Sodium and potassium intake as determinants of cardiovascular and renal health
Kieneker, Lyanne Marriët
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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
even require two or more antihypertensive medications to achieve their blood
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
on blood pressure levels is more pronounced at higher levels of sodium 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
(107)– which substantially limits the generalization of the findings. Moreover,
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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