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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
P
otassium is an extremely important
mineral, as supported by the recent industrialized societies lower in Kþ intake, but
From the Department of In- Dietary Guidelines for Americans they also differ from prehistoric cultures with
ternal Medicine, University of
Texas Southwestern Medical
and the Food and Drug Administration respect to Naþ intake. The daily intake of salt
Center, Dallas (B.F.P.); and designation that Kþ is a “nutrient of public in Western industrialized societies is about 3
Biomedical Research Depart- health concern” because of its general under- times higher than the daily intake of Kþ on a
ment, Diabetes and Obesity
Research Institute, Cedars-
consumption across the US population.1 molar basis, whereas salt intake in primitive
Sinai Medical Center, Beverly Underconsumption of Kþ is associated with cultures is approximately 7 times lower than
Hills, CA (D.J.C.). hypertension and cardiovascular diseases, Kþ intake.6
2 common adverse diet-related health out- The changes in Kþ and Naþ intake over
comes in the United States.1 In 2004, the time reflect a shift from traditional plant-
Food and Nutrition Board of the Institute based diets high in Kþ and low in Naþ (char-
of Medicine2 recommended intake levels of acterized by fruits, leafy greens, roots, and
4700 mg/d. Despite these recommendations, tubers) to processed foods high in Naþ and
data from the National Health and Nutrition low in Kþ. The transition to processed foods
Examination Survey (NHANES) 2007 to began approximately 10,000 years ago with
2008 estimated mean intakes in the United the onset of agriculture. This time period is
States to be 2290 mg/d for women and short in comparison to the preceding several
3026 mg/d for men, substantially lower million-year period dating from the Stone
than the suggested values.3 This relative Age to the onset of agriculture. Inadequate con-
“deficiency” of dietary Kþ is even more note- sumption of Kþ combined with excessive intake
worthy when one considers that the Kþ of Naþ contributes to the pathophysiology of
intake of prehistoric humans was estimated various chronic diseases such as obesity, hyper-
to be 15,000 mg/d, which actually exceeds tension, diabetes, kidney stones, and bone
the NHANES recommendations by a factor disease.
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 delivery to more distal portions of the tubule.
response to dietary Kþ contribute to the phy- The increase in KS-WNK1 in response to high
siological regulation of renal Kþ excretion.22-25 Kþ intake also antagonizes the effect of long
Under normal circumstances, long WNK1 WNK1 to stimulate endocytosis of ROMK.
prevents the ability of WNK4 (another mem- In addition, KS-WNK1 exerts a stimulatory
ber of the WNK family) to inhibit the activity effect on the ENaC. In total, increases in
of the Naþ-Cl cotransporter in the DCT. KS-WNK1 in response to dietary Kþ loading
Thus, increased activity of long WNK1 leads facilitates Kþ secretion through the combined
to a net increase in NaCl reabsorption. Dietary effects of increased Naþ delivery through the
Kþ loading increases the abundance of down-regulation of Naþ-Cl cotransport in
KS-WNK1, which has the effect to block the the early DCT, increased electrogenic Naþ reab-
inhibitory effect of long WNK1 on WNK4. sorption via the ENaC, and greater abundance
The net effect is inhibition of Naþ-Cl of ROMK. These effects can occur indepen-
cotransport in the DCT and increased Naþ dently of any change in mineralocorticoid
activity, suggesting an intrinsic sensing capa- way to rapidly initiate the kaliuretic response,
bility of this segment to changes in dietary Kþ.19 thereby facilitating maintenance of Kþ homeo-
Recent studies26,27 suggest that extracel- stasis in the setting of high Kþ intake. For
lular Kþ modulates the WNK axis by altering example, the kaliuretic response to a Kþ
membrane voltage and changing intracellular load is greater when given as a meal
chloride concentration. An increased plasma compared with an intravenous infusion even
Kþ concentration as with increased dietary in a setting in which plasma Kþ concentra-
intake would depolarize cells in the DCT1, tion is identical.37 Gastric delivery of Kþ
resulting in increased intracellular Cl concen- leads to an almost complete dephosphoryla-
tration. This increase alters WNK4 activity in tion of the Naþ-Cl cotransporter in the early
such a way that activity of NCC is decreased. DCT, causing decreased activity of the trans-
The unique sensitivity of WNK4 to Cl is porter, thus enhancing the delivery of Naþ to
consistent with this model. the ASDN.38-40 The downstream shift in Naþ
High Kþ intake also has a stimulatory reabsorption from the DCT to the ENaC in
effect on the release of aldosterone at the level the ASDN as well as increased Kþ secretion
of the adrenal gland. Increased aldosterone in the maxi-K channel due to increased flow
compliments the effect of KS-WNK1 in the account for the increase in renal Kþ excre-
DCT.28,29 Aldosterone up-regulates serum- tion. This rapid natriuretic response to
and glucocorticoid-dependent protein kinase 1, increases in dietary Kþ intake is consistent
which, in turn, phosphorylates WNK4. This with the blood pressureelowering effect of
modification prevents WNK4 from inhibiting Kþ-rich diets discussed further below. These
the ROMK channel and the ENaC.28,30 Serum- data suggest that splanchnic sensing of Kþ
and glucocorticoid-dependent protein kinase 1 can initiate the renal excretory response inde-
also increases ENaC expression and activity pendent of change in plasma Kþ concentra-
through effects on the ubiquitin-protein ligase tion or mineralocorticoid activity.
Nedd4-2.31 It should be emphasized that the The great facility and prodigious capacity
absence of angiotensin II is a critical factor in of the healthy (normal) kidney to excrete Kþ
the ability of high Kþ intake to bring about suggests and substantiates metabolic benefits
the changes necessary to facilitate Kþ secretion associated with the consumption of a high-
without excessive Naþ reabsorption, a phenom- Kþ diet. These health benefits are discussed
enon referred to as the aldosterone paradox. below (see Table 1).
Kþ-rich foods, such as fruits and vegeta-
bles, are also rich in precursors to bicarbonate CLINICAL BENEFITS OF Kþ
ions. The alkali present in such a diet directly SUPPLEMENTATION
affects the determinants of Kþ transport in the
DCT so as to facilitate the renal excretion of Hypertension
the co-ingested Kþ load.32,33 For example, Epidemiological studies41 have established
ENaC abundance is increased when luminal that Kþ intake is inversely related to the
or basolateral HCO 3 and pH are elevated. prevalence of hypertension. In addition, Kþ
In addition, increased intracellular pH in- supplements and avoidance of hypokalemia,
creases the activity of ENaC, ROMK, and lower blood pressure in people with hyperten-
maxi-Kþ channels. These effects of an alkaline sion, whereas blood pressure increases in
pH provide an additional mechanism to people with hypertension placed on a low-Kþ
facilitate Kþ excretion after the ingestion of diet. This increase in blood pressure is associ-
such foods. ated with increased renal Naþ reabsorption.42
A total of 17,000 adults participated in the
ENTERIC SENSING OF Kþ INTAKE NHANES III, and data obtained from this
A number of enteric solute sensors capable of study43 suggested that increased dietary Kþ
responding to dietary Naþ, Kþ, and phosphate intakes were associated with lower blood
have been identified that signal the kidney to pressures. Another study44 called Dietary
rapidly alter ion excretion or reabsorption.34-36 Approaches to Stop Hypertension trial also
In this regard, the ability to sense Kþ within found beneficial effects of a Kþ-rich diet on
the gastrointestinal tract may have evolved as a 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 high-Naþ foods. The effects of an increased
vegetables and 1700 mg/d of Kþ with the ratio of long WNK1 to KS-WNK1 in the
diet of the Dietary Approaches to Stop Hyper- kidney under conditions of modern-day high-
tension trial, which included 8.5 servings/d of Naþ, low-Kþ diet could be central to the path-
fruits and vegetables and 4100 mg/d of Kþ. ogenesis of salt-sensitive hypertension.51
These findings specifically indicated that the In addition to effects leading to renal salt
high-Kþ diet was associated with lower blood retention, low Kþ intake may contribute to
pressure by an average of 2.8/1.1 mm Hg in all increased sympathetic tone as a mechanism
participants and by an average of 7.2/2.8 mm causing hypertension. As recently reviewed,
Hg in those with hypertension. In addition, an Naþ excess and Kþ deficiency can alter the
increased Kþ intake of 2300 to 3900 mg/d electrolyte and hormonal composition of the
substantially reduced blood pressure by an cerebral spinal fluid, activating sensors, which
average of 1.8/1.0 mm Hg in people with through the hypothalamus leads to neurohu-
normal blood pressure and 4.4/2.5 mm Hg moral activation.52 In addition, Naþ retention
in people with hypertension, as reported in a and Kþ depletion have been linked to direct
meta-analysis of 33 randomized controlled vascular effects, eventuating in increased
trials including 2609 individuals.45 Blood vascular tone.
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- –
↓ [Cl ]
analysis46 of 21 randomized controlled trials (+)
reported that higher Kþ consumption resulted Na+ (+) Increased NaCl
NCC WNK4
in lower blood pressure and this was more reabsorption
Cl– (+)
pronounced in patients with hypertension or
those consuming a high-Naþ diet. L-WNK1
It has long been appreciated that Kþ has
KS-WNK1
will lead to a decreased activity of NCC in the with CKD comparing a diet rich in animal or
DCT1. Urinary calcium decreases in a manner vegetable protein for 7 days. Despite equivalent
similar to that which occurs with thiazide protein and phosphorus concentrations in the
diureticeinduced inhibition of NCC. Increased diet, ingestion of the vegetarian diet had lower
dietary Kþ intake derived from Kþ-rich foods, serum phosphorus levels and significantly
such as fruits and vegetables, in prospective reduced fibroblast growth factor 23 levels,
trials64,65 has been shown to significantly which was again consistent with the reduced
reduce the risk of kidney stones in both men gastrointestinal absorption of phosphate. These
and women as compared with those with low data suggest that ingestion of a diet rich in plant
Kþ intake. protein could be a viable strategy to maintain
adequate protein intake with less tendency to
USE OF Kþ-ENRICHED DIET IN CHRONIC cause phosphorus overload.
KIDNEY DISEASE
Although ingestion of a Kþ-enriched diet can Control of Metabolic Acidosis
safely provide the aforementioned benefits to The reduction in renal mass in CKD leads to
patients with normal renal function, develop- decreased capacity for net acid excretion,
ment of life-threatening hyperkalemia may resulting in the development of chronic meta-
limit the ability to use such a diet in patients bolic acidosis. Current guidelines suggest that
with chronic kidney disease (CKD). This metabolic acidosis should be treated with the
toxicity creates a therapeutic dilemma because goal of maintaining the serum bicarbonate
a diet rich in fruits and vegetables may offer concentration in the normal range (23-29
benefits that are unique to patients with mEq/L) to avoid complications of chronic
CKD. These benefits are discussed below. acidosis, including protein-energy wasting,
insulin resistance, bone demineralization, and
Phosphorus Control progression of renal disease.69,70 The usual
Two important aspects of nutritional manage- therapy is oral NaHCO3, but this approach is
ment in patients with CKD are maintenance of associated with increased Naþ intake and can
adequate protein intake and prevention of exacerbate the volume expansion and hyper-
phosphate overload and hyperphosphatemia. tension commonly present in CKD. In addi-
This can be problematic because organic phos- tion some patients are intolerant because of
phorus is bound to protein and the amount of complications of bloating. Because the modern
protein eaten will predictably determine phos- Western diet leads to increased net acid pro-
phorus intake. Organic phosphorus from duction, an alternative approach is to increase
plant protein has a lower absorption rate the consumption of fruits and vegetables,
than does phosphorus from animal protein, which is associated with alkali precursors
ranging from 40% to 50%, because phos- and is not accompanied by a salt load.71,72
phorus from plants is in the form of phytates This strategy was tested in a group of pa-
and mammals lack phytases. Phosphorus in tients with stage 2 CKD due to hypertensive
animal protein is in the form of organic phos- nephrosclerosis. Urine indices of renal injury
phate, which is readily hydrolyzed and were measured and compared after 30 days
absorbed.66 of increased fruit and vegetable consumption
In a model of progressive CKD, rats were vs oral NaHCO3 therapy. Reduction in urinary
fed either a casein-based or a grain-based pro- albumin and N-acetyl b-D-glucosaminidase
tein diet, both of which had equivalent total was similar between the 2 groups. In addition,
phosphorus content. Despite maintaining the the fruit and vegetable diet (which is rich in
same serum phosphorous concentration, the Kþ, as discussed previously) resulted in a
casein-fed animals had increased urinary significantly greater reduction in systolic blood
phosphorus excretion and increased serum pressure.73 In a similar study,74 71 patients
fibroblast growth factor 23 levels as compared with stage 4 CKD and serum bicarbonate level
with the grain-fed rats, which was consistent less than 22 mEq/L were randomized to 1 year
with increased gastrointestinal absorption with of sodium bicarbonate at 1.0 mEq/kg per day
the casein-based diet.67 Phosphate homeostasis or increased fruits and vegetables to reduce
was examined in a crossover trial68 of 9 patients dietary acid by half. Serum bicarbonate levels
increased with the dietary intervention, found in salt substitutes and some herbal
although less than in the bicarbonate group, medications), discontinuing prescribed or over-
whose alkali dose would be expected to almost the-counter drugs known to interfere with renal
completely neutralize the dietary acid load. Kþ excretion (nonsteroidal anti-inflammatory
The aforementioned markers of kidney injury drugs), and ensuring effective diuretic therapy
declined similarly in the 2 groups. These find- (Table 2).76
ings suggest that the alkali load afforded by a Pharmacological management of hyperka-
diet rich in fruits and vegetables can slow lemia has relied for more than 50 years on
the progression of CKD through correction the chronic use of sodium polystyrene sulfo-
of metabolic acidosis. In addition to avoiding nate (Kayexalate), which binds Kþ in the
the salt load and potential volume overload gastrointestinal tract; however, this is poorly
that can complicate NaHCO3 therapy, the tolerated and has been linked to gastrointes-
diet is associated with reduction in blood pres- tinal toxicity. Moreover, long-term administra-
sure, possibly related to increased Kþ intake. tion is linked to serious adverse effects such
Importantly, there were no complications as rare cases of intestinal necrosis, resulting
due to hyperkalemia, but only patients with in a blackbox warning by the Food and
plasma Kþ levels 4.6 mEq/L or less were Drug Administration. Recently, there are new
enrolled in the study. oral compoundsdpatiromer (Veltassa) and
sodium zirconium cyclosilicatedthat are Kþ-
Management of Hyperkalemia binding drugs shown to be effective in pre-
Although there are clear benefits of ingestion venting development of hyperkalemia.
of Kþ, the development of hyperkalemia Patiromer is approved for clinical use, and
(defined by serum Kþ levels >5.0 mEq/L) sodium zirconium cyclosilicate is pending
can be a limiting factor in implementing approval. Both agents exhibit good tolerability
such a diet because of the risk of cardiac and are not associated with serious adverse
arrhythmias and increased mortality.75 The effects. Recently, clinical trials found that these
risk of hyperkalemia is particularly high in compounds lower the risk of incident hyper-
patients with CKD and in the setting of drugs kalemia associated with RAAS blockade in
that interfere with Kþ homeostasis, such as people with diabetes, those with heart failure,
renin-angiotensin-aldosterone system (RAAS) and/or those who have CKD. Patiromer is a
blockers. The initial approach to managing nonabsorbed polymer that binds Kþ in the
hyperkalemia is eliminating other sources of gastrointestinal tract, predominately in the
Kþ such as supplements (including those colon. Patiromer effectively decreases serum
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504 Mayo Clin Proc. April 2016;91(4):496-508 http://dx.doi.org/10.1016/j.mayocp.2016.01.012
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BENEFITS OF HIGH-POTASSIUM DIET WITHOUT TOXICITY
diet. There are 2 new therapeutic options to 8. Hené RJ, Koomans HA, Boer P, Dorhout Mees EJ. Adaptation
to chronic potassium loading in normal man. Miner Electrolyte
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Correspondence: Address to Deborah J. Clegg, PhD, ascending limb. Am J Physiol Renal Physiol. 2012;303(5):
Biomedical Research Department, Diabetes and Obesity F667-F673.
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