sodium-potassium pump that actively pumps potassium into the cell while moving sodium out of the cell. Both minerals are essential nutrients needed for maintenance of total body fluid volume, acid and electrolyte balance, and normal cell function (18-20). Serum sodium and potassium are normally maintained within narrow limits (typically between 135 to 145 mmol/L and 3.5 to 5.0 mmol/L, respectively) (21-24). The kidney is the principal organ involved in maintenance of sodium and potassium homeostasis, balancing intake with urinary excretion. In the setting of normal kidney function, the vast majority of sodium and potassium is reabsorbed in the proximal tubule and the loop of Henle (25). The most important factors driving sodium and potassium secretion are serum sodium and potassium levels, aldosterone concentration, distal delivery of sodium and potassium, and distal tubular fluid flow rate.
In healthy individuals, approximately 90% of ingested sodium is excreted in the urine, whereas of the potassium ingested, approximately 77% is excreted (19). During a 24-hour period, urinary excretion of sodium and potassium vary in response to fluctuations in intake caused by the spacing of meals and changes in activity. A circadian rhythm remains when sodium and potassium intake and activity are evenly spread over a 24-hour period, whereby the excretion is lower at night and in the morning and is higher in the afternoon (26, 27).
Dietary intake of sodium and potassium
Although the minimum intake of sodium necessary for proper bodily function is estimated to be as little as 200–500 mg/day(19, 28), data from around the world suggest that the population average sodium consumption is well above this minimal physiological need. In many countries the average sodium consumption is far above 2 g/day (equivalent to 5 g salt/day), the maximum value for intake recommended for adults by the WHO (29-31). The WHO recommendation for dietary potassium intake is 90 mmol/day (3.5 g/d). However, the average
potassium consumption in many countries, including the Netherlands, is below this recommendation (30, 32-34).
The imbalance between the needs and current intakes may be partly explained by the rapid changes in diets which have occurred since the second half of the twentieth century. The increasing globalization of food systems, rapid urbanization, and economic development have led to a shift from largely plant-based diets high in potassium, fiber, and anti-oxidants, to processed energy-dense foods high in fat, sugar, and sodium (35). This is so pronounced that compared with the pre-agricultural and post-agricultural diets of our human ancestors, sodium intake increased with 400% in current Western diets, while potassium intake declined with 400% (36).
Measurement of dietary sodium and potassium intake
Reliable information about intake is essential to enable examination of the effects of sodium and potassium intake on health and disease. Several different methods are used to assess an individual’s mean intake of dietary sodium and potassium. The accuracy of most of these methods is, however, doubtful, since each method is –to a small or large extent– subject to errors and could therefore attenuate diet-disease associations (37).
Dietary questionnaires, including food frequency questionnaires (FFQs), 24-hour dietary recalls, and food diaries, for the estimation of sodium and potassium intake are widely used. However, these self-reported dietary methods are time consuming and are prone to recall- and report bias. Errors in the estimation of especially sodium intake, but also potassium intake, can arise from 1) the reliance on incomplete and infrequently updated food composition tables to determine the sodium and potassium content of reported food, 2) inaccurate reporting of the types and quantity of food consumed, often leading to a underestimation of intake, especially of sodium intake, since sodium is highly correlated with energy intake, and 3) the lack of information on salt added at the table, from condiments, or during cooking (37).
Another frequently used method for the assessment of intake of sodium and potassium is estimating sodium and potassium intake by the use of spot urine samples. This is a relatively cheap method and is easy for participants to collect.
However, due to day-to-day variation of sodium and potassium intake and the circadian rhythm of sodium and potassium excretion, measurement of intake of these minerals in spot urine collections has been shown to be inaccurate as a measure of individual intake in clinical settings or epidemiological studies (38, 39). Numerous equations are published that attempt to estimate 24-hour sodium excretion using spot urine samples (40-42). These equations, however, were developed and validated in the healthy, general population. Moreover, of these equations, two were developed in a Japanese general population setting, a population with a much higher sodium intake relative to, for example, the United States or the Netherlands (40, 41). These equations can therefore not be used to accurately estimate an individual’s mean sodium intake and also not to accurately estimate an individual’s mean potassium intake, since the equations were only validated for sodium intake.
Finally, some studies have assessed the intake of sodium and potassium by measuring 24-hour urinary excretion of these minerals. As approximately 90% of ingested sodium in healthy individuals is excreted in the urine, 24-hour urinary sodium excretion is considered the gold standard for assessing dietary sodium intake (19, 37). Of the potassium ingested, approximately 77% is excreted in the urine, and therefore urinary potassium excretion is considered an accurate proxy for potassium intake (19). Importantly, due to substantial variability in sodium and potassium intake over time, it has been shown that averaging multiple 24-hour urine collections provides the most accurate characterization of an individual’s mean sodium and potassium intake (43, 44). Only a few large epidemiological cohort studies have collected 24-hour urine collections for reasons of costs, logistics, and burden.
Interaction between sodium and potassium
The biologic interaction of sodium and potassium was already the focus in some studies in the mid-1870’s (45) and it still remains a topic of interest today. The natriuretic effects of potassium have been described in several studies (46). It is also observed that raising dietary potassium intake can blunt the effects of high dietary sodium intake and that the effect of increased potassium intake
and in salt sensitive individuals (46-50). Therefore, sodium and potassium must be concomitantly considered in the investigation of the association of either of these cations with outcomes. However, not every epidemiologic study has done this so far.
Sodium and potassium intake and the risk to develop hypertension
Data derived from observational studies, randomized controlled trials, and meta-analyses have shown that excess sodium intake plays a major role in the pathogenesis of elevated blood pressure and hypertension (51-55). In contrast, the role of potassium intake in the development of increased blood pressure is less clear. Although most meta-analyses of randomized controlled trials found an overall blood pressure-lowering effect (47, 56, 57), a more comprehensive meta-analysis comprising 21 randomized controlled trials that lasted for at least 4 weeks, observed this effect only among hypertensive subjects (49). Moreover, long-term prospective cohort studies on the association of dietary potassium and risk of hypertension are limited, and the majority observed no independent relationship (58-62), except one, in which an inverse association was found (63). Importantly, these observational studies all relied on 24-hour dietary recalls (61, 63), FFQs (58, 59, 62), or spot urine samples (60), which are less objective methods to assess potassium intake compared to 24-hour urine collections (19, 37, 64). Therefore, in Chapter 2, we prospectively investigated the association of urinary potassium excretion, measured in multiple 24-hour urine collections as accurate estimate of intake, and the risk of developing hypertension in a population-based cohort, while taking into account the effects of urinary sodium excretion in this association.
Sodium and potassium intake and incident cardiovascular disease
Since a reduction in sodium intake lowers blood pressure (51-55), it has been assumed that it would also reduce subsequent risk of CVD. There is indeed strong and convincing evidence that high sodium intake (>5 g sodium/day, equivalent to 12.5 g salt/day) is associated with an increased risk of CVD morbidity and mortality, and that reduction of excess sodium intake to moderate intake will lower risk of CVD, including IHD and stroke (55, 65-68). However, several studies
have reported that intake of sodium below 3 g/day may also be associated with an increased risk of CVD morbidity and mortality (66, 67, 69-72). The results of these studies, and the absence of high quality randomized controlled trials indicating that a reduction of sodium intake to low levels will decrease CVD risk, have led to the assumption that there might be a J-shaped association between sodium intake and CVD morbidity and mortality.
Of all CVDs, stroke is amongst the most disastrous and disabling (73). However, the evidence for the association of sodium intake with risk of stroke is even less consistent, with overall positive associations (66, 74-76), positive associations only present in subgroups (77, 78), null associations (79-83), but also, recently, a prospective cohort study which included 101,945 persons from 17 countries reported a J-shaped association (67). This inconsistency of the evidence might lie in methodological limitations of the studies, i.e. all studies, except one (83), relied on dietary questionnaires or spot urine samples, which are less reliable methods for the assessment of sodium intake compared to measurement of sodium in multiple 24-hour urine collections (19, 37). In Chapter 3, we investigated whether urinary sodium excretion, assessed in multiple 24-hour urine collections as accurate measure of intake, was associated with risk of stroke in a population-based cohort.
Only a few observational cohort studies have examined the association of dietary potassium intake with risk of CVD, IHD, and stroke. Meta-analyses of these few observational studies have reported nonsignificant inverse associations of potassium intake with risks of CVD and IHD. Besides these inverse trends, both meta-analyses concluded that higher dietary potassium intake is associated with a lower risk of stroke, specifically ischemic stroke, but with significant heterogeneity among studies (32, 49). Of note, again, nearly all studies relied on FFQs or 24-hour dietary recalls, which are less objective and precise for the assessment of potassium, compared to potassium measured in 24-hour urine samples (64, 84-87). Therefore, in Chapter 4 we prospectively examined the association between urinary potassium excretion, as estimate of intake, and risk of developing CVD, IHD, stroke, and heart failure, again while taking into account urinary sodium excretion.
Sodium and potassium intake and the rate of renal function decline
Hypertension is not only a major risk factor for developing CVD, but it is also associated with renal function decline and risk of developing CKD (88, 89). Reduction of elevated blood pressure is therefore fundamental in preventing and slowing the progression of CKD towards end-stage renal disease. Despite evidence that high sodium intake and low potassium intake may increase blood pressure, it is uncertain whether risk of initiation or progression of CKD is also affected by intakes of sodium and potassium.
Some experimental animal models have shown that high sodium intake induces kidney injury (90, 91). This finding is confirmed in some (92, 93), but not all (94-96), observational studies among CKD patients. The association of potassium intake with risk of CKD progression is less clear, since experimental animal models have shown that chronic potassium deficiency induces kidney injury (97), whereas one observational study in CKD patients did not observe an association (98), and another observational study showed that high potassium intake was associated with an increased risk of CKD progression in CKD patients (93). Longitudinal studies in populations with a relatively preserved kidney function, however, have generally observed no associations of sodium intake (99, 100) and inverse associations with potassium intake (99-101) with risk of renal outcomes (i.e. incident CKD, changes in eGFR or albuminuria, or end-stage renal disease). Importantly, all these cohorts included high-risk populations, i.e. subjects with either established CKD, vascular disease or diabetes mellitus, and the majority of these cohorts relied spot urine collections (99, 100), which is a less reliable measure of sodium and potassium intake compared to measurement in 24-hour urine samples, which is considered the gold standard (19, 37, 64). Therefore, in Chapter 5, we examined the prospective associations of urinary sodium and potassium excretion, as estimates of intake, with the risk of developing CKD in a population-based cohort, and investigated whether these potential associations could be modified by baseline hypertension status.
When CKD progresses to end-stage renal disease, renal replacement therapy is needed. Renal transplantation is preferred, since this renders a better quality of life, extended life duration, and lower costs compared to dialysis (102). Before transplantation, CKD patients are generally advised to limit potassium intake
because of the risk of hyperkalemia (103). After transplantation, however, there is usually no clear incentive to increase potassium intake. Despite that low potassium intake might be associated with elevated blood pressure, and that high blood pressure is a major risk factor for graft failure in renal transplant recipients (RTRs) (104), it is likely that RTRs maintain their habitual dietary potassium restrictions after transplantation. In Chapter 6, we therefore assessed the intake of potassium of RTRs and compared this intake to healthy controls. In the same chapter, we furthermore examined the association between urinary potassium excretion, as estimate of intake, and risk of graft failure and mortality in a cohort stable RTRs. Moreover, we explored whether the potential association between urinary potassium excretion and risk of graft failure could be explained by blood pressure or ammoniagenesis, a process that may induce progressive, tubulointerstitial damage (97, 105).
Disturbances in electrolyte balance
With advancing CKD, the kidney has a remarkable ability to maintain homeostasis, including the regulation of water balance (106). However, disturbances in plasma sodium, but particularly plasma potassium, are more common in patients with CKD compared to the general population. This disturbance in plasma potassium typically presents as hypokalemia (<3.5 mmol/L) as a consequence of diuretic administration (107), but CKD patients also have a higher risk of having hyperkalemia (≥5.0 mmol/L) due to impaired kidney function and frequent use of renin angiotensin aldosterone system inhibitors (108).
In subjects with CKD, as well as in subjects without impaired kidney function, both hypo- and hyperkalemia are associated with higher risk of all-cause mortality (109-112). Whereas prospective cohort studies in CKD patients have shown that hypokalemia is associated with increased risk of developing of end-stage renal disease (110, 113, 114), the association with risk of developing de novo CKD is not well established. A Japanese study observed that potassium concentrations <4.0 mmol/L were associated with an increased risk of developing CKD (115). However, this study excluded all individuals using blood pressure lowering medication, including diuretics –the main risk factor for hypokalemia in the general population
Chen et al. (116) observed that lower levels of potassium were associated with higher CKD risk, only among individuals not taking thiazide and loop diuretics. To further examine this association, we prospectively examined whether plasma potassium was associated with risk of developing CKD in a population-based cohort free of CKD at baseline in Chapter 7. We furthermore explored the role of the use of diuretics in this potential association.
Aims of this Thesis
Public health interventions aimed at decreasing dietary sodium intake and increasing dietary potassium intake may be potential cost effective measures for reducing the burden of morbidity and mortality from non-communicable diseases. However, the evidence on the potential beneficial effects of a decreased intake sodium and an increased intake of potassium on blood pressure and blood pressure-related outcomes including CVD and CKD is not entirely consistent. Therefore, the aim of this thesis is to investigate the possible roles of sodium and potassium intake, as well as of plasma potassium, in the development of hypertension, CVD, and renal function decline including CKD and renal graft failure, while concomitantly considering sodium and potassium in these investigations. In Chapter 2, we prospectively investigated the association of urinary potassium excretion, measured in multiple 24-hour urine collections as accurate estimate of intake, and the risk of developing hypertension in a population-based cohort, while taking into account the effects of urinary sodium excretion in this association. In Chapter 3, the association of urinary sodium excretion, measured in multiple 24-hour urine collections as accurate estimate of intake, with risk of developing stroke is investigated in the same population-based cohort. In Chapter 4, the prospective association of urinary potassium excretion, again measured in multiple 24-hour urine collections, with risk of developing IHD, stroke, heart failure, and total CVD is examined, while taking into account urinary sodium excretion. In Chapter 5, the prospective associations of urinary sodium and potassium excretion, as estimates of intake, with risk of developing CKD is investigated in a population-based cohort. In Chapter 6, we assessed the intake of potassium in RTRs and compared this intake to healthy controls Furthermore, we prospectively explored the association of urinary potassium excretion and risk
of graft failure and mortality in RTRs and assessed whether blood pressure or ammoniagenesis could play a role in this potential association. Finally, in Chapter 7, the association of plasma potassium with risk of developing CKD is studied in a population-based cohort and we furthermore explored the role of diuretics in this potential association.
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CHAPTER 2
Urinary potassium excretion and risk of
developing hypertension: Prevention of
Renal and Vascular End-stage Disease
study
Lyanne M. Kieneker Ron T. Gansevoort Kenneth J. Mukamal Rudolf A. de Boer Gerjan Navis Stephan J.L. Bakker Michel M. Joosten Hypertension 2014; 4: 769-776ABSTRACT
Background: Previous prospective cohort studies on the association between potassium intake and risk of hypertension have almost exclusively relied on self-reported dietary data, while repeated 24-hour urine excretions, as estimate of dietary uptake, may provide a more objective and quantitative estimate of this association.
Methods: Risk of hypertension (defined as blood pressure ≥140/90 mm Hg or initiation of blood pressure-lowering drugs) was prospectively studied in 5,511 normotensive subjects aged 28 to 75 years not using blood pressure-lowering drugs at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Potassium excretion was measured in 2 24-hour urine specimens at baseline (1997-1998) and midway during follow-up (2001-2003). Results: Baseline median potassium excretion was 70 mmol/24h (interquartile range, 57-85 mmol/24h), which corresponds to a dietary potassium intake of ~91 mmol/24h. During a median follow-up of 7.6 years (interquartile range, 5.0-9.3 years), 1,172 subjects developed hypertension. The lowest sex-specific tertile of potassium excretion (men: <68 mmol/24h; women: <58 mmol/24h) had an increased risk of hypertension after multivariable adjustment (hazard ratio, 1.20; 95% confidence interval, 1.05-1.37), compared with the upper 2 tertiles (Pnonlinearity=0.008). The proportion of hypertension attributable to low potassium excretion was 6.2% (95% confidence interval, 1.7%-10.9%). No association was found between the sodium to potassium excretion ratio and risk of hypertension after multivariable adjustment.
Conclusions: Low urinary potassium excretion was associated with an increased risk of developing hypertension. Dietary strategies to increase potassium intake to the recommended level of 90 mmol/day may have the potential to reduce the incidence of hypertension.
INTRODUCTION
Potassium is an essential mineral which is thought to play an important role in blood pressure regulation (1). Potassium supplementation has been shown to significantly reduce blood pressure in some, but not all randomized controlled trials. Although most meta-analyses of these randomized controlled trials (2-4) found an overall blood pressure-lowering effect, a more comprehensive meta-analysis (5), comprising 21 randomized controlled trials that lasted for ≥4 weeks, observed this effect only among hypertensive subjects.
Long-term prospective cohort studies on the association between dietary potassium and risk of hypertension are limited, and the majority observed no independent relationship (6-10), except one, in which an inverse association was found (11). These observational studies predominantly relied on 24-hour dietary recalls (9, 11) or food frequency questionnaires (6, 7, 10) to assess potassium intake. Such self-reported dietary methods, however, are less objective than urinary measures to assess dietary intake (12). Although 24-hour urine collections are considered the most direct method for estimating dietary potassium (12), few large epidemiological cohort studies have collected them for reasons of costs, logistics and burden.
Hence, the aim of this study was to prospectively examine the association between repeated 24-hour urinary potassium excretions and risk of developing hypertension among subjects free of hypertension at baseline in a cohort with long-term follow-up.
MATERIALS AND METHODS
Study design and population
The Prevention of Renal and Vascular End-stage Disease (PREVEND) study is a prospective investigation of albuminuria, renal, and cardiovascular disease in a large cohort drawn from the general population. Details of this study are described elsewhere (13, 14). In total, 8,592 individuals constitute the PREVEND cohort and completed an extensive examination in 1997 and 1998 (baseline).
We excluded subjects with hypertension at baseline (n=3,040), subjects requiring dialysis (n=12) and subjects with missing values of urinary analytes at baseline (n=29), leaving 5,511 participants for the analyses. Of these, 4,546 participants completed a second examination between 2001 and 2003, 3,928 participants completed a third examination between 2003 and 2006, and 3,528 participants completed a fourth examination between 2006 and 2008.
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 (15). In brief, each of the examinations 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. 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 examination by indirect potentiometry with a MEGA clinical chemistry analyzer (Merck, Darmstadt, Germany) (16). The potassium concentration in mmol/L was multiplied by the urine volume in L/24h to obtain a value in mmol/24h. For each of the 2 examinations, we calculated the average value of the paired 24-hour collections.
Ascertainment of hypertension
During both visits of each of the 4 examinations, 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, Florida) as described previously (17). The mean of the last 2 recordings from each visit was used. Use of antihypertensive medications was ascertained by a questionnaire at each examination and was complemented by information from a pharmacy-dispensing registry, which has complete information on drug use of >90% of subjects in the PREVEND study.
For this study, incident hypertension was defined as hypertension that occurred after baseline, which included systolic blood pressure of ≥140 mm Hg, a diastolic blood pressure of ≥90 mm Hg, or the use of antihypertensive drugs, in concordance with recommendations from the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (18). Antihypertensive medication use, for the definition of hypertension, included 5 second-level Anatomical Therapeutic Chemical codes: C02 (antihypertensives), C03 (diuretics), C07 (β-blockers), C08 (calcium channel blockers), and C09 (inhibitors).
Assessment of covariates
Body mass index (BMI) was calculated as weight (kilograms) divided by height squared (square meter). Smoking status was categorized as never, former, current <6 cigarettes/day, current 6-20 cigarettes/day, and current >20 cigarettes/day. Alcohol intake was categorized as none, 1 to 4 drinks/month, 2 to 7 drinks/week, 1 to 3 drinks/day, and 4 or more 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).
Statistical analyses
Baseline characteristics are presented according to sex-specific tertiles of urinary potassium excretion. Continuous data are presented as mean with SD or as median and interquartile range (IQR) in case of skewed distribution. Categorical
data are presented as percentiles. We calculated the Pearson product–moment correlation coefficient for the paired 24-hour urine specimens at the first and second examination, and for the averaged potassium excretions of the first and the second examination, as estimates of the intraclass correlation coefficient of reliability R (19).
To study the association between potassium excretion (as a categorical [tertiles] and a continuous variable) and risk of hypertension, we used time-dependent Cox proportional hazards regression analyses. For events occurring before the second examination (i.e., between 1997-2003), the average of the 2 baseline 24-hour urinary excretions of potassium (and sodium alike) 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 were used, because using cumulative averages of dietary factors yield stronger associations than either only baseline or most recent dietary factors (20). 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 round that participants attended, the incidence of hypertension, death, relocation to an unknown destination, or 1 January, 2009 (end of follow-up). Hazard ratios (HRs) are reported with 95% confidence intervals (CIs).
We included covariables in our models as linear variables if appropriate, or as categorical if discrete, or if their association with hypertension was nonlinear. Additional adjustment for income, as marker of socioeconomic status did not provide further information after accounting for education. Adjustment for race/ ethnicity in the multivariable model did not affect the association between urinary potassium excretion and risk of hypertension and was therefore not included as a confounder. We tested for multicollinearity between urinary excretions of electrolyte and creatinine. All variance inflation factors were <5, which indicates that there is no proof for multicollinearity. We evaluated effect modification by age, sex, BMI, smoking behavior, and 24-hour urinary sodium and albumin excretion in the analyses of risk of hypertension by fitting models containing both main effects and their cross-product terms. The population attributable risk was calculated using the formula p(HR-1)/(1 + p[HR-1]), where p is the prevalence
associated multivariable-adjusted HR. Upper and lower 95% CIs of the population attributable risk were derived using this formula and the upper and lower 95% CI estimates of the multivariable-adjusted HR.
Despite being considered the gold standard, even 24-hour urine collections may be subject to quality control concerns because of collection errors. To account for potential inadequacies in the timed 24-hour urine collections, we examined the difference between expected and actually measured 24-hour urine volume (21). 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=([urinary creatinine]×24-hour urine volume)/[serum creatinine]), where creatinine clearance was estimated using the Cockcroft-Gault formula (22).
In addition to the analyses on urinary potassium excretion and our previous analyses on urinary sodium excretion and risk of hypertension (23), we also examined the association between the urinary sodium to potassium (Na-K) excretion ratio and risk of hypertension with time-dependent Cox proportional hazards regression analyses. We evaluated effect modification by age, sex, BMI, smoking behavior, and 24-hour urinary albumin excretion by fitting models containing both main effects and their cross-product terms.
All P values are 2 tailed. P value <0.05 was considered statistically significant. All analyses were conducted using the statistical package IBM SPSS (version 20.0.1; SPSS, Chicago, IL) and SAS (version 9.2; SAS Institute, Cary, NC) software.
RESULTS
The median 24-hour potassium excretion for the 2 urine specimens at baseline was 70 mmol (IQR, 57-85 mmol), with a higher value in men (77 mmol; IQR, 63-92) than in women (65 mmol; IQR, 53-78). This median urinary excretion corresponds to a daily dietary potassium intake of ≈91 mmol/24h (≈3,550 mg/day), assuming a gastrointestinal absorption of 77% (24, 25). Baseline characteristics are shown according to sex-specific tertiles of urinary potassium excretion (Table 1). At
baseline, subjects who had a higher potassium excretion were more likely to be younger and had a higher BMI. Men and women in the highest tertile of urinary potassium excretion were less likely to smoke and consumed more alcohol and sodium than men and women in the lowest tertile of excretion. Higher urinary potassium levels were univariately associated with higher plasma levels of aldosterone. The within-subject correlations for potassium excretion between the paired 24-hour urine specimens at the first and second examination were
r=0.59 (P<0.0001; n=5,489) and r=0.64 (P<0.0001; n=4,410), respectively. The
within-subject correlation between the averaged potassium excretions of the first and the second examination (separated by a median of 4.3 years [IQR, 4.0-4.8 years]) was r=0.49 (P<0.0001; N=4,429).
Table 1. Baseline characteristics according to sex-specific tertiles of urinary potassium
excretion in 5,511 participants of the PREVEND study.
Tertiles of urinary potassium excretion,
mmol/24h P value for trend* Male <68 68-86 >86 Female <58 58-74 >74 Participants, n 1,836 1,838 1,837 Women, % 54.7 54.7 54.7 Age, y 45.9 ± 11.6 45.7 ± 10.8 44.2 ± 10.1 <0.001 Race, whites, % 90.7 96.6 98.4 <0.001
Parental history of hypertension, % 27.2 29.1 30.8 0.02
Smoking status, never, % 29.0 30.1 32.9 <0.001
Alcohol consumption, none, % 27.6 21.7 17.7 <0.001
Education, high, % 27.9 35.7 43.0 <0.001
BMI, kg/m2 24.7 ± 3.8 25.2 ± 3.8 25.4 ± 3.9 <0.001
Blood pressure
Systolic, mm Hg 118 ± 11 119 ± 11 119 ± 11 0.02
Diastolic, mm Hg 70 ± 7 70 ± 7 70 ± 7 0.76
Total cholesterol, mmol/L 5.5 ± 1.1 5.5 ± 1.1 5.4 ± 1.0 0.001
HDL cholesterol, mmol/L 1.3 ± 0.4 1.4 ± 0.4 1.4 ± 0.4 0.004
Triglycerides, mmol/L 1.1 (0.8-1.5) 1.0 (0.8-1.4) 1.0 (0.8-1.4) 0.002
Lipid-lowering drugs, % 2.9 3.4 2.4 0.37
Table 1. Continued
Tertiles of urinary potassium excretion,
mmol/24h P value for
trend*
Male <68 68-86 >86
Female <58 58-74 >74
Glucose-lowering drugs, % 0.6 0.5 0.4 0.49
eGFR, mL/min per 1.73 m² 87 (77-97) 87 (77-98) 87 (78-97) 0.96
Proton-pump inhibitors, % 2.3 3.0 2.5 0.70
Plasma potassium, mmol/L† 4.4 ± 0.6 4.3 ± 0.3 4.4 ± 0.6 0.13
Plasma sodium, mmol/L† 142 ± 2 142 ± 3 142 ± 2 0.36
Plasma renin, µIU/mL‡ 19 (12-29) 18 (12-28) 19 (12-28) 0.46
Plasma aldosterone, pg/mL§ 117 (93-149) 118 (93-151) 122 (96-160) 0.001
Urinary excretion of:
Potassium, mmol/24-hour 52 (45-57) 70 (65-76) 92 (83-103) <0.001
Sodium, mmol/24-hour 115 (88-145) 138 (110-170) 154 (122-187) <0.001
Sodium to potassium ratio 2.3 (1.8-2.9) 2.0 (1.6-2.4) 1.6 (1.3-2.0) <0.001
Calcium, mmol/24-hour 3.2 (2.1-4.4) 3.8 (2.7-5.0) 4.1 (2.9-5.5) <0.001
Magnesium, mmol/24-hour 3.3 (2.5-4.0) 3.9 (3.1-4.8) 4.4 (3.4-5.4) <0.001
Creatinine, mmol/24-hour 10.4 (8.7-12.8) 11.9 (10.0-14.3) 13.0 (10.9-16.1) <0.001
Albumin, mg/24-hour 7.3 (5.3-11.8) 8.0 (6.0-12.1) 8.9 (6.4-14.2) <0.001
Continuous variables are reported as mean ± SD or median (interquartile range), and categorical variables are reported as percentage. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; and PREVEND, Prevention of Renal and Vascular End-Stage Disease. * Determined by χ2 test (categorical variables), linear regression (continuous variables). †Available in 4,627 subjects. ‡ Available in 5,336 subjects. § Available in 4,847 subjects.
During a median follow-up of 7.6 years (IQR, 5.0-9.3 years), 1,172 hypertension cases were detected. The association between urinary potassium excretion and risk of hypertension was nonlinear (P=0.008 for nonlinearity; Table 2). The multivariable-adjusted spline curve confirmed the nonlinear inverse association of urinary potassium excretion with risk of hypertension (Figure 1). Because of the nonlinear association between urinary potassium excretion and risk of hypertension, we combined the upper 2 tertiles of the distribution in further analyses because the increased risk of hypertension was observed only for lower levels of potassium excretion. The lowest sex-specific tertile (men: <68 mmol/24h; women: <58 mmol/24h) had an increased risk of developing hypertension after multivariable adjustment (HR, 1.20; 95% CI, 1.05-1.37) compared with the upper 2 tertiles. In further analyses, we included plasma aldosterone or urinary creatinine
excretion in the multivariable model. This did not appreciably alter the association (HR lowest tertile compared to the upper 2 tertiles, 1.20; 95% CI, 1.05-1.37 and 1.22; 1.06-1.39, respectively). The higher risk associated with low potassium excretion was generally similar in analyses stratified by selected characteristics (Supplemental Figure 1), with no evidence for effect modification by age, BMI, sex, smoking status, alcohol consumption, urinary sodium excretion, or urinary albumin excretion (all P>0.10 for interaction). The proportion of hypertension attributable to low potassium excretion was 6.2% (95% CI, 1.7%-10.9%).
Similar results were found when we accounted for potential inadequacies in the timed 24-hour urine collections by excluding subjects with potential over- or under collections based on the difference between a subject’s estimated and measured volume of 24-hour urine sample (HR first tertile compared with the upper 2 tertiles, 1.23; 95% CI, 1.07-1.40; n=5239, n=1115). Consistent with Figure 1, we observed a curvilinear association between lower levels of potassium excretion and increased risk of hypertension when we divided the population into sex-specific deciles instead of tertiles. The HRs for the lowest 4 deciles of the distribution of potassium excretion were 1.30 (95% CI, 1.06-1.61), 1.12 (95% CI, 0.90-1.37), 1.12 (95% CI, 0.93-1.36) and 1.07 (95% CI, 0.88-1.30), respectively, as compared with the upper 6 deciles.
Na-K excretion ratio
The median Na-K excretion ratio at baseline was 2.0 (IQR, 1.5-2.5), and was slightly lower in women (1.9; IQR, 1.5-2.4) than in men (2.0; IQR, 1.6-2.5). The within-subject correlations for the Na-K excretion ratio between the paired 24-hour urine specimens at the first and second examination were r=0.49 (P<0.0001; n=5,492) and r=0.56 (P<0.0001; n=4,415), respectively. The within-subject correlation between the averaged Na-K excretion ratios of first and the second examination (4.3 years later) was r=0.22 (P<0.0001; n=4,431).
There was no evidence for a deviation from linearity in the association between the Na-K excretion ratio and risk of hypertension (P=0.49 for nonlinearity; Supplemental Table 1). After adjustment for age and sex, a higher Na-K excretion
