REVIEW

Achieving the Benefits of a High-Potassium,

Paleolithic Diet, Without the Toxicity
Biff F. Palmer, MD, and Deborah J. Clegg, PhD

Abstract

The average US dietary intake of Kþ is well below the current recommended nutritional requirements.
This deficiency is even more striking when comparing our current intake with that of our ancestors, who
consumed large amounts of dietary Kþ. Kþ deficiency has been implicated in many diseases including
cardiovascular disease, kidney stones, and osteoporosis. Importantly, dietary supplementation of Kþ has
favorable effects on reducing blood pressure, decreasing the risk of stroke, improving bone health, and
reducing the risk of nephrolithiasis. For this comprehensive review, we scanned the literature using
PubMed and MEDLINE using the following search terms: potassium intake, renal potassium excretion, and
prevention of hyperkalemia. Articles were selected for inclusion if they represented primary data or review
articles published between 1980 and 2015 in high-impact journals. The normal kidney has the capacity to
tightly regulate Kþ homoeostasis. We discuss new findings with respect to sensing mechanisms by which
the kidney maintains Kþ homeostasis in the gastrointestinal tract and distal tubule. There are widely
prescribed hypertensive medications that cause hyperkalemia and thus require dietary Kþ restriction. We
conclude by discussing newly approved drugs capable of binding Kþ in the gastrointestinal tract and
speculate that this new pharmacology might allow diet liberalization in patients at risk for hyperkalemia,
affording them the numerous benefits of a Kþ-rich diet.
ª 2016 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2016;91(4):496-508

greater than 4.4,5 Not only are diets of Western

From the Department of In-
ternal Medicine, University of
Texas Southwestern Medical
Center, Dallas (B.F.P.); and
Biomedical Research Depart-
ment, Diabetes and Obesity
Research Institute, Cedars-
Sinai Medical Center, Beverly
Hills, CA (D.J.C.).
P
otassium is an extremely important
mineral, as supported by the recent
Dietary Guidelines for Americans
and the Food and Drug Administration
designation that Kþ is a “nutrient of public
health concern” because of its general under-
consumption across the US population.1
Underconsumption of Kþ is associated with
hypertension and cardiovascular diseases,
2 common adverse diet-related health out-
comes in the United States.1 In 2004, the
Food and Nutrition Board of the Institute
of Medicine2 recommended intake levels of
4700 mg/d. Despite these recommendations,
data from the National Health and Nutrition
Examination Survey (NHANES) 2007 to
2008 estimated mean intakes in the United
States to be 2290 mg/d for women and
3026 mg/d for men, substantially lower
than the suggested values.3 This relative
“deficiency” of dietary Kþ is even more note-
worthy when one considers that the Kþ
intake of prehistoric humans was estimated
to be 15,000 mg/d, which actually exceeds
the NHANES recommendations by a factor
industrialized societies lower in Kþ intake, but
they also differ from prehistoric cultures with
respect to Naþ intake. The daily intake of salt
in Western industrialized societies is about 3
times higher than the daily intake of Kþ on a
molar basis, whereas salt intake in primitive
cultures is approximately 7 times lower than
Kþ intake.6
The changes in Kþ and Naþ intake over
time reflect a shift from traditional plant-
based diets high in Kþ and low in Naþ (char-
acterized by fruits, leafy greens, roots, and
tubers) to processed foods high in Naþ and
low in Kþ. The transition to processed foods
began approximately 10,000 years ago with
the onset of agriculture. This time period is
short in comparison to the preceding several
million-year period dating from the Stone
Age to the onset of agriculture. Inadequate con-
sumption of Kþ combined with excessive intake
of Naþ contributes to the pathophysiology of
various chronic diseases such as obesity, hyper-
tension, diabetes, kidney stones, and bone
disease.

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www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
BENEFITS OF HIGH-POTASSIUM DIET WITHOUT TOXICITY
One prevailing hypothesis is that our cur-
rent diet represents a mismatch between what
our body has the capability to metabolize and
what we are actually consuming. The normal
kidney has the capacity to maintain Kþ ho-
meostasis in the setting of high dietary intake.
As an example, serum Kþ levels are main-
tained in the normal range even when dietary
Kþ intake is increased to approximately 15 g/d
for 20 days.7,8 This ability to maintain a normal
serum Kþ concentration when challenged with
large intake over a prolonged period of time
suggests that humans are able to consume and
excrete high Kþ loads (Table 1). The mechanism
by which the kidney is able to maintain Kþ
homeostasis in the setting of high intake is
discussed below.
OVERVIEW OF RENAL Kþ HANDLING
Kþ is freely filtered by the glomerulus, and then
mostly reabsorbed in the proximal tubule and
thick ascending limb such that only a small
amount reaches the distal nephron. Reabsorp-
tion in the proximal tubule is primarily through
the paracellular pathway and is in rough
proportion to Naþ and water. The apical
membrane Naþ-Kþ-2Cl cotransporter medi-
ates transcellular Kþ transport in the thick
ascending limb of Henle. In the early distal
convoluted tubule (DCT), Kþ secretion begins
and progressively increases in magnitude into
the cortical collecting duct. As recently reviewed,
the secretory component of Kþ handling is
that which varies and is regulated according to
physiological needs.9
The major Kþsecretory mechanism in the
distal nephron is electrogenic secretion through
the ROMK (renal outer medullary Kþ) channel.
A second channel (maxi-Kþ or BK channel)
also mediates Kþ secretion under conditions
of increased flow. In addition to stimulating
maxi-Kþ channels, tubular flow augments elec-
trogenic Kþ secretion by diluting luminal Kþ
concentration and stimulating Naþ reabsorp-
tion through the epithelial Naþ channel
(ENaC). In part, this stimulatory effect can be
traced to a mechanosensitive property by which
shear stress increases the open probability of
the ENaC.10
The biomechanical characteristics of Naþ
and Kþ transport in the distal nephron are
ideally suited to buffer any increase in
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ARTICLE HIGHLIGHTS
n Over several million years, physiology and metabolism of
humans evolved to retain Naþ and excrete Kþ in response to a
diet that was low in Naþ and high in Kþ. With the onset of
agriculture and industrialization, there has been a precipitous
drop in dietary Kþ consumption and an equal rise in dietary salt
consumption, contributing to disease onset. This is further sup-
ported by the fact that the newest Dietary Guidelines for
Americans have listed Kþ as a “nutrient of public health concern”
because of its inadequate consumption. Low Kþ intake is then
implicated in various chronic diseases including hypertension,
cardiovascular disease, osteoporosis, and nephrolithiasis.
n The ability to maintain Kþ homeostasis in the setting of high
dietary intake is regulated by the normal kidney. In addition to the
well-recognized role of aldosterone in renal Kþ secretion, recent
findings have identified the presence of an enteric Kþ sensing
mechanism that can initiate the renal secretory process upon Kþ
entry into the gastrointestinal tract. In addition, the distal convo-
luted tubule has been identified as a Kþ sensor capable of initiating
Kþ exertion independent of mineralocorticoid activity.
n Increased dietary Kþ intake has been linked to various health
benefits including decreased blood pressure, reduced risk of
stroke, improved bone health, and a reduction in the risk of
renal stone disease. At the same time, drugs used to treat
hypertension result in increased Kþ concentrations, requiring
dietary restriction of Kþ-enriched foods.
n A plant-based (Kþ-enriched) diet offers benefits that include
reduced phosphorus absorption and improvement in metabolic
acidosis. A limitation of such a diet can be the development of
hyperkalemia in patients with impaired renal Kþ excretion.
n New drugs designed to bind Kþ in the gastrointestinal tract are
now available. These drugs have been shown to be effective in
maintaining normokalemia in the setting of ongoing use of blockers
of the renin-angiotensin-aldosterone system in patients previously
intolerant of these drugs due to hyperkalemia. These drugs may
allow patients to liberalize their diets so as to receive the benefits
of a Kþ-enriched diet without development of hyperkalemia.
extracellular Kþ concentration following a
Kþ-rich diet. A protein-enriched meal high
in Kþ content, typical of early humans, would
lead to an increase in glomerular filtration rate
and tubular flow.11 Increased flow through the
distal nephron increases distal Naþ delivery
497

TABLE 1. Health Benefits of a High-Kþ Diet
d Decreased blood pressure
: Effect greater in blacks and in the setting of high-Naþ intake
: Mechanism
n Increased urinary Naþ excretion
n Decreased adrenergic outflow
n Direct effect of Kþ on vascular tone
d Decreased risk of stroke
: Related to improved blood pressure
: Blood pressureeindependent effects
d Favorable effect on bone health
: Alkali load in a diet
: Direct effect of Kþ
d Decreased risk of nephrolithiasis
: Alkali load
: Effect of Kþ in the distal convoluted tubule to decrease urinary Ca2þ
excretion
d Benefits in patients with chronic kidney disease
: Decreased gastrointestinal absorption of phosphate with plant protein
compared with animal protein
: Better control of metabolic acidosis
and dilutes luminal Kþ concentration, both of
which augment electrogenic Kþ secretion
through the ROMK channel. Along with the
flow-mediated activation of maxi-Kþ channels,
these events enhance renal Kþ secretion, thus
providing a defense against development of
hyperkalemia.
The renal response to a high-Kþ, low-Naþ
diet has been studied in experimental rats.12,13
Animals were fed a diet high in Kþ and low in
Naþ for several days and given exogenous
deoxycorticosterone to ensure a steady-state
level of mineralocorticoid activity. Renal Kþ
handling was then examined after an acute
KCl load. In the initial 2 hours following the
intraperitoneal injection of KCl, there was a
large increase in renal Kþ excretion, primarily
due to increased secretion into the collecting
duct. This increased Kþ secretory capacity
is likely due to increased density of both
ROMK and maxi-Kþ channels, which are
both known to increase under conditions of
high-Kþ intake.14 Over the next 4 hours, renal
Kþ excretion continued to be high, but kaliu-
resis was mostly due to high flow through the
collecting duct. The timing of the 2 phases is
important because the effect of high flow to
simulate renal Kþ secretion would be maximal
only when Kþ channels are maximally expressed.
Increased medullary recycling and accu-
mulation of Kþ in the interstitium of the
n n
498 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
kidney decreases Naþ reabsorption both in
the thick ascending limb and in the proximal
tubule, thus providing a mechanism for high
Kþ intake to increase tubular flow.15-18 Given
the high capacity of the proximal tubule and
thick ascending limb to reabsorb Naþ, more
recent studies have focused on how Kþ intake
modulates transport in the low-capacity early
DCT as a way to adjust tubular flow to Kþ
secretory sites. In the setting of a high-Kþ,
low-Naþ diet, inhibiting transport in high-
capacity upstream segments might lack the
precision necessary to ensure that the delivery
of Naþ is appropriate to maximally stimulate
Kþ secretion and at the same time not be
excessive, predisposing to volume depletion.
DISTAL TUBULE AS A Kþ SENSOR
The DCT is composed of a proximal portion
(DCT1) in which salt transport is driven exclu-
sively by the thiazide-sensitive NaCl cotrans-
porter (NCC) (Figure 1). In the distal portion
of the DCT (DCT2), electroneutral NaCl
transport coexists with electrogenic Naþ
and Kþ transport pathways.18,19 Aldosterone
sensitivity begins in the DCT2 and extends
to the collecting duct. Changes in transport
in the early DCT control the delivery of
NaCl to the downstream connecting tubule
and collecting duct in which the ENaC medi-
ates electrogenic Naþ reabsorption and in
which Kþ is secreted. In this regard, cells
of the early DCT play a substantial, albeit in-
direct, role in Kþ secretion.
The low-capacity nature of the DCT and
its location immediately upstream from the
aldosterone-sensitive distal nephron (ASDN)
makes this segment a more likely site for changes
in dietary Kþ intake to modulate Naþ transport
and ensure that the downstream delivery of
Naþ is precisely the amount needed to ensure
maintenance of Kþ homeostasis without causing
unwanted effects on volume.
Increased dietary Kþ intake leads to an
inhibitory effect on Naþ transport in this
segment and does so through effects on
members of the with no lysine family of
kinases (WNK).20,21 WNK lysine-deficient pro-
tein kinase 1 (WNK1) and its shorter spliced
variant kidney specific (KS)-WNK1 are highly
expressed in the DCT and connecting duct.
KS-WNK1 functions as a physiological antago-
nist to the actions of long WNK1. Changes in
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BENEFITS OF HIGH-POTASSIUM DIET WITHOUT TOXICITY

Increased K + intake ↑ Aldosterone

NaCl Na+ K+
(+) (+)
NCC ENaC ROMK
sor Maxi-K+
Enteric sen Na+
Na+
DCT1 DCT2 and CD

↓ Proximal
Na+ reabsorption

Medullary recycling of K+
and ↓ reabsorption of Na+
in thick ascending limb

FIGURE 1. Older studies suggest that high dietary Kþ intake inhibits Naþ reabsorption in the proximal nephron and thick ascending
limb of Henle, causing increased flow and delivery of Naþ to the aldosterone-sensitive distal nephron, resulting in increased Kþ
excretion. More recent studies suggest that this process is more regionalized to the distal nephron and implicates the distal convoluted
tubule (DCT) as a renal Kþ sensor. The proximal portion of the DCT (DCT1) reabsorbs NaCl in an electroneutral fashion via the
Naþ-Cl cotransporter (NCC). High dietary intake achieved through changes in plasma Kþ concentration leads to an inhibitory effect
on NCC activity. As a result, Naþ delivery and flow are increased to the aldosterone-sensitive Kþ secretory segments located in the
later portions of the DCT (DCT2) and collecting duct (CD). Increased plasma Kþ concentration stimulates aldosterone release from
the adrenal gland, which, in turn, facilitates electrogenic Kþ secretion through the renal outer medullary Kþ (ROMK) channel. Both
increased flow and aldosterone stimulate Kþ secretion through the maxi-K channel. Increased Kþ secretion may begin upon Kþ entry
into the gastrointestinal tract before any change in plasma Kþ concentration through an enteric sensing mechanism, which leads to an
inhibitory effect on NCC activity. ENaC ¼ epithelial Naþ channel.

the ratio of KS-WNK1 and long WNK1 in
response to dietary Kþ contribute to the phy-
siological regulation of renal Kþ excretion.22-25
Under normal circumstances, long WNK1
prevents the ability of WNK4 (another mem-
ber of the WNK family) to inhibit the activity
of the Naþ-Cl cotransporter in the DCT.
Thus, increased activity of long WNK1 leads
to a net increase in NaCl reabsorption. Dietary
Kþ loading increases the abundance of
KS-WNK1, which has the effect to block the
inhibitory effect of long WNK1 on WNK4.
The net effect is inhibition of Naþ-Cl
cotransport in the DCT and increased Naþ
delivery to more distal portions of the tubule.
The increase in KS-WNK1 in response to high
Kþ intake also antagonizes the effect of long
WNK1 to stimulate endocytosis of ROMK.
In addition, KS-WNK1 exerts a stimulatory
effect on the ENaC. In total, increases in
KS-WNK1 in response to dietary Kþ loading
facilitates Kþ secretion through the combined
effects of increased Naþ delivery through the
down-regulation of Naþ-Cl cotransport in
the early DCT, increased electrogenic Naþ reab-
sorption via the ENaC, and greater abundance
of ROMK. These effects can occur indepen-
dently of any change in mineralocorticoid

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www.mayoclinicproceedings.org

activity, suggesting an intrinsic sensing capa-
bility of this segment to changes in dietary Kþ.19
Recent studies26,27 suggest that extracel-
lular Kþ modulates the WNK axis by altering
membrane voltage and changing intracellular
chloride concentration. An increased plasma
Kþ concentration as with increased dietary
intake would depolarize cells in the DCT1,
resulting in increased intracellular Cl concen-
tration. This increase alters WNK4 activity in
such a way that activity of NCC is decreased.
The unique sensitivity of WNK4 to Cl is
consistent with this model.
High Kþ intake also has a stimulatory
effect on the release of aldosterone at the level
of the adrenal gland. Increased aldosterone
compliments the effect of KS-WNK1 in the
DCT.28,29 Aldosterone up-regulates serum-
and glucocorticoid-dependent protein kinase 1,
which, in turn, phosphorylates WNK4. This
modification prevents WNK4 from inhibiting
the ROMK channel and the ENaC.28,30 Serum-
and glucocorticoid-dependent protein kinase 1
also increases ENaC expression and activity
through effects on the ubiquitin-protein ligase
Nedd4-2.31 It should be emphasized that the
absence of angiotensin II is a critical factor in
the ability of high Kþ intake to bring about
the changes necessary to facilitate Kþ secretion
without excessive Naþ reabsorption, a phenom-
enon referred to as the aldosterone paradox.
Kþ-rich foods, such as fruits and vegeta-
bles, are also rich in precursors to bicarbonate
ions. The alkali present in such a diet directly
affects the determinants of Kþ transport in the
DCT so as to facilitate the renal excretion of
the co-ingested Kþ load.32,33 For example,
ENaC abundance is increased when luminal
or basolateral HCO 3 and pH are elevated.
In addition, increased intracellular pH in-
creases the activity of ENaC, ROMK, and
maxi-Kþ channels. These effects of an alkaline
pH provide an additional mechanism to
facilitate Kþ excretion after the ingestion of
such foods.
ENTERIC SENSING OF Kþ INTAKE
A number of enteric solute sensors capable of
responding to dietary Naþ, Kþ, and phosphate
have been identified that signal the kidney to
rapidly alter ion excretion or reabsorption.34-36
In this regard, the ability to sense Kþ within
the gastrointestinal tract may have evolved as a
n n
500 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
way to rapidly initiate the kaliuretic response,
thereby facilitating maintenance of Kþ homeo-
stasis in the setting of high Kþ intake. For
example, the kaliuretic response to a Kþ
load is greater when given as a meal
compared with an intravenous infusion even
in a setting in which plasma Kþ concentra-
tion is identical.37 Gastric delivery of Kþ
leads to an almost complete dephosphoryla-
tion of the Naþ-Cl cotransporter in the early
DCT, causing decreased activity of the trans-
porter, thus enhancing the delivery of Naþ to
the ASDN.38-40 The downstream shift in Naþ
reabsorption from the DCT to the ENaC in
the ASDN as well as increased Kþ secretion
in the maxi-K channel due to increased flow
account for the increase in renal Kþ excre-
tion. This rapid natriuretic response to
increases in dietary Kþ intake is consistent
with the blood pressureelowering effect of
Kþ-rich diets discussed further below. These
data suggest that splanchnic sensing of Kþ
can initiate the renal excretory response inde-
pendent of change in plasma Kþ concentra-
tion or mineralocorticoid activity.
The great facility and prodigious capacity
of the healthy (normal) kidney to excrete Kþ
suggests and substantiates metabolic benefits
associated with the consumption of a high-
Kþ diet. These health benefits are discussed
below (see Table 1).
CLINICAL BENEFITS OF Kþ
SUPPLEMENTATION
Hypertension
Epidemiological studies41 have established
that Kþ intake is inversely related to the
prevalence of hypertension. In addition, Kþ
supplements and avoidance of hypokalemia,
lower blood pressure in people with hyperten-
sion, whereas blood pressure increases in
people with hypertension placed on a low-Kþ
diet. This increase in blood pressure is associ-
ated with increased renal Naþ reabsorption.42
A total of 17,000 adults participated in the
NHANES III, and data obtained from this
study43 suggested that increased dietary Kþ
intakes were associated with lower blood
pressures. Another study44 called Dietary
Approaches to Stop Hypertension trial also
found beneficial effects of a Kþ-rich diet on
blood pressure. The study compared diets
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BENEFITS OF HIGH-POTASSIUM DIET WITHOUT TOXICITY
that consisted of 3.5 servings/d of fruits and
vegetables and 1700 mg/d of Kþ with the
diet of the Dietary Approaches to Stop Hyper-
tension trial, which included 8.5 servings/d of
fruits and vegetables and 4100 mg/d of Kþ.
These findings specifically indicated that the
high-Kþ diet was associated with lower blood
pressure by an average of 2.8/1.1 mm Hg in all
participants and by an average of 7.2/2.8 mm
Hg in those with hypertension. In addition, an
increased Kþ intake of 2300 to 3900 mg/d
substantially reduced blood pressure by an
average of 1.8/1.0 mm Hg in people with
normal blood pressure and 4.4/2.5 mm Hg
in people with hypertension, as reported in a
meta-analysis of 33 randomized controlled
trials including 2609 individuals.45 Blood
pressure lowering was affected by race, as
the effect was more pronounced in black indi-
viduals, as well as in those who consumed
larger amounts of Naþ. Lastly, another meta-
analysis46 of 21 randomized controlled trials
reported that higher Kþ consumption resulted
in lower blood pressure and this was more
pronounced in patients with hypertension or
those consuming a high-Naþ diet.
It has long been appreciated that Kþ has
natriuretic and diuretic effects. As discussed
previously, dietary Kþ intake leads to changes
in KS-WNK1 and long WNK1, which affect
Naþ handling. These effects may be important
in the observed relationship between dietary
Kþ intake and hypertension. A diet deficient
in Kþ increases the ratio of long WNK1 to
KS-WNK1. This response can be viewed as
physiological because long WNK1 increases
retrieval of ROMK and therefore limits secre-
tion under conditions of low Kþ intake. How-
ever, long WNK1 also leads to a stimulatory
effect on ENaC activity as well as alters
WNK4 so that NaCl cotransport is increased
in the early DCT.47-49 These effects suggest
that a Kþ-deficient diet will reduce Kþ secre-
tion at the expense of increased Naþ retention,
thus potentially contributing to increased
blood pressure (Figure 2).
Under conditions of dietary Kþ deficiency,
renal conservation of Kþ and Naþ may have
evolved as an adaptation during development
because typically dietary Kþ and Naþ defi-
ciency likely occurred together.50 Importantly,
this adaptation is potentially deleterious in our
present setting of consumption of low-Kþ,
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high-Naþ foods. The effects of an increased
ratio of long WNK1 to KS-WNK1 in the
kidney under conditions of modern-day high-
Naþ, low-Kþ diet could be central to the path-
ogenesis of salt-sensitive hypertension.51
In addition to effects leading to renal salt
retention, low Kþ intake may contribute to
increased sympathetic tone as a mechanism
causing hypertension. As recently reviewed,
Naþ excess and Kþ deficiency can alter the
electrolyte and hormonal composition of the
cerebral spinal fluid, activating sensors, which
through the hypothalamus leads to neurohu-
moral activation.52 In addition, Naþ retention
and Kþ depletion have been linked to direct
vascular effects, eventuating in increased
vascular tone.
–
↓ [Cl ]
(+)
Na+ (+) Increased NaCl
NCC WNK4
reabsorption
Cl– (+)
L-WNK1
KS-WNK1
(+) Increased Na+
Na+ ENaC L-WNK1
reabsorption via the ENaC
L-WNK1
(–) KS-WNK1
ROMK K+ Decreased K+ secretion
FIGURE 2. Effect of decreased dietary Kþ on Naþ transport in the distal
tubule. Decreased dietary Kþ achieved through a decrease in plasma Kþ
concentration hyperpolarizes cells in the proximal portion of the distal
convoluted tubule (DCT1), leading to decreased intracellular Cl concen-
tration, which, in turn, activates WNK lysine-deficient protein kinase 4
(WNK4). Kþ deficiency is associated with increases in the ratio of long
WNK lysine-deficient protein kinase 1 (WNK1) to kidney specific
(KS)-WNK1. An increase in this ratio (L-WNK1/KS-WNK1) leads to an
increased retrieval of renal outer medullary Kþ (ROMK) from the apical
membrane, thereby minimizing Kþ secretion, which would be an appro-
priate response to the Kþ-deficient diet. Increased L-WNK1/KS-WNK1 also
alters WNK4 activity such that activity of the thiazide-sensitive Naþ-Cl
cotransporter (NCC) is increased. In addition, increased L-WNK1 leads to
an increased activity of the epithelial Naþ channel (ENaC). These last 2
effects lead to salt retention and thus could explain the genesis of salt-
sensitive hypertension in patients ingesting Kþ-deficient diets.
501

Stroke
Several large epidemiological studies have
suggested that increased Kþ intake is associ-
ated with a decreased risk of stroke. A pro-
spective study53 of more than 43,000 men
followed for 8 years found that men in the
top quintile of dietary Kþ intake (median
intake, 4300 mg/d) were significantly less
likely (62%) to have a stroke than those
in the lowest quintile of Kþ intake (median
intake, 2400 mg/d). This inverse association
was especially strong in men with hypertension.
Furthermore, an analysis of 11 cohort studies
with a total of 127,038 participants reported
that Kþ intake in the range of 90 to 120
mmol/d was associated with a decreased risk
of stroke (relative risk, 0.79; 95% CI, 0.68-
0.93).46 Ingestion of a low-Kþ diet (<34.6
mmol/d) in 9805 men and women followed
for an average of 19 years experienced a 28%
higher risk of stroke.54 In 90,137 postmeno-
pausal women aged 50 to 79 years followed pro-
spectively for an average of 11 years, higher Kþ
intake was associated with a lower risk of all
strokes and ischemic stroke.55
Taken together, these epidemiological data
suggest that a modest increase in fruits and
vegetable intake (rich sources of dietary Kþ),
especially in those with hypertension and/or
relatively low-Kþ intakes, could significantly
reduce the risk of stroke.56 Although much
of the ability of increased Kþ consumption
to lower the risk of stroke is through its effects
to lower blood pressure, studies in experi-
mental animals support additional mecha-
nisms for stroke prevention primarily related
to the inhibition of atherosclerotic lesion
formation and progression. Increased extracel-
lular Kþ concentration achieved through
increased intake has been found to decrease
vascular smooth muscle cell proliferation and
migration, free radical formation, and platelet
aggregation.57
Osteoporosis
Kþ-rich foods, such as fruits and vegetables,
are rich in precursors to bicarbonate ions,
which buffer acids in the body. The modern
Western diet tends to be relatively low in sour-
ces of alkali (fruits and vegetables) and high in
sources of acid (fish, meats, and cheeses).
When the quantity of bicarbonate ions is
insufficient to maintain normal pH, the body
n n
502 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
mobilizes alkaline calcium salts from the
bone to neutralize the acids consumed in the
diet and generated by metabolism. Increased
consumption of fruits and vegetables reduces
the net acid content of the diet and may preserve
calcium in bones, which might otherwise be
mobilized to maintain normal pH. In addition
to providing a more alkaline diet, the larger
amount of Kþ in fruits and vegetables may
exert an anion-independent effect on bone meta-
bolism. Addition of KCl to Kþ-depleted mouse
calvariae reduces bone resorption and net
calcium efflux and increases bone collagen
synthesis.58
In a study59 of 18 postmenopausal
women, potassium bicarbonate supplementa-
tion decreased urinary acid and calcium excre-
tion, resulting in increased biomarkers of bone
formation and decreased biomarkers of bone
resorption. In a study60 of 266 elderly post-
menopausal women, increased dietary Kþ as
determined from 24-hour urine collections
was associated with significantly higher hip
(at 1 and 5 years) and total body (at 5 years)
bone mineral densities as compared with those
with lower amounts of Kþ intake. Increased
fruits and vegetable intake accompanied by
higher levels of Kþ consumption have been
found to exert similar beneficial effects on
bone mineral density, including biomarkers
of bone formation in premenopausal and post-
menopausal women and elderly men.61 Over-
all, ingestion of Kþ-rich fruits and vegetables
may help lower the risk of osteoporosis.
Nephrolithiasis
Abnormally high urinary calcium (hypercal-
ciuria) and low urinary citrate concentrations
increase the risk of developing kidney stones.
In individuals with a history of developing
calcium-containing kidney stones, increased
dietary acid loads are significantly associated
with increased urinary calcium excretion and
decreased urinary citrate. Kþ deprivation has
also been found to increase urinary calcium
excretion as well as reduce urinary citrate.62,63
Increasing dietary Kþ (and thereby increasing
the alkali content) facilitated by increasing fruit
and vegetable consumption, or by taking potas-
sium bicarbonate supplements, has been found
to decrease urinary calcium and increase urinary
citrate and lower urinary urate. As discussed
earlier, increasing plasma Kþ concentration
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BENEFITS OF HIGH-POTASSIUM DIET WITHOUT TOXICITY
will lead to a decreased activity of NCC in the
DCT1. Urinary calcium decreases in a manner
similar to that which occurs with thiazide
diureticeinduced inhibition of NCC. Increased
dietary Kþ intake derived from Kþ-rich foods,
such as fruits and vegetables, in prospective
trials64,65 has been shown to significantly
reduce the risk of kidney stones in both men
and women as compared with those with low
Kþ intake.
USE OF Kþ-ENRICHED DIET IN CHRONIC
KIDNEY DISEASE
Although ingestion of a Kþ-enriched diet can
safely provide the aforementioned benefits to
patients with normal renal function, develop-
ment of life-threatening hyperkalemia may
limit the ability to use such a diet in patients
with chronic kidney disease (CKD). This
toxicity creates a therapeutic dilemma because
a diet rich in fruits and vegetables may offer
benefits that are unique to patients with
CKD. These benefits are discussed below.
Phosphorus Control
Two important aspects of nutritional manage-
ment in patients with CKD are maintenance of
adequate protein intake and prevention of
phosphate overload and hyperphosphatemia.
This can be problematic because organic phos-
phorus is bound to protein and the amount of
protein eaten will predictably determine phos-
phorus intake. Organic phosphorus from
plant protein has a lower absorption rate
than does phosphorus from animal protein,
ranging from 40% to 50%, because phos-
phorus from plants is in the form of phytates
and mammals lack phytases. Phosphorus in
animal protein is in the form of organic phos-
phate, which is readily hydrolyzed and
absorbed.66
In a model of progressive CKD, rats were
fed either a casein-based or a grain-based pro-
tein diet, both of which had equivalent total
phosphorus content. Despite maintaining the
same serum phosphorous concentration, the
casein-fed animals had increased urinary
phosphorus excretion and increased serum
fibroblast growth factor 23 levels as compared
with the grain-fed rats, which was consistent
with increased gastrointestinal absorption with
the casein-based diet.67 Phosphate homeostasis
was examined in a crossover trial68 of 9 patients
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with CKD comparing a diet rich in animal or
vegetable protein for 7 days. Despite equivalent
protein and phosphorus concentrations in the
diet, ingestion of the vegetarian diet had lower
serum phosphorus levels and significantly
reduced fibroblast growth factor 23 levels,
which was again consistent with the reduced
gastrointestinal absorption of phosphate. These
data suggest that ingestion of a diet rich in plant
protein could be a viable strategy to maintain
adequate protein intake with less tendency to
cause phosphorus overload.
Control of Metabolic Acidosis
The reduction in renal mass in CKD leads to
decreased capacity for net acid excretion,
resulting in the development of chronic meta-
bolic acidosis. Current guidelines suggest that
metabolic acidosis should be treated with the
goal of maintaining the serum bicarbonate
concentration in the normal range (23-29
mEq/L) to avoid complications of chronic
acidosis, including protein-energy wasting,
insulin resistance, bone demineralization, and
progression of renal disease.69,70 The usual
therapy is oral NaHCO3, but this approach is
associated with increased Naþ intake and can
exacerbate the volume expansion and hyper-
tension commonly present in CKD. In addi-
tion some patients are intolerant because of
complications of bloating. Because the modern
Western diet leads to increased net acid pro-
duction, an alternative approach is to increase
the consumption of fruits and vegetables,
which is associated with alkali precursors
and is not accompanied by a salt load.71,72
This strategy was tested in a group of pa-
tients with stage 2 CKD due to hypertensive
nephrosclerosis. Urine indices of renal injury
were measured and compared after 30 days
of increased fruit and vegetable consumption
vs oral NaHCO3 therapy. Reduction in urinary
albumin and N-acetyl b-D-glucosaminidase
was similar between the 2 groups. In addition,
the fruit and vegetable diet (which is rich in
Kþ, as discussed previously) resulted in a
significantly greater reduction in systolic blood
pressure.73 In a similar study,74 71 patients
with stage 4 CKD and serum bicarbonate level
less than 22 mEq/L were randomized to 1 year
of sodium bicarbonate at 1.0 mEq/kg per day
or increased fruits and vegetables to reduce
dietary acid by half. Serum bicarbonate levels
503
 MAYO CLINIC PROCEEDINGS

increased with the dietary intervention,
although less than in the bicarbonate group,
whose alkali dose would be expected to almost
completely neutralize the dietary acid load.
The aforementioned markers of kidney injury
declined similarly in the 2 groups. These find-
ings suggest that the alkali load afforded by a
diet rich in fruits and vegetables can slow
the progression of CKD through correction
of metabolic acidosis. In addition to avoiding
the salt load and potential volume overload
that can complicate NaHCO3 therapy, the
diet is associated with reduction in blood pres-
sure, possibly related to increased Kþ intake.
Importantly, there were no complications
due to hyperkalemia, but only patients with
plasma Kþ levels 4.6 mEq/L or less were
enrolled in the study.
Management of Hyperkalemia
Although there are clear benefits of ingestion
of Kþ, the development of hyperkalemia
(defined by serum Kþ levels >5.0 mEq/L)
can be a limiting factor in implementing
such a diet because of the risk of cardiac
arrhythmias and increased mortality.75 The
risk of hyperkalemia is particularly high in
patients with CKD and in the setting of drugs
that interfere with Kþ homeostasis, such as
renin-angiotensin-aldosterone system (RAAS)
blockers. The initial approach to managing
hyperkalemia is eliminating other sources of
Kþ such as supplements (including those
found in salt substitutes and some herbal
medications), discontinuing prescribed or over-
the-counter drugs known to interfere with renal
Kþ excretion (nonsteroidal anti-inflammatory
drugs), and ensuring effective diuretic therapy
(Table 2).76
Pharmacological management of hyperka-
lemia has relied for more than 50 years on
the chronic use of sodium polystyrene sulfo-
nate (Kayexalate), which binds Kþ in the
gastrointestinal tract; however, this is poorly
tolerated and has been linked to gastrointes-
tinal toxicity. Moreover, long-term administra-
tion is linked to serious adverse effects such
as rare cases of intestinal necrosis, resulting
in a blackbox warning by the Food and
Drug Administration. Recently, there are new
oral compoundsdpatiromer (Veltassa) and
sodium zirconium cyclosilicatedthat are Kþ-
binding drugs shown to be effective in pre-
venting development of hyperkalemia.
Patiromer is approved for clinical use, and
sodium zirconium cyclosilicate is pending
approval. Both agents exhibit good tolerability
and are not associated with serious adverse
effects. Recently, clinical trials found that these
compounds lower the risk of incident hyper-
kalemia associated with RAAS blockade in
people with diabetes, those with heart failure,
and/or those who have CKD. Patiromer is a
nonabsorbed polymer that binds Kþ in the
gastrointestinal tract, predominately in the
colon. Patiromer effectively decreases serum

TABLE 2. Approach to Minimize Risk of Hyperkalemia When Ingesting High-Kþ Diet

d Accurately assess level of renal function to better define risk
d Discontinue drugs that interfere with renal Kþ secretion, inquire about herbal preparations, and discontinue
nonsteroidal anti-inflammatory drugs to include the selective cyclooxygenase 2 inhibitors
d Inquire about Kþ-containing salt substitutes
d Thiazide or loop diuretics (loop diuretics necessary when estimated glomerular filtration rate is <30 mL/min)
d Sodium bicarbonate to correct metabolic acidosis in patients with chronic kidney disease
d Initiate therapy with low-dose ACE inhibitor or angiotensin receptor blocker
B Measure Kþ 1 wk after the initiation of therapy or after increasing the dose of the drug
B For increases in Kþ concentration up to 5.5 mEq/L, decrease the dose of the drug; if taking some combination of
ACE inhibitor, angiotensin receptor blocker, and aldosterone receptor blocker, discontinue one and recheck Kþ
concentration
B The dose of spironolactone should not exceed 25 mg/d when used with an ACE inhibitor or angiotensin
receptor blocker; this combination of drugs should be avoided with a glomerular filtration rate of <30 mL/min
B For Kþ concentration 5.6 mEq/L despite above steps, discontinue drugs
d Consider long-term use of new Kþ-binding drugs (patiromer or sodium zirconium cyclosilicate)

ACE ¼ angiotensin-converting enzyme.

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BENEFITS OF HIGH-POTASSIUM DIET WITHOUT TOXICITY
Kþ concentrations in high-risk patients taking
RAAS blockers, including those with heart
failure, those with CKD, and those with dia-
betic nephropathy.77 In a study of more than
300 patients with diabetic nephropathy with
either mild to moderate hyperkalemia, the
drug lowered the serum Kþ concentration in
a dose-dependent manner, with the greatest
reduction in those with higher starting values.
The drug remained effective in controlling
plasma Kþ concentration over a 44-week
maintenance phase despite ongoing adminis-
tration of RAAS inhibitors.78 The drug was
well tolerated, with the main adverse events
being constipation (infrequent and self-limiting)
and hypomagnesemia, which required magne-
sium replacement in a small number of
participants.
Sodium zirconium cyclosilicate is a nonab-
sorbed microporous compound that binds Kþ
throughout the gastrointestinal tract. The pore
size renders it highly selective for the Kþ ion as
compared with calcium or magnesium ions.
Like patiromer, this drug has also been shown
effective in lowering plasma Kþ concentration
in a dose-dependent manner, with a greater
reduction in those with the highest levels.79,80
However, despite being well tolerated, there
are reports of edema at higher doses.
Importantly, dietary Kþ intake was not
specifically controlled in the clinical trials
with patiromer and sodium zirconium cyclosi-
licate. Although the effectiveness of these
drugs in patients purposely ingesting a Kþ-
enriched diet has not been studied, their
ability to control plasma Kþ concentration in
those patients with a history of hyperkalemia
despite ongoing use of RAAS blockers suggests
that these agents could prove useful in allow-
ing patients at risk for hyperkalemia to liber-
alize their diets to include Kþ-rich sources
such as fruits and vegetables. In addition to
improving the quality of life through liber-
alization of diets, these high-risk patients
could enjoy the cardiovascular and metabolic
benefits afforded by such a dietary change.
IMPLEMENTATION OF Kþ-ENRICHED DIETS
IN PATIENTS AT RISK FOR HYPERKALEMIA
In a recent observational study81 of patients
with type 2 diabetes, higher urinary Kþ excre-
tion was associated with lower cardiovascular
complications and a slower decline of renal
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function, further supporting the association
between increased Kþ intake and cardiovascu-
lar benefits. Importantly, participants in this
trial had normal baseline renal function. There
are no long-term studies examining the bene-
fits of a Kþ-enriched diet in patients with CKD
because of the concern for development of life-
threatening hyperkalemia. In addition to the
potential benefits of better phosphate control
and amelioration of metabolic acidosis dis-
cussed previously, one speculation arises
whether liberalization of dietary Kþ in patients
with CKD may provide long-term cardiovas-
cular benefits. Management of patients with
CKD typically involves some degree of Kþ
restriction, which is further reinforced as
patients transition to end-stage renal disease
and ultimately dialysis. With the advent of
novel Kþ-binding agents, it is interesting to
speculate whether clinical trials focusing on
liberalization of the diet to include sources of
Kþ might provide cardiovascular benefits in
this patient population. Although not specif-
ically tested as an approach to prevent diet-
induced hyperkalemia, these new compounds
are well tolerated and could be used to study
whether patients with CKD would benefit
from liberalization of dietary Kþ, potentially
contributing to a better quality of life.
CONCLUSION
There are abundant data suggesting that inges-
tion of Kþ-rich foods is beneficial and may
reduce the incidence of stroke, hypertension,
nephrolithiasis, and osteoporosis. The data
on dietary consumption indicate that Western
diets are high in processed foods, high in Naþ
content, and low in Kþ. The kidney is
designed to handle significantly higher Kþ
loads than are currently consumed in our
diet. Furthermore, patients who could most
benefit from increasing their intake of Kþ-
rich foods are the very same patients who
are unable to do so because of reductions in
renal function. Specifically, cardiovascular dis-
ease is prevalent in patients with reduced renal
function, and therefore one would argue that
this patient population would benefit the
most from ingesting diets enriched in Kþ.
Currently, the standard treatment for hyper-
tension in these patients is the use of RAAS
blockers, pharmacology that results in hyper-
kalemia, necessitating the use of a low-Kþ
505

diet. There are 2 new therapeutic options to
chronically treat hyperkalemia, affording the
speculation that these drugs may allow for
liberalization of dietary Kþ so as to maximize
cardiovascular benefits.
It is important to rethink the role of Kþ in
the diet, especially when it is recognized that
Western diets result in overconsumption of
Naþ and underconsumption of Kþ, leading
to increased disease prevalence. People are
actively seeking dietary changes and are
embracing diets such as the Paleolithic diet
that tout their benefits of reduced consump-
tion of processed foods (and thereby Naþ)
and increased consumption of fruits and vege-
tables (and thereby Kþ). We conclude by
restating that Kþ, an often underappreciated
cation/mineral, may be directly related to
health benefits.
Abbreviations and Acronyms: ASDN = aldosterone-
sensitive distal nephron; CKD = chronic kidney disease;
DCT = distal convoluted tubule; DCT1 = proximal portion
of the distal convoluted tubule; DCT2 = distal portion of
the distal convoluted tubule; ENaC = epithelial Naþ
channel; KS = kidney specific; NCC = NaCl cotransporter;
NHANES = National Health and Nutrition Examination
Survey; RAAS = renin-angiotensin-aldosterone system;
ROMK = renal outer medullary Kþ; WNK = with no lysine
family of kinases; WNK1 = WNK lysine-deficient protein
kinase 1; WNK4 = WNK lysine-deficient protein kinase 4
Correspondence: Address to Deborah J. Clegg, PhD,
Biomedical Research Department, Diabetes and Obesity
Research Institute, Cedars-Sinai Medical Center, Beverly
Hills, CA (Deborah.clegg@cshs.org).
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