Review Article

Disorders of Potassium Homeostasis: Pathophysiology and

Management
Sumedh S Hoskote*, Shashank R Joshi**, Amit K Ghosh***
Abstract
Disorders of potassium homeostasis are common electrolyte abnormalities encountered in hospitalized patients.
Hypokalemia and hyperkalemia have been estimated to occur in about 21% and 3% of hospitalized patients,
respectively; though the morbidity and mortality associated with the latter is significantly higher. Potassium is a
predominantly intracellular ion and the understanding of its dynamics between intra- and extracellular fluid milieus,
along with its handling by the kidneys, is important in the diagnosis and treatment of potassium disorders. This
article aims to provide a clinically relevant update on management of potassium disorders for internists.

INTRODUCTION

otassium is the main intracellular ion in the body

and its levels are crucial to normal homeostasis. It is mainly
contained within the intracellular fluid (ICF) compartment,
with only about 2% of the total body potassium residing
in the extracellular fluid (ECF).1 Nearly 80% of the cellular
stores are present in muscle, with erythrocytes, liver
and bone accounting for most of the remainder1 (Fig. 1).
The normal ratio between extracellular and intracellular
concentrations is important for maintenance of the resting
membrane potential and neuromuscular functioning.
Also, intracellularly, potassium participates in several vital
functions, such as cell growth, maintenance of cell volume,
DNA and protein synthesis, enzymatic function and acidbase balance. Disorders of potassium balance are important
causes of ambulatory and in-hospital morbidity. In this
review, we will discuss the pathophysiology of potassium
transport, mechanisms and management of potassium
disorders commonly encountered in clinical practice.

leading to death. The ECF acts as an intermediary between

the intracellular stores and the input/output mechanisms.
Potassium excretion matches the dietary intake, in the
absence of disease, and is executed predominantly by
the kidney, with about a 10% contribution from the large
intestine.
Potassium transfer between the extra- and intracellular
milieus is affected by a variety of other endogenous and
exogenous factors (Fig. 1). Cellular potassium uptake is
promoted by catecholamines and drugs activating 2
adrenoceptors, and inhibited by -antagonist drugs.
States of acidosis and alkalosis affect potassium because
it compensates for the movement of protons (hydrogen
ions). In acidosis, H+ ions move into cells and, to maintain
electrical balance, K+ ions move out into the ECF; and
vice-versa in alkalosis. A hyperosmolar ECF environment
can promote potassium efflux from the cells leading to
depletion of intracellular potassium (and, hence, total body

PATHOPHYSIOLOGY
Movement of Potassium Between ICF and ECF
Normal daily potassium intake is approximately 40-100
mEq, which is absorbed from the gut, enters the ECF and
is rapidly redistributed into the intracellular compartment
due to the action of post-prandial insulin. This is essential
because an additional 100 mEq of K+ in plasma would
increase plasma K+ concentration several fold, rapidly
*Research Associate, Joshi Clinic, **Endocrinologist, Lilavati Hospital,
Bhatia Hospital and Joshi Clinic; Department of Endocrinology, Seth
GS Medical College and KEM Hospital; Mumbai. ***Associate Professor,
Mayo Clinic, Rochester, Minnesota.

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Fig. 1 : Potassium homeostasis: Movement between intra- and

extracellular fluids.
Movement of potassium between the body compartments is controlled
by various internal and external factors. Potassium predominantly
resides intracellularly, with only about 2% being present in the
extracellular fluid. RBCs, red blood cells. Data from Giebisch G.1

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685

potassium). Finally, because potassium is predominantly

contained intracellularly, even if 1% of the cellular K+ content
were to be added to the ECF (due to lysis of cells, such as
rhabdomyolysis or hemolysis), it could result in severe
hyperkalemia.
Potassium Handling in the Nephron
Potassium handling by the nephron is unique, in that not
only is it reabsorbed but it is also secreted by the tubule; and
the amount excreted depends on the dietary intake.
Potassium is freely filtered at the glomerulus and
approximately 65% of the filtered load is reabsorbed in
the proximal convoluted tubule (PCT), which is tied to
the reabsorption of sodium and water. This takes place
isotonically and the K+ concentration of the fluid entering the
loop of Henle almost equals that of plasma. In the descending
part of the loop of Henle, the K+ concentration increases
(greater than that accounted for by the reabsorption of
water) owing to entry of K+ into the lumen, possibly driven
by the high K+ concentration of the medullary collecting
ducts.2 In the thick ascending part of the loop of Henle
(TALH), the Na+/K+/2Cl- cotransporter present on the luminal
border is responsible for reabsorption of potassium. This
is also the site of action of the loop diuretics, including
furosemide. The next segment, the distal convoluted tubule
(DCT), has been shown to be involved, to a small extent, in
secretion of K+ into the luminal fluid.3
The collecting duct (CD) is responsible for nearly all
the K+ secretion into the urine. The principal cells express
sodium and potassium ion channels on their luminal
surface. Since the electrochemical force for Na+ entry into
cells is much higher than that for K+, sodium reabsorption
predominates, thus creating a negative charge in the
lumen. This negative charge attracts K+ into the lumen and
also repels chloride, via the paracellular pathway, into the
peritubular capillaries. Aldosterone increases the activity of
the luminal Na+ channels, while also enhancing the function
of the basolateral Na+/K+/ATPase pump, thus amplifying the
entire process. Also, any factor increasing distal Na+ flow,
such as diuretic therapy or osmotic agents (e.g. mannitol,
high glucose in uncontrolled diabetes; which prevent
absorption of solutes due to increased tonicity of luminal
fluid) can lead to greater K+ secretion.
Finally, the acid-base status of the body and the
extracellular K+ affect each other via renal mechanisms. In
metabolic alkalosis, excess HCO3- is filtered, which leads
to increased distal HCO 3- delivery and bicarbonaturia.
Since HCO3- is a poorly reabsorbed anion, it makes the
luminal charge more negative and draws out K+ from the
collecting duct epithelium, leading to increased kaliuresis
and hypokalemia. Hypokalemia increases renal tubular
acid (ammonium ion) generation and, for each mole of
acid generated and excreted in urine, one mole of base
(HCO3-) is added to blood. Thus, it contributes towards the
metabolic alkalosis. In hyperkalemia, the converse occurs
and renal ammoniagenesis is impaired, leading to metabolic
acidosis.4
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Transtubular Potassium Gradient (TTKG)

The TTKG is a quick laboratory measure that gives
information about renal K+ secretory function.5 The aim is
to measure the K+ added into the tubular lumen as it passes
through the cortical collecting duct (CCD). Assuming that
the osmolality of the CCD luminal fluid is equal to that of
plasma, a simple ratio of CCD K+ concentration to the plasma
K+ concentration will yield the TTKG.
TTKG = [K+]CCD / [K+]Plasma
However, because it is clinically impractical to obtain
CCD fluid, the parameters are derived using urinary
measurements. TTKG is calculated as:

[K]Urine /OSM Urine [K]Urine OSMPlasma
TTKG =
=
X

[K]Plasma /OSM Plasma [K]Plasma OSMUrine
Normal TTKG is about 8-9, which may increase up to 11
if dietary potassium is increased. The TTKG is applied in the
appropriate clinical setting to estimate renal K+ secretion.6
In the setting of hypokalemia, a TTKG greater than 3 implies
renal K+ wastage, while in hyperkalemia, a TTKG lower than
7 implies impaired renal K+ secretion.6

HYPOKALEMIA
Hypokalemia is defined as a plasma K+ concentration
lower than 3.5 mEq/L. 7 It occurs in about 21% of all
hospitalized patients8 and goes undertreated in nearly a
fourth of all cases.9 Clinically, diuretic use is the commonest
cause of hypokalemia.10 Manifestations of hypokalemia
are consequences of the effects on the muscle resting
membrane potential (RMP) and on the acid-base status
(described above under Pathophysiology).
In muscles, low plasma K+ leads to a hyperpolarized
myocyte that tends to be more refractory to excitation. This
causes fatigue, myalgia and weakness, most pronounced in
the large proximal skeletal muscles, like those of the hip and
thigh. Worsening hypokalemia produces respiratory muscle
weakness and, eventually, generalized muscle paralysis,
including paralytic ileus.
In cardiac myocytes, potassium ion conductance is
directly related to the plasma K+ concentration.11 Hence,
hypokalemia reduces K + conductance and leads to a
prolonged repolarization phase of the cardiac action
potential, reflected in the electrocardiogram (ECG) as a
prolonged QT (or QU) interval. Other ECG changes include
flattening or inversion of the T wave, a prominent U-wave
(Fig. 2) and ST-segment depression. Patients receiving
digitalis treatment are prone to increased toxicity in the
setting of hypokalemia because digitalis and potassium
inhibit each others binding at the Na+/K+/ATPase pump.12
Causes
There are many disease processes that lead to or include
hypokalemia (Table 1). Broadly, hypokalemia can be
caused by a shift of K+ into the intracellular compartment,
increased loss from the gut or integument, or from

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JAPI VOL. 56 SEPTEMBER 2008

Table 1 : Causes of hypokalemia

Redistribution to ICF
Metabolic alkalosis

Insulin

Autonomic causes
Stress, catecholamines

2-agonists, -antagonists

Anabolic states (Vitamin B12 or GM-CSF therapy)

Hypokalemic periodic paralysis

Pseudohypokalemia
Extra-renal Losses

Secretory diarrhea or laxative abuse

Excessive sweating

Intestinal neoplasms
VIPoma
Villous adenoma & McKittrick-Wheelock syndrome
Renal Losses

Primary mineralocorticoid excess
Primary hyperaldosteronism (Conn syndrome)
Cushing syndrome
CAH (CYP 11B1 or CYP 17)
Glucocorticoid-remediable hyperaldosteronism

Hyperaldosteronism due to hyperreninemia
Chronic low circulating volume
Renin secreting tumor
Renovascular and malignant hypertension

Pseudohyperaldosteronism
Liddle syndrome
11 -HSD2 deficiency or antagonism (licorice, Cd++)

Increased distal Na+ delivery
Diuretics
Bartter syndromes
Gitelman syndrome

Increased distal delivery of non-reabsorbed anions
Renal tubular acidosis Type 2
Ketoacids (DKA), Penicillins
Bicarbonaturia from metabolic alkalosis

Renal Tubular Acidosis Type 1
Miscellaneous

Reduced dietary intake (<40 mEq/day)

Barium toxicity, hypomagnesemia

Hypothermia

Fig. 2 : Electrocardiogram (ECG) showing effects of hypokalemia.

The left panel shows a normal ECG (serum K+ = 4.4 mEq/L), while
the right panel shows the ECG in hypokalemia (serum K+ = 3 mEq/L).
Flattening of the T wave and a prominent U wave are seen in
hypokalemia.

ICF, Intracellular fluid; GM-CSF, Granulocyte-Monocyte Colony

Stimulating Factor; VIPoma, tumor secreting Vasoactive Intestinal
Polypeptide; CAH, Congenital Adrenal Hyperplasia; CYP 11B1,
11 -hydroxylase; CYP 17, 17 -hydroxylase; 11 -HSD2, 11
-hydroxysteroid dehydrogenase-2; DKA, Diabetic ketoacidosis

intrinsic renal disease. Dynamics of K+ exchange between

ICF and ECF compartments have already been described
(Fig.1). To prevent a spuriously low serum K + reading
(pseudohypokalemia), blood samples should be maintained
at cool ambient temperatures13 and analyzed without much
delay to prevent cellular uptake of K+. A similar phenomenon
also occurs due to K+ uptake by the abnormal white cells
in myeloproliferative disorders.14 Several unique causes of
hypokalemia need special mention.
Hypokalemic periodic paralysis (HypoKPP) is an
autosomal-dominant inherited disorder involving mutations
of ion channels present on the muscle sarcolemma. Attacks
of paralysis occur, beginning in adolescence, after rest
JAPI VOL. 56 SEPTEMBER 2008

following exercise or ingestion of a carbohydrate-rich

meal.15 Both these scenarios normally involve intracellular K+
uptake; but this process is abnormally increased in HypoKPP.
Serum K+ levels are low during the attack. HypoKPP warrants
K+ replacement despite being a disorder of transcellular
K+ shift. Thyrotoxic periodic paralysis (TPP) is a disorder
characterized by elevated thyroxine, hypokalemia and
paralysis that most commonly occurs in patients of East and
Southeast Asian extraction.16 The importance of recognizing
this condition is that it is self-limited and administration of
K+ supplementation can result in rebound hyperkalemia in
nearly half the patients.16
2-agonists are potent promoters of cellular K+ uptake
and, for this reason, they are important in the management
of hyperkalemia. Recently, a bizarre cause of hypokalemia
was reported in heroin abusers. Clenbuterol (a drug used
to treat airway obstruction in horses) was found to be an
adulterant in heroin, and led to hypokalemia, in addition
to the autonomic effects (tachycardia, palpitations).17 This
drug may also be abused by athletes for its propensity to
increase lean muscle mass and reduce body fat.
Losses from the skin and gastrointestinal tract, if severe,
can give rise to significant electrolyte depletion, resulting
in hypokalemia. Infectious secretory diarrheas account for
the vast majority of these. A pancreatic tumor secreting
vasoactive intestinal polypeptide (VIPoma) is an exceedingly
rare entity, while a villous adenoma only infrequently
produces diarrhea sufficient to cause hypokalemia. Rectal
neoplasms (commonly villous adenomas) producing
electrolyte hypersecretion constitute the McKittrickWheelock syndrome.18
Diseases causing increased renal K+ loss can be grouped
as: (1) those resulting from increased mineralocorticoid
effect, (2) those producing increased delivery of Na+ to
the distal nephron segments, and (3) those producing
increased delivery of unabsorbed anions to the distal
nephron segments. Some specific renal disorders have been
discussed in detail.
Primary mineralocorticoid excess can result from
primary hyperaldosteronism i.e., Conn syndrome (increased
production of aldosterone from a benign or malignant adrenal
neoplasm), or from generalized adrenal hyperfunction
(Cushing syndrome). Increased mineralocorticoid action
can occur due to mineralocorticoids produced in congenital
adrenal hyperplasia. Inborn deficiencies of the 11

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-hydroxylase (CYP 11B1) and 17 -hydroxylase (CYP 17)

enzymes lead to increased levels of 11-deoxycorticosterone.
Genetically male children with CYP 17 deficiency manifest
as pseudohermaphroditism (female genitalia), while
females present in later life with primary amenorrhea. Both
deficiencies have adult-onset forms as well.
Liddle syndrome is a rare autosomal dominant genetic
disorder manifested by a gain-of-function of the epithelial
sodium channel (ENaC) of the principal cell in the
collecting duct.19 Excessive Na+ is reabsorbed and, as a
direct consequence, excessive K+ is secreted leading to
hypokalemia. Patients are volume overloaded, leading
to hypertension in the setting of a suppressed reninangiotensin-aldosterone (RAA) axis. A loss-of-function
mutation of the ENaC produces aldosterone resistance, a
syndrome exactly the opposite of Liddle syndrome, which
is discussed later.
Another condition producing a similar picture to
that of Liddle syndrome is the syndrome of apparent
mineralocorticoid excess. Cortisol secreted by the
adrenals possesses some mineralocorticoid action but, in
aldosterone target tissues, the enzyme 11 -hydroxysteroid
dehydrogenase-2 (11-HSD2) converts cortisol to a
non-mineralocorticoid, cortisone. 20 Symptoms of
hyperaldosteronism develop if the activity of this enzyme
is lacking, or in the presence of inhibitors (licorice 21 or
cadmium from tobacco smoke22).
Glucocorticoid-remediable hyperaldosteronism is a
genetic condition wherein the gene for 11 -hydroxylase
(the enzyme upregulated by corticotropin to synthesize
cortisol) contains the correct promoter but carries the
bases for aldosterone synthase in its coding region (chimeric
gene duplication).23 Hence, aldosterone synthesis occurs
in the region of the adrenal (zona fasciculata) responsible
for cortisol secretion. Administration of dexamethasone
can diagnose as well as manage this condition, because
suppression of corticotropin takes away the stimulus for
excessive aldosterone synthesis.
Bartter syndrome is a group of genetic conditions
resulting from defective reabsorption of sodium from the
TALH due to a variety of dysfunctional ion-transport proteins.
These include the Na+/K+/2Cl- cotransporter (Bartter I),24 the
apical (luminal) potassium channel (Bartter II)25 and two
defects in the basolateral chloride channel responsible for
potasium-chloride flux through the tubular cell (Bartter III
& IV).26 Recently, a milder variant of Bartter syndrome with
hypocalcemia has also been described (Bartter V). 27 All
the Bartter syndrome genetic defects are inherited in an
autosomal recessive fashion, except for Bartter syndrome
V, which follows autosomal dominant inheritance.
Reabsorption of Na + is impaired and the resultant
excessive natriuresis has two important implications there
is increased distal Na+ flow and the volume depletion causes
activation of the RAA axis. Both factors are responsible
for the excessive K+ excretion, leading to hypokalemia.
In the TALH, K+ absorption is reduced and, consequently,
688

its backflow into the lumen is also reduced. Since it is

this luminal positive charge that drives transcellular
reabsorption of other cations like Ca++ and Mg++, Bartter
syndrome is associated with hypocalcemia (hypercalciuria)
and hypomagnesemia. This fact is utilized in differentiating
Bartter syndrome from Gitelman syndrome, of which
hypocalciuria is a hallmark.28
Gitelman syndrome is an autosomal recessive genetic
defect resulting in dysfunction of Na + absorption by
the thiazide-sensitive Na + /Cl - cotransporter (NCCT )
located in the DCT.29 It is characterized by hypokalemia,
metabolic alkalosis, hypomagnesemia, and hypocalciuria.30
Hypomagnesemia is considered the hallmark of NCCT
dysfunction31 and is thought to occur due to reduced
activity of epithelial Mg++ receptors,32 while hypocalciuria
occurs due to increased proximal tubular reabsorption of
Ca++.32
Renal tubular acidosis (RTA) is an umbrella term for
the common presentation of hyperchloremic metabolic
acidosis with a normal anion gap, caused by a renal tubular
dysfunction. There are four types of RTA and all, except type
4, produce hypokalemia.
RTA Type 1, also known as distal RTA, is caused by an
impairment in acidification of urine due to dysfunctional
acid secretion in the collecting ducts. There is also an
associated defect of K+ conservation, the mechanism of
which is uncertain. The urinary excretion of ammonium
(NH4+) is disproportionately low compared to the blood
pH, which produces the characteristic finding of urine pH
greater than 5.5 even in the setting of acidosis,33 aiding
in the differentiation from RTA Type 2. Chronic acidosis is
responsible for the renal calculi formed in Type 1 RTA by
two synergistic mechanisms. Acidosis reduces calcium
reabsorption, increasing the Ca++ concentration in tubular
fluid, while simultaneously enhancing citrate reabsorption,
reducing its concentration.34 Usually, calcium binds citrate
to form a soluble compound but, due to the imbalance in
this ratio, calcium binds phosphate to produce a 50-times
less soluble compound that precipitates in the alkaline urine
to produce renal calculi.
RTA Type 2, also known as proximal RTA, can occur as a
primary condition, with or without features of generalized
proximal tubular dysfunction (Fanconi syndrome), or
secondary to drugs such as carbonic anhydrase (CA)
inhibitors. The result is impaired proximal reabsorption
of HCO3-. Distal sites in the nephron receive more than
the usual HCO3- load and, since they are not as adept at
its reabsorption, the HCO3- is lost. Bicarbonaturia is the
characteristic of this condition. Eventually, the plasma
HCO3- drops to a lower level, at which a new equilibrium
is established and HCO 3 - is no longer lost in urine.
Bicarbonate replacement therapy is difficult because a
fractional HCO3- excretion of more than 15% is observed
and HCO3- may be lost before the desired pH normalization
is achieved.35 Interestingly, the defect in proximal tubular
function protects these patients from renal calculi and

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nephrocalcinosis because of the normal/increased citrate

in the tubular fluid. In RTA Type 2, relative to Type 1, a large
quantity of HCO3- needs to be replaced (5-15 mmol/kg/day
vs. 1-2 mmol/kg/day). Since alkali replacement itself causes
hypokalemia, the K+ replacement required in RTA Type 2 is
greater than that required in RTA Type 1.
RTA Type 3 is a rare condition caused by a mutation of
the intracellular form of CA (CA-II).36 The deficiency of a
functional CA-II enzyme gives rise to impaired proximal
HCO3- reabsorption as well as impaired distal acid secretion
i.e. features of both RTA types 1 and 2. Other associated
features are osteoporosis, cerebral calcifications and mental
retardation.
Diagnosis
Hypokalemia should be suspected in any patient
presenting with generalized or proximal muscle weakness
or cardiac arrhythmias. History of gastrointestinal losses,
use of any medications (especially diuretics), renal disease
and history of familial conditions should be actively sought.
Conditions leading to transcellular K+ shift can be excluded
with a good history and physical examination. Laboratory
values for serum and urinary electrolytes, along with the
blood pressure and plasma renin activity (PRA), are the main
tools in narrowing down the causes of hypokalemia.
The headings listed in Table 1 (see Renal losses) each
represent a pathophysiologic mechanism in the process
causing hypokalemia and each is a distinct endpoint in the
diagnostic pathway (Fig. 3).
Once transcellular shift has been excluded, the first
step is to find out if K+ has been lost via renal or extrarenal mechanisms. A daily urinary K+ excretion of > 20
mEq suggests renal K+ wastage. If a renal cause has been
found, the next factor to ascertain is the aldosterone
status, since that is the main stimulus for K+ loss. One of
the reliable clinical manifestations of hyperaldosteronism
is hypertension and, hence, the blood pressure (BP) guides
the further diagnostic course. If the BP is low or normal, we
can eliminate aldosterone as the cause for hypokalemia.
The other reasons for increased K+ loss are increased distal
delivery of Na+ or HCO3-. These causes are looked for using
serum HCO3- and urinary chloride. Increased distal Na+ flow
is the result of impaired Na+ reabsorption due to an inherited
defect of the transporters (Bartter and Gitelman syndromes)
or due to their blockade by diuretics. These disorders
secondarily cause metabolic alkalosis, producing elevated
serum HCO3-. Because Cl- is simultaneously reabsorbed with
Na+, the above conditions lead to Cl- loss as well, causing a
high daily Cl- excretion. On the other hand, an extra-renal
cause of metabolic alkalosis (like vomiting or nasogastric
suction) leads to increased serum HCO3- with a resultant
increased tubular HCO3-, whose negative charge repels
chloride. The Cl- is driven out of the tubular lumen, leading
to low urinary Cl- excretion. In case the serum HCO3- is low,
renal tubular acidosis is diagnosed.
Elevated BP implies excess mineralocorticoid action;
however, this may be due to or independent of renin levels.
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Fig. 3 : Algorithm for diagnosis of hypokalemia.

UK, urinary potassium; GI, gastrointestinal; BP, blood pressure; Aldo,
aldosterone; CAH, congenital adrenal hyperplasia; HTN, hypertension;
UCl, urinary chloride; RTA, renal tubular acidosis.

Hence, plasma renin activity should be tested prior to

aldosterone. Conditions like Liddle syndrome give a clinical
picture of hyperaldosteronism despite a suppressed RAA
axis because their pathophysiology mimics aldosterone
excess at the level of the target tissues.
Treatment
Hypokalemia caused due to true potassium deficit
should be treated with K+ replacement, though if serious
complications are expected, hypokalemia resulting from
transcellular shifts may also be treated similarly.37 Potassium
chloride or acetate are used depending on coexistent
alkalosis or acidosis, respectively.38 Other modalities can be
employed depending on the specific underlying pathologic
condition. If acidosis and hypokalemia coexist, the
hypokalemia must be treated before the acidosis because
alkali administration can further aggravate hypokalemia.
The 2005 American Heart Association (AHA) guidelines
recommend K+ replacement for serum levels below 2.5
mEq/L to avert risk of cardiac arrhythmias.39 Replacement
should be carried out gradually, rather than rapidly, unless
the patients severity so demands. It is difficult to estimate
the K+ requirement because the ECF concentration does
not reflect body stores. Hence, it is important to frequently
monitor serum K+ while administering therapy. Response to
treatment improves with co-administration of magnesium
replacement, especially in hypokalemia that is refractory
to therapy. Care must be taken to avoid overcorrection
of the deficit, because rebound hyperkalemia is a serious
complication of therapy.
Some authors recommend that replacement should be
initiated with oral potassium chloride because a greater
rise in ECF potassium can be achieved with this route
at the expense of fewer adverse events and parenteral
administration should be reserved for patients unable to
take enteral doses.40 According to the AHA guidelines,39

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K + replacement should be empiric, with a maximum

intravenous potassium chloride infusion rate of 10-20
mEq/L, while continuously monitoring the ECG. If K+ is
infused via a central line, it should be ensured that the tip
of the catheter is not in the right atrium. If cardiac arrest is
imminent, a rapid dose of 10 mEq over 5 minutes is required
and may be repeated once. The therapeutic requirement
for such a rapid infusion must be recorded on the patients
chart.

HYPERKALEMIA
Hyperkalemia is defined as a plasma K+ concentration
greater than 5 mEq/L. It occurs in about 3.3% of all
hospitalized patients,41 most commonly in patients of
chronic renal insufficiency,39 and can carry a high rate
of mortality.41 As for hypokalemia, the manifestations of
hyperkalemia also relate to neuromuscular and acid-base
effects. Increased ECF K+ concentration forces K+ into the
cells through the always-open leaky potassium channels,
leading to a slight depolarization. A constant state of
depolarization affects excitability and, once again, the
effect is fatigue and weakness. If severe, respiratory muscle
weakness can be a life-threatening complication.
In cardiac myocytes, hyperkalemia causes increased
K+ conductance.11 Since the K+ current is responsible for
repolarization, the first manifestation of hyperkalemia is
a rapid repolarization, reflected on the ECG as a sharp,
peaked T wave. Increased K+ conductance also makes the
RMP more negative, to a level at which Na+ channels start
getting inactivated.42 Hyperkalemia can also induce an
atrioventricular nodal block,43 reflected as a prolonged
PR interval and a ventricular rhythm with wide QRS
complexes.42 P wave amplitude decreases, and may not
be detectable, due to an electrical paralysis of the atria.44
With increasing severity of hyperkalemia, the widened QRS
tends to merge with the peaked T wave (Fig. 4), producing
a characteristic sine wave pattern.45 Eventually, the cardiac
arrhythmia deteriorates into ventricular fibrillation or
asystole, leading to death.
Causes
The various causes of hyperkalemia fall into two main
pathophysiologic groups movement of K+ from the ICF
to the ECF and impaired renal excretion (Table 2). Factors
causing transcellular shift of K+ have already been discussed
(Fig. 1). Renal causes can, again, be either related to a
defective mineralocorticoid action or due to an intrinsic
tubular inability to secrete potassium. Oliguric renal failure
can, by virtue of reduced renal perfusion and glomerular
filtration rate (GFR), cause reduced K+ secretion. Additionally,
the initiating pathologic process may entail catabolism
and metabolic acidosis, both of which would increase
serum K+. Thus, two separate mechanisms are responsible
for hyperkalemia in oliguric renal failure. This may be
compensated by RAA axis activation, but decompensation
occurs if GFR falls below a critical value of about 10 mL/
min.
690

Primary aldosterone deficiency can result from either

a generalized adrenal cortex failure (Addisons disease) or
from an inborn enzyme defect such as the 21-hydroxylase
(CYP 21A2) deficiency. The CYP 21A2 deficiency, which
may present in childhood or adulthood, causes congenital
adrenal hyperplasia and presents with virilization and
hypotension. Hyporeninemic hypoaldosteronism is a
condition commonly seen in association with diabetic
nephropathy and usually occurs in the presence of some
underlying renal pathology causing volume expansion.46
The volume expansion secondarily causes suppression of
the RAA axis, eventually manifesting as hyperkalemia.
Many drugs interact with the RAA axis. Non-steroidal
anti-inflammatory drugs (NSAIDs) cause hyporeninemia by
impairing prostaglandin synthesis in the juxtaglomerular
apparatus, which are essential for renin release. Additionally,
hypoaldosteronism can be caused by fluoride toxicity and
heparin, which act as inhibitors of aldosterone synthesis,
or by the angiotensin-converting enzyme inhibitors
(ACEI) or angiotensin-receptor blockers, which antagonize
angiotensin, the main stimulus for aldosterone release from
the adrenals.
Impaired K + secretion can result from receptorantagonism of aldosterone (spironolactone) or from
blockade of the principal cell Na+ channel (ENaC) by drugs
like amiloride, triamterene, amantadine and trimethoprim.
RTA Type 4, also known as hyperkalemic distal RTA, is
usually the consequence of some other underlying renal
pathology. There is reduced secretion of K +, leading to
chronic hyperkalemia. And, as discussed earlier (see
Pathophysiology), hyperkalemia impairs NH4+ production
in the collecting duct, leading to defective generation of
acid for excretion, and metabolic acidosis. Type 4 RTA should
be taken as a descriptive term rather than as a discreet
pathology, because any condition in which the RAA axis
is interrupted can potentially produce Type 4 RTA. Lastly,
pseudohypoaldosteronism is a rare familial condition in
which there is a defective gene coding for the ENaC.47 This

Fig. 4 : Electrocardiogram (ECG) of a patient with severe hyperkalemia.

The ECG shows a wide QRS complex merging with the peaked T wave,
producing a sine-wave pattern. Right axis deviation (I, aVF) can also be
appreciated.

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Table 2 : Causes of hyperkalemia

Redistribution to ECF

Metabolic acidosis

Massive cell rupture
Rhabdomyolysis, burns, hemolysis
Tumor lysis syndrome

Hyperosmolarity (e.g. severe hyperglycemia)

Insulin resistance or deficiency

Drugs
-blocker therapy
Digitalis
Succinylcholine

Hyperkalemic periodic paralysis
Impaired Renal Excretion

Oliguric renal failure

Primary mineralocorticoid deficiency
Addisons disease
Congenital adrenal hyperplasia (CYP 21A2)

Secondary mineralocorticoid deficiency
Hyporeninemic hypoaldosteronism
NSAIDs
ACE Inhibitors or ARBs
Heparin and fluoride

Impaired K+ secretion
Renal tubular acidosis Type 4
Potassium-sparing diuretics
Amantadine, trimethoprim
Aldosterone resistance
(pseudohypoaldosteronism)
Miscellaneous

Pseudohyperkalemia

Exercise-induced hyperkalemia (self-limiting)

Fig. 5 : Algorithm for approach to hyperkalemia.

DKA, diabetic ketoacidosis; GFR, glomerular filtration rate; ACEI,
angiotensin-converting enzyme inhibitors; NSAIDs, nonsteroidal antiinflammatory drugs; CSA, cyclosporine.
* low aldosterone

ECF, Extracellular fluid; CYP 21A2, 21-hydroxylase; ACE, Angiotensin

converting enzyme; ARBs, Angiotensin receptor blockers; NSAIDs, Nonsteroidal antiinflammatory drugs

loss-of-function mutation produces aldosterone resistance

and, in spite of elevated aldosterone levels, the kidneys
continue to lose Na+ and retain K+.
Diagnosis
The initial presentation of hyperkalemia can be
paralysis, cardiac arrhythmias or ileus. 48 History of
diabetes, medications and any familial disorders should
be sought. Laboratory values of serum electrolytes,
osmolality, blood urea nitrogen (BUN) and creatinine,
along with urine electrolytes should be obtained. The
diagnostic approach to hyperkalemia is detailed in
Fig. 5.
Treatment
Treatment of hyperkalemia involves three major steps:
(1) to reverse the cardiac effects, (2) to promote intracellular
uptake, and (3) to remove excess potassium from the body.
Later, on subsidence of the acute event, patients need to
be put on a maintenance regimen to prevent episodes of
hyperkalemia. Various treatment modalities and dosages
are summarized in Table 3.39,48,49
According to the 2005 AHA guidelines,39 management
should be guided by the serum K+ level. In mild hyperkalemia
(5-6 mEq/L), furosemide and sodium polystyrene sulfonate
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should be used. For moderate hyperkalemia (6-7 mEq/L),

an intracellular shift of K+ should be achieved using an
insulin-glucose drip, sodium bicarbonate and salbutamol.
In severe hyperkalemia (>7 mEq/L with toxic ECG changes),
the cardiac toxicity needs to be controlled at the earliest to
prevent the advent of fatal arrhythmias. Calcium chloride (or
gluconate) can be used as an infusion to achieve membrane
stabilization. In addition to calcium, all the modalities
mentioned above should be employed to lower serum K+
levels. In refractory cases, hemodialysis may be used as a
last resort of treatment.
In summary, disorders of potassium metabolism
are commonly encountered in clinical practice. Taking
an excellent clinical history, along with a thorough
understanding of potassium pathophysiology, will help
the clinician to make an accurate diagnosis and initiate
appropriate treatment. Additionally, anticipating potassium
disorders in patients receiving medications like diuretics
(hypokalemia) or ACEI (hyperkalemia), especially in patient
with co-morbid illness and chronic kidney disease, will help
in ensuring patient safety and optimizing patient care.

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Table 3 : Treatment of hyperkalemia

Therapeutic target
Dose and route
Onset
and medications

Duration
of action

Membrane effects
Calcium chloride
5-10 mL of 10% solution
Immediate
30 min.
or gluconate
IV over 2-5 min.
Intracellular shift of K+
Insulin-glucose drip
10 Units Regular insulin IV
15-30 min.
2-6 h.

with 50 mL of 50% glucose
Salbutamol
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15-30 min.
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by neubulizer over 15 min.
Sodium bicarbonate
50 mEq IV over 5 min.
15-30 min.
1-2 h.


Removal of excess K+
Furosemide
40-80 mg furosemide IV, with
15-60 min.
4 h.

saline if coexistent

valume depletion
Sodium polystyrene
15-30 g in 50-100 mL of 20%
1-2 h.
4-6 h.
sulfonate
sorbitol, either orally or as a

retention enema
Hemodialysis
15-30 min.

Long-term maintenance therapy
Restriction of K+ intake to < 2-3 g/day
Discontinuation of drugs interfering with K+ homeostasis
Enhanced K+ excretion: furosemide, thiazides
Fludrocortisone (in hypoaldosteronism)
Long-term sodium polystyrene sulfonate therapy

Comments

Can worsen digitalis toxicity. Monitor

ECG, stop if bradycardia develops.
Glucose unnecessary if
blood sugar > 250 mg/dl
Synergistic with insulin. May cause
a brief rise in plasma K+.
Should be used along with insulin
and salbutamol; may be less
effective in ESRD
Causes kaliuresis. Only effective if
adequate renal response to loop diuretics.
Sorbitol may be associated with bowel
necrosis. May lead to Na+ retention.
Rectal route acts faster.
Avoid ultrafiltration in the first hour
of dialysis

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