Potassium Homeostasis, Oxidative Stress, and Human Disease

Abstract

Potassium is the most abundant cation in the intracellular fluid and it plays a vital role in the maintenance of normal cell functions. Thus, potassium homeostasis across the cell membrane, is very critical because a tilt in this balance can result in different diseases that could be life threatening. Both Oxidative stress (OS) and potassium imbalance can cause life threatening health conditions. OS and abnormalities in potassium channel have been reported in neurodegenerative diseases. This review highlights the major factors involved in potassium homeostasis (dietary, hormonal, genetic, and physiologic influences), and discusses the major diseases and abnormalities associated with potassium imbalance including hypokalemia, hyperkalemia, hypertension, chronic kidney disease, and Gordon's syndrome, Bartter syndrome, and Gitelman syndrome.

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© 2017 International Journal of Clinical and Experimental Physiology | Published by Wolters Kluwer - Medknow 111
Abstract
Review Article
IntRoductIon
Electrolyte balance is important for general functioning of the
body, and it is closely monitored in clinical settings because
electrolytic abnormalities are caused by a wide variety of factors
and may lead to a wide variety of disorders. The most common
electrolytes in the body are sodium, potassium, and chloride
that are often measured in the laboratory using ion-selective
electrodes technology. Maintenance of the balance between
water and electrolyte composition of the body in a healthy
individual requires specic stringent homeostatic mechanisms.
Water constitutes 60% of the lean body mass, and it is
described in terms of intracellular uid (ICF) and extracellular
uid (ECF). ECF includes the uid inside blood cells and blood
plasma. A constant osmotic equilibrium is maintained between
the ICF and ECF, however, their electrolyte composition
differs. ECF contains mostly sodium cations while the ICF has
an abundance of potassium cations primarily in muscles.[1-4]
However, about 2% of the total body potassium can be found
in the ECF. In a normal healthy person, the plasma potassium
is maintained within a narrow range of 3.5–5.0 mEq/L.[5]
Potassium homeostasis involves redistribution of potassium
between cells ICF and the ECF. The control of the movement
of potassium from intracellular to extracellular space is one of
the ways that the body’s potassium balance is maintained. The
body has a way to maintain this balance for example, when
potassium is lost through the renal system, the body pushes
out cellular potassium which prevents the expected drop in
plasma potassium level. Potassium intake, renal excretion, and
loss through the gastrointestinal tract are crucial in potassium
homeostasis.[6]
Potassium homeostasis is highly inuenced by the activities
of the sodium and potassium pump (Na+-K+-ATPase) which
facilitates the active transport of sodium and potassium ions
across the cell membrane against their concentration gradients.
The Na+-K+-ATPase is found in the membrane of almost all
animal cells, and it pumps sodium ions (Na+) out of the cell
and potassium ion (K+) into the cell. This pump keeps the
K+ - balance between the ICF and ECF primarily through a
buffering that involves hydrolysis of ATP to generate energy,
Potassium is the most abundant cation in the intracellular uid, and it plays a vital role in the maintenance of normal cell functions. Thus,
potassium homeostasis across the cell membrane is very critical because a tilt in this balance can result in different diseases that could be
life-threatening. Both oxidative stress (OS) and potassium imbalance can cause signicant adverse health conditions. OS and abnormalities
in potassium channel have been reported in neurodegenerative diseases. This review highlights the major factors involved in potassium
homeostasis (dietary, hormonal, genetic, and physiologic inuences), and discusses the major diseases and abnormalities associated with
potassium imbalance including hypokalemia, hyperkalemia, hypertension, chronic kidney disease, and Gordon’s syndrome, Bartter syndrome,
and Gitelman syndrome.
Keywords: Differential diagnosis, hyperkalemia, hypokalemia, oxidative stress, potassium excretion, potassium homeostasis
Address for correspondence: Dr. Paul B Tchounwou,
Molecular Toxicology Research Laboratory, National Institutes
of Health RCMI‑Center for Environmental Health, Jackson State
University, 1400 Lynch Street, Box 18540, Jackson, MS 39217, USA.
E‑mail: paul.b.tchounwou@jsums.edu
Potassium Homeostasis, Oxidative Stress, and Human Disease
Udensi K Udensi1,2, Paul B Tchounwou1
1Molecular Toxicology Research Laboratory, National Institutes of Health RCMI‑Center for Environmental Health, College of Science, Engineering and Technology,
Jackson State University, Jackson, MS 39217, 2Department of Pathology and Laboratory Medicine, Veterans Affairs Puget Sound Health Care System, Seattle,
WA 98108, USA
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How to cite this article: Udensi UK, Tchounwou PB. Potassium
homeostasis, oxidative stress, and human disease. Int J Clin Exp Physiol
2017;4:111-22.
Received: 03rd September, 2017; Revised: 14th September, 2017; Accepted: 20th September, 2017
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International Journal of Clinical and Experimental Physiology ¦ Volume 4 ¦ Issue 3 ¦ July-September 2017
112
and for each ATP hydrolyzed, two K+ are transported inside
while three Na+ are pushed out of the cell. This maintains high
Na+ in the ECF and high K+ in the ICF and creates an electrical
gradient.[7] The cytoplasm becomes negatively charged as the
number of Na+ leaving the cell is higher than the number of
K+ entering the cell (i.e., more positive charged ions leave the
cell). This electrical gradient is used in neurons and muscles
for nervous system function and muscular contraction.[8] This
K+ and Na+ interchange inuences K homeostasis. When the
body needs to retain more Na+, renal K+ secretion is induced
leading to an increase in the delivery and reabsorption of
Na+ by the distal nephron. This conversely forces the passive
K+ efux across the apical membrane.[9]
Apart from K+ loss through the renal system, extrarenal
mechanisms also affect the normal potassium homeostasis.
Extrarenal mechanism includes potassium uptake by both liver
and muscle generally and intestinal secretion of potassium.
Extrarenal tissues regulate acute potassium tolerance while
the kidneys manage chronic potassium balance. Several
hormones, including insulin, epinephrine, aldosterone, and
glucocorticoids are involved in the maintenance of normal
extrarenal potassium metabolism.[10] These hormones
enhance potassium uptake by the liver and muscle. The
in and out of cell movement of potassium could be also
affected by changes in acid–base balance.[11] This depends
on the exchange of hydrogen ions for potassium across the
cell membrane. A shift of H+ out of the cell and potassium
into the cell occurs when there is an increase in serum
pH (decrease in H+ concentration). Conversely, under acidic
condition (acidemia), a shift of potassium out of the cell
occurs. A signicant rise in serum potassium may result from
a sudden increase in plasma osmolality which shifts water out
of the cell and drags in some potassium with the water.[12] A
screenshot of the major conditions associated with potassium
imbalance which causes different health abnormalities
and diseases is shown in Figure 1, and these conditions
include hypo and hyperkalemia, pseudohyperkalemia, and
pseudohypoaldosteronism.[13-17] They are discussed more in
detail later in this review.
The kidney is the seat of the body’s K+ metabolism, and it
maintains the body’s K+ content by controlling K+ intake and
K+ excretion/loss. Figure 2 shows the factors that affect renal
potassium excretion. Some of the important factors regulating
K+ movement across the cell under normal conditions are insulin
and catecholamines.[18] Insulin, catecholamines, aldosterone,
and alkalemia force potassium into the cells while increase in
osmolality and acidemia shift potassium out of the cell.[12] The
kidney moderates the activities of aldosterone which when
over produced facilitates K+ loss. Under normal conditions,
intracellular K+ buffers the effect of a fall in extracellular
K+ concentrations by moving into the extracellular space,
but the overproduction of aldosterone affects this balance
and causes continued loss of K+.[19] Another organ involved
in K+ homeostasis is the colon. The colon is the major site of
gut regulation of potassium excretion. Potassium excretion
through the colon is minimal during normal conditions, but
its role increases as the renal function worsens as seen in renal
insufciency or during acute potassium overload when the
kidneys are overwhelmed.[12,20]
Skeletal muscle is also implicated in extracellular
K+ concentration regulation. This was demonstrated by studies
in rats using a K+ clamp technique. According to the report,
there was a decrease in muscle sodium pump pool size due to
K+ deprivation. In addition, glucocorticoid treatment-induced
increase in muscle Na+-K+-ATPase alpha2 levels. Furthermore,
the body can adapt to changes in renal and extrarenal
K+ balance without signicantly altering plasma K+ level.[21]
The Na+-K+-ATPase mechanism is still under investigation.
However, there is evidence that insulin may inuence the
activity and expression of muscle Na+-K+-ATPase. Insulin
forces K+ into the cells. Insulin apart from regulating glucose
metabolism after a meal also shift dietary K+ into cells until the
kidney excretes the K+ load to re-establish K+ homeostasis.[22-24]
The ability of skeletal muscle to buffer declines in extracellular
K+ concentrations by donating some components of its
intracellular stores.[25]
There are also genes involved in K+ homeostasis, especially
with-no-lysine K (WNK) genes which act at the distal convoluted
tubule (DCT). The WNK genes act as molecular switches and
activate the thiazide-sensitive NaCl cotransporter (NCC). Low
intracellular chloride level triggers the activation of NCC
by WNK kinases resulting in reabsorption of potassium at
the DCT and preventing loss of potassium.[26] Mutations of
the WNK1 and WNK4 genes have been observed in some
patients with hyperkalemia and hypertension caused by
pseudohypoaldosteronism type II (PHA2).[27]
PotassIum Imbalance, oxIdatIve stRess and
dIsease
Oxidative stress (OS) is known to adversely affect health
outcomes in humans. It inuences the activities of inammatory
mediators and other cellular processes involved in the
initiation, promotion, and progression of human neoplasms
Figure 1: Major Conditions Associated with Potassium Imbalance that
causes different health abnormalities and diseases
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Udensi and Tchounwou: Potassium homeostasis and human health
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and pathogenesis of neurodegenerative diseases such as
Alzheimer’s disease, Huntington’s disease, Lou Gehrig’s
disease, multiple sclerosis, and Parkinson’s disease, as
well as atherosclerosis, autism, cancer, heart failure, and
myocardial infarction.[28,29] Likewise, abnormalities in
potassium channel have been reported in neurodegenerative
diseases including amyotrophic lateral sclerosis, a lethal
neurodegenerative disease commonly called Lou Gehrig’s
disease,[30] and Parkinson’s disease such that potassium channel
blockers are part of the treatment regimen in Parkinson’s
disease.[31] Enzymes that are involved in OS also affect
potassium activities. An example is heme oxygenase-1 (HO-1)
whose expression is increased in the central nervous system
following an ischemic insult. HO-1 is active in cancer cells and
is suggested to also increase expression of HO-1. It can also
can induce apoptosis by regulating K(+) channels, especially
regulation of Kv2.1.[32] Koong et al.[33] studied how free radicals
produced after exposure to hypoxia and reoxygenation activate
voltage-dependent K+ ion channels in tumor cells in vitro. They
reported that potassium (K+) channels are activated following
reoxygenation suggesting that the activation of K+ currents is
one of the early responses to OS.[33]
Sources of potassium
Potassium-rich foods include meats (pork), sh (rocksh,
cod, and tuna), milk, yogurt, beans (soybeans, lima beans,
and kidney beans), tomatoes, potatoes, spinach, carrot, and
fruits (bananas, beet green, prune juice, peaches, oranges,
cantaloupe, honeydew melon, and winter squash).[34] Ingestion
of K+ rich diets inuences plasma concentration of potassium.[6]
Increased potassium intake can occur through intravenous (IV)
or oral potassium supplementation. Another potential but
very rare source is hemolysis from packed red blood cells
transfusion.[35] Enteric solute sensors are said to modulate the
activities of dietary Na+, K+, and phosphate. After meal, the
enteric sensors detect these ions and send signals to the kidney
to buffer the effect through ion excretion or reabsorption.
Through this mechanism, the enteric sensors may enhance
Figure 2: Factors Affecting Renal Potassium Excretion. Potassium intake, intracellular potassium concentration, distal delivery of sodium, urine flow
rate, mineralocorticoid activity, and tubular responsiveness to mineralocorticoid affect renal potassium excretion
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Udensi and Tchounwou: Potassium homeostasis and human health
International Journal of Clinical and Experimental Physiology ¦ Volume 4 ¦ Issue 3 ¦ July-September 2017
114
the clearance of the K+ from diet or infusion.[36-38] A study has
also suggested that dietary K+ intake through a splanchnic
sensing mechanism can signal increases in renal K+ excretion
independent of changes in plasma K+ concentration or
aldosterone.[20]
Aldosterone and potassium balance
Aldosterone, a mineralocorticoid hormone is known
to moderate the body’s electrolyte balance including
potassium.[10] It is involved in the response to two opposite
physiological conditions (aldosterone paradox): hypovolemia
and hyperkalemia. One of its key mechanisms is the stimulation
of Na+ reabsorption and K+ secretion in the aldosterone-sensitive
distal nephron (ASDN).[39] Aldosterone acts by increasing the
number of open sodium channels in the luminal membrane
of the principal cells in the cortical collecting tubule,
leading to increased sodium reabsorption hyperkalemia.[40]
Aldosterone and renin-angiotensin system work together under
hypovolemic condition. Low volume triggers the activation
of the renin-angiotensin system which induces increased
aldosterone secretion.[41] The increase in circulating aldosterone
stimulates renal Na+ retention that facilitates the restoration of
ECF volume without affecting renal K+ secretion. However,
during hyperkalemia, aldosterone release is mediated by
a direct effect of K+ on cells in the zona glomerulosa. The
increase in circulating aldosterone stimulates renal K+ secretion
which restores the serum K+ concentration to normal without
affecting renal Na+ retention.[6,10]
Understanding aldosterone paradox is a complex process and
it is important for the kidney to differentiate between the two
opposite conditions for effective response. Angiotensin II is
suggested as the key sensor of the difference between volume
depletion and hyperkalemia. This is because activation of
the renin-angiotensin-aldosterone system (RAAS) controls
volume depletion and angiotensin II is not affected by plasma
K+ concentration.[18] In addition, renal K+ secretion and
Na+ retention remain stable under normal condition but under
pathophysiologic conditions, there is increase in distal Na+ and
water delivery coupled to increased aldosterone levels which results
in renal K+ wasting.[18] A recent study suggests that a blockade of
renin-angiotensin-aldosterone activity may adversely affect
extrarenal/transcellular potassium disposition as well as cause a
reduction in potassium excretion in humans with renal impairment.
Reduced aldosterone production impairs the responsiveness of
the renal system and potassium metabolism.[42,43] Aldosterone is
a drug target for certain human diseases. For example, reducing
plasma aldosterone level has shown promise in reducing the risks
associated with cardiovascular and renal problems in hypertensive
humans but can produce hyperkalemia.[42] An emerging study is
Figure 3: Molecular Interactions of Potassium Responsive Genes/Proteins: With‑no‑lysine K 4 has shown interaction with claudin group of proteins and
other proteins known to be involved in forming a physical barrier around cell to prevent solutes and water from passing freely through the paracellular
space. Image created with MiMI plugin for Cytoscape
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Udensi and Tchounwou: Potassium homeostasis and human health
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suggesting that microRNAs may be involved in the modulation of
RAAS that triggers cardiovascular inammation seen in potassium
imbalance.[44]
Vasopressin and potassium balance
Vasopressin is an important hormone that affects renal
K+ balance. Vasopressin stabilizes renal K+ secretion during
changes in ow rate.[45] Arginine vasopressin can induce an
increase of low-conductance K+ channel activity of principal
cells in rat cortical collecting duct (CCD) by the stimulating
cAMP-dependent protein kinase. An increase of low-conductance
K+ channel activity may lead to hormone-induced K+ secretion
in a rat CCD. A combination of endogenous vasopressin
suppression and decreased distal K+ secretion can prevent
excessive K+ loss under full hydration and water diuresis.[46]
Gene regulation of potassium homeostasis
The activities of some genes have been identified to
regulate potassium homeostasis. Notable among the
genes are mammalian WNK kinases which constitute a
family of four serine-threonine protein kinases, WNK1-4.
Mutations of WNK1 and WNK4 in human cause PHA2,
an autosomal-dominant Mendelian disease characterized
by hypertension and hyperkalemia.[47] WNK proteins act as
molecular switches with discrete functional states that have
different effects on downstream ion channels, transporters,
and the paracellular pathway. Mutations in the gene encoding
the kinase WNK4 can cause pseudohypoaldosteronism
type II (PHAII). PHAII also called Gordon syndrome is a
rare syndrome featuring hypertension and hyperkalemic
metabolic acidosis. Wnk4 is a molecular switch that regulates
the balance between NaCl reabsorption and K+ secretion by
altering the mass and function of the DCT through its effect
on NCC.[48] Further explanation of aldosterone paradox has
been made by the implication of the activity of the WNK4
in the distal nephron. These effects enable the distal nephron
to allow either maximal NaCl reabsorption or maximal
K+ secretion in response to hypovolemia or hyperkalemia,
respectively.[49] WNK4 has shown interaction with claudin
group of proteins (claudin 1 (CLDN1), claudin 2 (CLDN2),
claudin 3 (CLDN3), and claudin 4 (CLDN4). This interaction
network is illustrated in Figure 3.
Claudins are tight junction proteins involved in forming a
physical barrier around cell to prevent solutes and water
from passing freely through the paracellular space.[50,51]
CLDN2 forms a cation-selective pore in tight junctions while
CLDN4 restricts the passage of cations through epithelial
tight junctions. Claudins 1, 3, and 4 may be involved in
separating the potassium-rich endolymph from the sodium-rich
intrastrial uid.[52] Other genes that network with WNK4
are SLC12A3 solute carrier family 12 (sodium/chloride
transporter), member 3. SLC12A3 contributes in maintaining
electrolyte homeostasis by encoding a renal thiazide-sensitive
sodium-chloride cotransporter which mediates sodium
and chloride reabsorption in the DCT. Mutations in this
gene cause Gitelman syndrome (GS). Chloride channel,
voltage-sensitive Kb (CLCNKB) gene is another gene that
is involved in potassium homeostasis. The CLCNKB is
expressed predominantly in the kidney and may be important
for renal salt reabsorption. A mutation in CLCNKB results
in hypokalemia as seen in autosomal recessive Bartter
syndrome type 3 (BS3).[53-55] Aldosterone also stimulates the
expression of the serum and glucocorticoid-inducible kinase
1, which enhances the abundance of the epithelial sodium
channel, activates basolateral Na+/K+-ATPase activity.[39,56]
This increases the electrochemical driving force for sodium
reabsorption and K+ excretion[57] necessary for potassium
homeostasis regulation.
Tubular flow and potassium homeostasis
The urinary system is the major site of potassium homeostasis
regulation, and under normal physiological conditions, about
90% of potassium is excreted through the urine while the
remaining 10% or less is excreted through sweat, vomit, or
stool.[58,59] There are differences at the rate at which potassium
is secreted or excreted as the urine travels along the renal
tubule. Most potassium excretion occurs in the principal cells
of the CCD.[58] The late DCT, the connecting tubule, and the
CCD are the segments primarily involved in renal K+ secretion
and they are collectively called the ASDN. This is because
basal K+ secretion in these segments involves the renal outer
medullary K+ channel (ROMK) whose activity and abundance is
inuenced by aldosterone. Potassium/sodium pump determines
where, when and the amount of potassium to be excreted. That
is why luminal sodium delivery to the DCT and the CCD control
urinary potassium excretion. Aldosterone and other adrenal
corticosteroids with mineralocorticoid activity affect the rate
of potassium secretion.[60] The rates of Na+ reabsorption as well
as K+ secretion can be related to tubular ow rates. Sodium
reabsorption through epithelial sodium channels (ENaC)
located on the apical membrane of cortical collecting tubule
cells is driven by aldosterone and generates a negative
electrical potential in the tubular lumen, driving the secretion
of potassium at this site through the ROMK channels.[61] An
increase in tubular ow rates can directly affect the activity of
apical membrane Na+ channels and indirectly activate a class
of K+ channels, referred to as maxi-K, which under low ow
states are functionally inactive. This suggests that an increase
in glomerular ltration rate (GFR) after a protein-rich meal
would lead to an increase in distal ow activating the ENaC,
increasing intracellular Ca2+ concentration, and activating
maxi-K+ channels. The body uses this process to guide against
development of hyperkalemia as more K+ are secreted and
eliminated.[62] Renal potassium excretion can also be affected
by some medications such as potassium-sparing diuretics,
angiotensin-converting enzyme inhibitors, nonsteroidal
anti-inammatory drugs, and RAAS inhibitors.[63-66]
Circadian rhythm and potassium homeostasis
Like most body’s physiologic processes, K+ secretion/excretion
is regulated by circadian rhythm. The rate of urinary
K+ excretion changes during a 24-h period and this may be
due to changes in activity and uctuations in K+ intake caused
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by the spacing of meals. The circadian rhythm effect is used
to explain why K+ excretion is lower at night and in the early
morning hours and then increases in the afternoon in situations
when K+ intake and activity are evenly spread over a 24-h
period. The kidney is the principal organ responsible for the
regulation of the composition and volume of ECFs. Several
major parameters of kidney function, including renal plasma
ow, GFR, and tubular reabsorption and secretion have been
shown to exhibit strong circadian oscillations. Renal circadian
mechanisms contribute in maintaining homeostasis of water,
and three major ions (Na+, K+, and Cl−) and dysregulation of
the renal circadian rhythms may lead to the development of
hypertension and accelerated the progression of chronic kidney
disease (CKD) and cardiovascular disease in humans.[67-70]
Potassium balance and myocardial activity
Potassium is very important for regulating the normal
electrical activity of the heart. A shift in potassium balance
will adversely affect the heart.[71] Hypokalemia may result
in myocardial hyperexcitability which may lead to reentrant
arrhythmias. Conversely, increase in extracellular potassium
reduces myocardial excitability Electrocardiogram (EKG or
ECG) taken in hypokalemic state shows increased amplitude
and width of the P wave, prolongation of the PR interval,
T-wave attening and inversion, ST depression, prominent
U waves, and an obvious long QT interval because of fusion
of the T and U waves.[72] In addition, supraventricular and
ventricular ectopics, supraventricular tachyarrhythmia,
and life-threatening ventricular arrhythmias and Torsades
de Pointes develop as hypokalemic condition persists.[73]
Hypokalemia is often associated with hypomagnesemia, which
increases the risk of malignant ventricular arrhythmias.[74] On
the other hand, persistent hyperkalemia suppresses impulse
generation leading to bradycardia and conduction blocks and
eventually cardiac arrest.[75] However, serum potassium level
does not always correlate with the ECG changes. Thus, patients
with relatively normal ECGs may still experience sudden
hyperkalemic cardiac arrest.[76] In addition, hypo/hyperkalemia
can cause cardiac arrest in children.[77]
HyPokalemIa
Abnormal low blood potassium level of <3.5 mEq/L is
referred to as hypokalemia and it is a common electrolyte
disorder in clinical practice.[14] Hypokalemia can result
from inadequate potassium intake, excessive loss of
potassium, and transcellular shift of potassium which is
an abrupt movement of potassium from the ECF into ICF
in the cells. Often hypokalemic condition is caused by
drugs prescribed by physicians or due to inadequate intake.
Abnormal losses can occur through renal system induced by
metabolic alkalosis or loss in the stool induced by diarrhea.
Metabolic alkalosis is always associated with hypokalemia
and it is a salt-sensitive disorder in which there is selective
chloride depletion resulting from vomiting or nasogastric
drainage. Chloride-induced alkalosis can be corrected by
the administration of chloride, and this allows the body to
replenish its potassium store if potassium intake is insufcient.
Overproduction of aldosterone (hyperaldosteronism) also
causes metabolic alkalosis related severe hypokalemia
(serum potassium, <3.0 mEq/L). There is a relationship
between Cushin’s syndrome and hypokalemia.[14] Metabolic
acidosis, especially type I or classic distal renal tubular
acidosis associated with hypokalemia. Interestingly, the
severity of this condition is determined by the dietary sodium
and potassium intake and serum aldosterone concentrations
instead of the degree of acidosis. Untreated distal renal
tubular acidosis could lead to a life-threatening hypokalemic
Table 1: Factors that decrease plasma potassium (Hypokalemia)
Factor Mechanism Reference (PMID)§
Aldosterone Increases sodium resorption, and increases K+ secretion/excretion 25715092,15590995
Insulin Stimulates K+ entry into cells by increasing sodium efux (energy-dependent
process)
2540370
Magnesium depletion intracellular potassium concentration loss leading to renal potassium wasting 2255809
Beta-adrenergic agents Increases skeletal muscle uptake of K+2540370
Alkalosis (increased pH) Enhances cellular K+ uptake 25856925, 25709976
b2-Sympathomimetic Drugs e.g., albuterol Initial dose reduces serum potassium by 0.2 to 0.4 mEq/L 24094256, 15494380
Diuretics (thiazide and loop diuretics) block chloride-associated sodium reabsorption 9700180
Furosemide/bumetanide with metolazone Diuretic 2384955
Acetazolamide Impedes hydrogen-linked sodium reabsorption causing both hypokalemia/
metabolic acidosis
8977803
Genetic abnormalities 10959445
Liddle’s syndrome and 11b-hydroxysteroid
dehydrogenase deciency
Stimulate reabsorption of sodium by collecting duct cells leading to
mineralocorticoid excess
10959445
Bartter’s syndrome genetic mutations inactivate or impede the activity of chloride-associated
sodium transporters in the loop of Henle
10959445
Gitelman’s syndrome genetic mutations inactivate or impede the activity of chloride-associated
sodium transporters in early distal tubule
10959445
PMID§: Pubmed Identier. Hypokalemia is caused by inadequate potassium intake, excessive loss of potassium, and transcellular shift of potassium. The
Table describes the factors that contribute to hypokalemia, their mechanisms of action and the sources of information
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Udensi and Tchounwou: Potassium homeostasis and human health
International Journal of Clinical and Experimental Physiology ¦ Volume 4 ¦ Issue 3 ¦ July-September 2017 117
level (serum potassium, <2.0 mEq/L). As mentioned earlier
hypokalemia can result from extrarenal potassium loss as
seen in colonic pseudo-obstruction (Ogilvie’s syndrome).[78]
The factors that decrease plasma potassium level are shown
in Table 1.
Differential diagnosis for hypokalemia
In the diagnosis of hypokalemia, it is important to differentiate
true potassium depletion from pseudohypokalemia which
may be transient and arise from sampling errors, for instance,
if a blood sample is taken upstream of an infusion of saline,
dextrose, or other uids that have little or no potassium.
Sampling error may be conrmed from other hematological
tests that will demonstrate that the collected sample is a
mixture of blood and infused uid. Some of the important tests
for hypokalemia differential diagnosis include measurement
of blood magnesium, aldosterone and renin levels, diuretic
screen in urine, response to spironolactone and amiloride,
measurement of plasma cortisol level and the urinary
cortisol-cortisone ratio, and genetic testing.[5,79] Test parameters
that are considered in differential diagnosis of chronic
hypokalemia include blood pressure, acid-base equilibrium,
serum calcium concentration, 24-h urine potassium and calcium
excretion.[80,81] Hypomagnesemia can lead to increased urinary
potassium losses and hypokalemia.[79,82] Urine potassium is
measured to determine the pathophysiologic mechanism of
hypokalemia such as the rate of urinary potassium excretion.
Urine electrolyte determination may be assessed by determining
the ratio of urine potassium to urine creatinine.[14]
Hypokalemia can co-exist with other diseases and can be a
symptom of other diseases. For example, hyperthyroidism,
familial, or sporadic periodic paralysis are considered when
hypokalemia occurs with paralysis.[83] Figure 4 shows the
factors considered in the differential diagnosis of hypokalemia.
Determination of the acid–base balance, the blood pressure and
urine excretion rate are helpful when making the diagnosis of
hypokalemia of unknown cause. A common test performed
is the urine potassium-creatinine ratio (K/C). Poor potassium
intake, gastrointestinal losses, and a shift of potassium into cells
are suspected if K/C ratio is <1.5. Barter syndrome, GS, and
diuretic use are suspected if K/C ratio is >1.5 but with metabolic
alkalosis and normal blood pressure. Metabolic acidosis with
K/C ratio of >1.5 is associated with diabetic ketoacidosis
or type 1 or type 2 distal renal tubular acidosis. In addition,
metabolic alkalosis with a high urine K/C ratio and hypertension
have been seen in patients with hyperaldosteronism, Cushing
syndrome, congenital adrenal hyperplasia, renal artery stenosis,
mineralocorticoid excess.[79] GS and BS are some of the diseases
closely associated with hyperkalemia.
Gitelman syndrome
GS is an inherited renal tubular disorder mostly seen in
childhood or early adulthood and it is known to be caused by
a mutation in SLC12A3 gene which is a thiazide-sensitive
NCC.[53] Hypokalemia is one of its classical symptoms and it may
account for ~50% of all chronic hypokalemia cases.[84] Other
signs include hypotension, metabolic alkalosis, hypocalciuria
and hypomagnesemia and hypertrophy of the juxtaglomerular
Figure 4: Differential Diagnosis of Hypokalemia Based on Types and Causes of Potassium Imbalance
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Udensi and Tchounwou: Potassium homeostasis and human health
International Journal of Clinical and Experimental Physiology ¦ Volume 4 ¦ Issue 3 ¦ July-September 2017
118
complex with secondary hyperaldosteronism.[15,85] Hypokalemia
is often within the range 2.4–3.2 mmol/l and patients may have
low blood pressure and complaints of tiredness and increased
fatigability. Patients often misdiagnosed of Bartter’s syndrome
and futile attempts to treat with indomethacin.[86] GS can be
conrmed through genetic diagnosis by sequence analysis
of the SLC12A3 gene to observe if there is a compound
heterozygous mutation encoding the thiazide-sensitive sodium
chloride cotransporter.[87]
Bartter syndrome
BS is like GS characterized by hypokalemic alkalosis,
hypomagnesemia but with hyperreninemic hyperaldosteronemia
and normal blood pressure. BS also affects infants or early
childhood. Genetic analysis shows mutation in chloride
channel, voltage-sensitive Kb (CLCNKB) gene.[53,55] Both
BS and GS can be treated with potassium and magnesium
oral supplements, for example, ramipril and spironolactone.[88]
HyPeRkalemIa
Hyperkalemia is dened as a serum potassium >5.5 mEq/L,
the normal range is 3.5–5.5 mEq/L for adults.[5] The range is
age dependent and upper limit for young or premature infants,
could be up to 6.5 mEq/L. Since the kidneys are the major
organs involved in potassium metabolism, any impairment
of the kidneys that affects their ability to remove potassium
from the blood will lead to hyperkalemia. The condition
could be transient (pseudohyperkalemia), for instance, large
intake of potassium from diet or infusion.[16,89] A combination
of decreased renal potassium excretion and excessive
potassium intake through diet or through infusion will lead
to sustained hyperkalemia.[18] Prolonged fasting may induce
hyperkalemia.[90] Factors that contribute to impaired renal
potassium excretion include decrease in distal sodium delivery,
decrease in mineralocorticoid level or activity, and abnormal
collecting duct function.[12] Hyperkalemia can be an indicator
that cancer patients admitted for an emergency are at high risk
for developing a delirium.[91] Dysregulation in the expression
of WNK genes has been linked to hyperkalemia. For example,
KS-WNK1 expression is upregulated in hyperkalemia.[92,93]
Another rare but possible cause of hyperkalemia is the
shift of potassium from inside the cells to the outside. This
shifting of potassium can be caused by several factors
such as insulin deciency or acute acidosis. This condition
produces mild-to-moderate hyperkalemia but can exacerbate
hyperkalemia induced by high intake or impaired renal excretion
of potassium. Hyperkalemia is also a common complication in
very low birth weight infants, especially in infants with low
urinary ow rates during the rst few hours after birth.[94]
Hyperkalemia is a serious and potentially fatal condition that
can trigger a heart attack.[17] Although many individuals with
hyperkalemia are asymptomatic, common symptoms are
nonspecic and predominantly related to muscular or cardiac
function, especially cardiac arrest.[13,95,96] Weakness and fatigue
are the most common complaints. Potassium homeostasis is also
critical to prevent adverse events in patients with cardiovascular
disease. Studies have shown that low serum potassium levels
of <3.5 mEq/L increases the risk of ventricular arrhythmias in
patients with acute myocardial infarction.[97] The factors that
cause hyperkalemia are shown in Table 2.
Differential diagnosis of hyperkalemia
The symptoms of hyperkalemia resemble those of other
clinical diseases. An understanding of potassium physiology
is helpful when approaching patients with hyperkalemia.
Factors to be considered during the diagnosis of hyperkalemia
are shown in Figure 5. As mentioned previously, plasma
potassium concentration is inuenced by potassium intake,
the distribution of potassium between the cells and the ECF,
and urinary potassium excretion.[12,19,61,98]
Pseudohyperkalemia could be as a result of sampling error.[17,43]
Excess potassium can enter into the blood sample through
Table 2: Factors that increase plasma potassium (Hyperkalemia)
Factor Mechanism Reference (PMID)§
Acidosis (decreased pH) Impairs cellular K+ uptake 26022032, 6111930
Alpha-adrenergic agents Impairs cellular K+ uptake 19623566
Angiotensin-converting enzyme (ACE ) inhibitors, nonsteroidal
anti-inammatory drugs NSAIDs, and renin-angiotensin
aldosterone system (RAAS) inhibitors
Impair kidney potassium excretion 20087674, 2011243, 20030530,
20150448, 9672294, 8685062,
24804145
Cell/Muscle tissue, damage Intracellular K+ release, hemolysis, rhabdomyolysis 18317876
Succinylcholine Cell membrane depolarization 25611525, 25565545, 25603385
Catecholamine Facilitates K+ entry into cells by stimulating
cell-membrane Na+/K+ -ATPase activity
2540370
Potassium intake: diet (Potassium-rich foods e.g., meats, beans,
tomatoes, potatoes, and fruits); Infusion and potassium supplements
Increase in plasma potassium level 25456880, 23855149
Packed red blood cells transfusion (PRBCs) Hemolysis pushes K+ from ICF to ECF 17646488
Genetic Diseases e.g., Gordon’s syndrome Increased expression of WNK1 genes 17957199,1689952,15583131
Pseudohypoaldosteronism type II (PHA2) Mutations in WNK1 and WNK4 25904388
PMID§: Pubmed Identier. The Table describes the factors that contribute to hyperkalemia, their mechanisms of action and the sources of information.
A combination of decreased renal potassium excretion, excessive potassium intake through diet or through infusion and prolonged fasting may cause
hyperkalemia
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Udensi and Tchounwou: Potassium homeostasis and human health
International Journal of Clinical and Experimental Physiology ¦ Volume 4 ¦ Issue 3 ¦ July-September 2017 119
hemolysis or ischemic muscle cells due to tight tourniquet
or hand/arm exercise during the blood-drawing process.
Thrombocytosis (platelet count >600,000), leukocytosis
(white blood cell >200,000), or significant hemolysis
(serum hemoglobin >1.5 g/dl) can cause hyperkalemia. It is
advised to measure plasma potassium if thrombocytosis or
severe leukocytosis is present.[5,12] Arrhythmia is a feature of
hyperkalemia that could be life-threatening and that could also
be caused by other diseases.[99] It is important to differentiate
arrhythmia caused potassium imbalance from by other
electrolyte imbalance, for example, Na+, and Ca2+ or drug
for example, digitalis intoxication.[100] CKD and Gordon’s
syndrome are some of the diseases closely associated with
hyperkalemia.
Chronic kidney disease
The main function of the kidney is to lter wastes and excess
water out of the blood to be excreted as urine. The kidney is also
the seat of the body’s chemical balance including potassium.
Kidneys adapt to acute and chronic alterations in potassium
intake. When potassium intake is chronically high, the kidney is
prompted to excrete more potassium. Hyperkalemia is common
in patients with end-stage renal disease as in CKD.[90] In CKD
patients, K+ homeostasis appears to be well maintained until
the GFR falls below 15–20 ml/min. The kidney adapts as
more nephrons are lost due to CKD by making the remaining
nephrons to secrete more K+.[101] This adaptive response is
similar to that which occurs due to high dietary K+ intake
in normal subjects.[102] Early stages of renal disease may
not show signicant abnormalities in potassium activity but
renal failure hyperkalemia is a major complication in CKD
patients.[103] In the presence of renal failure, the proportion of
potassium excreted through the gut increases. In patients with
CKD, insulin-mediated glucose uptake is impaired, but cellular
K+ uptake remains normal.[89]
Gordon’s syndrome
This is a rare mineralocorticoid resistance, autosomal dominant
diseases which manifests as PHA. The major features
are dehydration, hypertension, severe hyperkalemia, and
metabolic acidosis, but with normal GFR. Gordon’s syndrome
is characterized by hypertension and hyperkalemia which
may be due to enhanced Na+ reabsorption and inhibition of
K+ secretion resulting from increased WNK1 expression.[104]
Intronic deletions in the WNK1 gene result in its overexpression
which causes PHA2, a disease with salt-sensitive hypertension
and hyperkalemia.[92] These symptoms have been attributed
to overexpression of WNK1.[104] Gordon’s syndrome can be
treated with thiazide diuretics.[16,105]
Hypertension and potassium homeostasis
High blood pressure can be influenced by the levels of
plasma potassium, low potassium causes hypertension, and
increasing potassium intake lowers blood pressure.[20,106] The
blood pressure of people with hypertension is lowered when
they are given K+ supplements. However, their blood pressure
increases when placed on a low K+ diet and can be worsened
by increased renal Na+ reabsorption.[98] Hypertension has been
one of the symptoms of potassium-dependent diseases such as
Gordon’s syndrome.[105]
conclusIon
Potassium is very important in maintaining cell function such
that any imbalance in K+ will have adverse health consequences.
As a result, the body has developed numerous mechanisms to
make adjustment for any shift in serum K+ homeostasis. All
Figure 5: Differential diagnosis of hyperkalemia based on types and causes of potassium imbalance
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Udensi and Tchounwou: Potassium homeostasis and human health
International Journal of Clinical and Experimental Physiology ¦ Volume 4 ¦ Issue 3 ¦ July-September 2017
120
the mechanisms involved are not well understood. However,
much has been learned on how the body maintains a proper
distribution of K+ within the body. There is also knowledge on
how the health effect of K+ imbalance could be managed. For
instance, hypokalemia can be managed by reducing potassium
losses, replenishing the potassium stores, for example, oral
potassium chloride administration, evaluating toxicities and
treating other underlying diseases, and determining the root
causes to prevent future occurrence. Hyperkalemia such as
hypokalemia treatment is based on balancing the body’s
potassium level. In hyperkalemic condition, the strategy is to
reduce the level of potassium in the blood. There are specic
treatment options depending on the potassium level and the
physiologic condition of the patient. Dialysis is the denitive
treatment of hyperkalemia. However, IV calcium can be used
to stabilize the myocardium.[107-111] Since enzymes that are
involved in OS also affect potassium activities, understanding
the interplay between potassium imbalance and OS will give
more insight into the pathophysiology of human diseases such
as cardiomyopathies, neurological syndromes, and cancer.
Financial support and sponsorship
This research was supported by a grant from the National
Institutes of Health (G12MD007581) through the RCMI Center
for Environmental Health at Jackson State University.
Conflicts of interest
There are no conicts of interest.
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