DISEASEOF

THE

MONTH

Hypokalemia-Consequences
I. DAVID
Division

WEINER

Hypokalemia

is one

of the most

abnormalities

asymptomatic

finding
or it can

mild weakness
can be simple,

Administration

commonly

in clinical

identified

only

be associated

with

to sudden
death. The
but if inappropriately

on

patients

who

epidemiology
and extrarenal

handling

Finally,
influence

dations

for

extensive
mation;

this

Medical

Center,

fluid

ranging

from

correction
of hypokabemia
performed
can lead

condition.

and

patient

shall

discuss

to many

Space
of the

comprehensive

diagnosis

the

of hypo-

the important
provide
general

management.

reference
thus,

the differential

we shall consider
therapy
and shall

factors
that
recommen-

limitations

primary

reviews

sources

are frequently

to the cortical

collecting

deficiency

disease

and

Most
disease

risk,

indicate

cases
states.

with

Patients

as many

of less than
diuretics
osmotic

the

need

of hypokalemia
receiving

as 50%

3.5 mEq/liter

occur

for
in the

diuretics

developing

( 1 ). As we will

later

are more likely to cause hypokabemia

diuretics.
Individuals
with secondary

of

setting

young
with

at

discuss,

through

interaction

that

with

morbidity

tolerate

risk

of

more

severe

but

neuulti-

severe

degrees

of

side-effects

than

the

produce

levels

salt

ciation

or

insuffigroup
at
renal

delivery

P.O. Box 100224, Division

of
University
of florida
College

reveal

various

lation

that

of a high

increase

bow-potas-

sodium
(3).

Americans.

that

Several

can

show

of hypertension

(3). Thus

contributes

intake,

This

asso-

Epidemiologic

expansion
may

(4).

also

Patients

strongly

indicates

potentiate
agents

hypertension
is not
type of hypertension

Hypokalemia

as a result

arrhythmias

of ventricular

evidence

to hypertension.

of hypokalemia-induced
One component
of this

neurohumoral

(8).

problem.

deficiency

studies

patients
factor

effect of thiazide
diuretics
is reduced
by hypoenhanced
by potassium
repletion
(5).
Finally,
may be more highly
sodium-dependent
in the

effect
of hypokabemia.
hypokalemia
predisposes
variety

important

studies
confirm
this association
in both healthy
in essential
hypertensive
patients
(4). The an-

to be salt retention

Hypokalemia

potassium

in African

of hypokalemia

volume

to in-

in many

an

health

in the presence

marked

The mechanism
completely
clear.
appears

serious

the prevalence

hypokalemia

cular

that

especially

and prospective
volunteers
and

that

this

as

Cross-sectional

is most

contribute

to hypertension

unrecognized

or worsen

with

presence

thiazide

alter

diets,

are linked

Both

the cardiovasand hypokab-

mortality.

contributes

is frequently

may

arrhythmias.

and

Hypokalemia
(3)

Ventricular

Correspondence
to Dr. Charles
S. Wingo,
Nephrology,
Hypertension
and Transplantation.
of Medicine,
Gainesville,
FL 32610.

organs

system,
effects

elderly.

tihypertensive
kalemia
and
blood
pressure

highest

than 1oop
hyperaldosteron-

with

conservation

diet,

the

patients

potassium

adults
less

ventricular

potassium

diseases

for

and mortality
related
to this
correlation
between
degree
of

emia-induced

of specific

high

those

morbidity
the

side-effects
of hypokalemia
affect
hypokalemia-related
hypertension

an etiology.

heart failure,
hepatic
constitute
a second

Finally,

of several

Two major
cular system:

underlying

ism, whether
due to congestive
ciency,
or nephrotic
syndrome,
risk.

function

Cardiovascular

Western

are

serum

the

the cardiovascular
kidneys
(2). These

of infor-

conservation
in
of spontaneous
are not receiving

possibility

to search

risk

and

hypokalemia

sium

the

at high

children

factors:

suggest

also

deficiency
and adverse
side-effects
is poor, possibly
the occurrence
of side-effects
is related
to both the
deficiency
and the underlying
disease
state. Overall,

pressure.

should

are

potassium
because
potassium

of evidence

in the typical

alters

mately
determine
the
condition.
Unfortunately,

lines

medications

(CCD)

and most prominently

affects
robogic
system,
muscles,
and

blood

any

and

Consequences

defined
by a serum potassium
level of less than 3.5 mEq/liter.
This very low frequency
of hypokalemia
is a testament
to two
of potassium

duct

cited.

of hypokalemia
is strongly
dependent
on the
In otherwise
healthy
adults
not receiving
less than 1 % will develop
hypokalemia,
as

the adequacy

of Medicine,

hypokalemia.

creased

and potent
mechanisms
for renal
potassium
states
of potassium
depletion.
The presence
hypokabemia
in otherwise
healthy
adults who

College

preclude

Epidemiology
The occurrence
patient
population.
any medications,

of Florida

Florida.

Potassium
to

the management
of
practitioners
to care
We

University

Gainesville,

electrolyte

symptoms

of hypokalemia
and its consequences
on renal
tissues
and shall briefly
discuss
the physiology

of potassium
kalemia.
should

have

Transplantation,

It can be an

routine

and Correction

S. WINGO

and

encountered
medicine.

worsening
symptoms,
and even death.
The purpose
of this article
is to discuss
hypokalemia
in sufficient
detail to allow
for

CHARLES

Hypertension

Veterans

and electrolyte
screening,

and

of Nephrology,

Gainesville

Causes

leads

of renal
the

hypertensive

retention.
effects

of

(6,7).
are

a second

cardiovascular

Several
prospective
patients
to the
arrhythmias,

at the

to intravas-

NaC1

highest

studies
show
development

including

risk

ventricular

for

arrhythmias,

side-

that
of a
fibril-

the

I 180

Journal

elderly

and

ease,

Society

patients

with

underlying

highest

risk

those

appear

to have

complications
ticular

of the American

the

(9, 10).

concern

pertensive

the

individuals

than

heart

of

sudden

with

the thiazide

that

in matched

( I 1 ). The effect is dose-related

comitant
use of potassium-sparing

and

dis-

tes

insipidus

nervous

is of par-

besides

its

in hy-

impairs

the

death

diuretic

hydro-

control

(2).

subjects

is decreased
by the
diuretics
( 1 1).

This

tive

con-

sensitivity

impairs
to insulin,

diabetic

resulting

public

Because

health

increasing

cations

from

in

industrialized

are

end-organ

related

of

to

the

of diabetes

cystic

duct

scarring

nations.

cyst

compli-

unclear.
of

de-

Potassium

depletion

complications

( 16).

Hypokabemia

impairing

their

muscle

cells,

tion necessary
flow to skeletal

for muscle
muscles.

patients

result

in

ability

weakness,

of these

easy

fatigabibity,

although

potassium

deficiency

can

when

blood-flow

leads

and

myalgias

occur

in cases

(16).
of

Pa-

(16).

that

ammoniagenesis,

Hypokalemia

can

through

acid-base

regulation.

profoundly
its

The

on
most

bolic alkabosis.
Hypokalemic
the effects
of hypokabemia
excretion.
The most
imal tubule HCO1
collecting
both

duct

KtATPase

(20);

Hypokalemia
acid-base
(2 1 ).
sis.

may

possibly
In

rare

produce

cases,

the

cobonic
these

because
also inhibits
such

severe

abnormality

is meta-

alkabosis
components

stimulation
isoforms

urinary

hepatic

increases

50%

turned

to the

on renal

hypokabemia

leads

to

concomitant

development

of respiratory

acidosis

can

mild

complication

polyuria,

is related

averaging

to both

increased

of hypokabemia
2 to 3 liters
thirst

and

is the development
per day
mild

(2).

The

nephrogenic

of

polyuria
diabe-

increased

of Potassium

average

70

mEq.

with
and

daily
Under

of

In hepatic

ammonia

can

re-

be sufficient

the symptoms

the

vast

90%

majority

of hepatic

role

potassium

is present

potassium

averages

of active

result

of

in a typical
excretion

the

intra-

in potassium
in the

uptake

in
and

in the
the

stool.

extracelbubar

homeostasis.

intracellular
by

equals

excreted

remainder

the

Western

space.

Intra-

largely

Na4-K-ATPase.

as a
Ap-

of total body
potassium
is present
in the
Consequently,
small changes
in the distribetween
the intra- and extracellular
fluid
proportionally

concentration.

functions

intake
conditions,

120 to 140 mEq/liter,

potassium

in

between
intake,
and extracellular

of potassium

of

an important

proximately
98%
intracellular
space.
bution
of potassium

is a balance
the intra-

normal

approximately

plays

potassium
apparently

is re-

veins.

burden

potassium

space

states

Approxi-

production
renal

that

hypokalemia

Homeostasis

between

Most

and

ammoniagenesis
or worsen

toxin

(19).

the

systemic

renal

of potassium

in

of

or worsen

One

ammonia
via

Distribution

store

fibro-

is independent

ammoniagenesis

tubule

circulation

increased

potassium

Polvuria
Another

this

(27).

The
is

spaces

be life-threatening.

the interstitial
effect

to the development,

potassium
concentration
and distribution
between

space.

result

interwith

supplementation,

is ammonia,

the development

Serum
excretion,

respiratory

and the development

of respiratory
acidosis.
hypokalemia
as a result of renal tubular aci-

activate

hypokalemia,

Consistent

encephabopathy.

tubule

systemic

Physiology

cellular

the

bicarbonate

encephabopathy

the

to cause

homeosta-

on acid-base

hepatic

of proximal

from

urine

acidification
secretion
(22),

contribute

of

proximal

mately

diet

may

that

(26).

can

symptoms,

intake,

excretion.

effects

intracellular
abdosterone

of
of H-

citrate

widespread

effects

of prox(18,19);

is
and

in the medublary

this

to

development

ammoniagenesis

decreases

potassium

encephabopathy

results
from
of net acid

via

(HKa,)

of

ho-

of renal

possibly

decreasing

minimizes

muscle
weakness
In patients
with
dosis,

and

acid-base

components

include
stimulation
and ammoniagenesis

secretion,

and

homeostasis
Hypokabemia

which

metabolic
on several

(HKa1)

systemic

multiple
common

direct effects
reabsorption

proton

the gastric

affect

effects

cyst

(26).

hypokalemia;

with
leads

Encephalopathv

subting

meostasis

of complement

observation

insufficiency,

Acid-Base

of
which

is the

with

associated

postulated

fibrosis

in the

hypokalemia

to increased

been

can

to arise

frequently

accumulation,

in serum

causes

profound

defecantidi-

(24).

appear

the

interstitial

Hypokalemia

to muscle

are

to

associated

the

causes

hyperaldosteronism,

mechanism

It has

to activation
beads

Hepatic

vigor-

and

beads

system.

changes

regulation.

frequently

cramping,

uncommon,

the depobariza-

especially

impaired

effects

sis

It can also reduce

blood
blood
flow can predis-

(I 7),

with

skeletal

maximally

preventing

cysts

Correcting

The

ammonia

by inhibiting

muscular-related

hyperpolarize

to develop

contraction.
The reduced

is combined

combination

several

can

to rhabdomyolysis

exercise

ralysis,

can

(25).

complement

hypothesis

Muscular

urine

concentration

These

(25).

Hypokalemia

by leading

meblitus.

also

the

with

disease.

epithebium

regression

medubbary

that,

cyclase.

un nary

increased

Hypokalemia

hypokalemia

adenylate

in association

to renal

interstitial

may

because

renal

with

II, a hormone

Disease

collecting

degree

hypokalemia

thirst.

to concentrate

to occur

meblitus

in

regulates

ability

of

Cystic

stitium,

The

kidneys

is associated

of angiotensin

hormone-stimulated

lead

hyperglycemia

that

treatment
effects

end-organ

and diabetes

suggests

mellitus

devastating

and

in worsening

evidence
(14, 15),

the

release

concerns

diabetes

hyperglycemia
crease

insulin

( I 2, 13). Hyperglycemia

patients

major

both

thirst

levels

effects,

Hypokabemia,

Hypokalemia

ous

other

appears

Renal

pose

Increased

system

activation

uretic

Hormonal

are

(23).

central

hypokalemia-related

hypokalemia

incidence

treated

is greater

ischemic

for

Diuretic-induced

because

chborothiazide

of Nephrology

The

to minimize
potassium

large

changes

large

intracellular

changes
deficiency.

shifts
from
the
to reduce
changes

in

in extracellular
Under

these

extracelluar
potassium

potassium
conditions,

intrato the extracellular

fluid,
in the transmembrane
potassium

Hypokalemia:

gradient.

With

muscle,

potassium

exhibit

sium

than

do

potassium

result

as

300

and

deficit

of 600

Potassium

is

Although

the typical

considerable

the

present

individual.

adapt

to a wide

absence

severity

Na

and
For

of 100 to

indicate

a total

varying

H
K

averages

amounts.

70 mEq/d,
dietary

there

of other

factors,

intake

without

deficiency

of

the

of

body

cominduce
a

in

this

to the

HCO3
primary

Potassium

mechanism

is

reabsorption
the

freely

of potassium

filtered

of Henle

reabsorption

(30).

occurs

the primary
whereas

CCD

the

(OMCD

outer

At least

three

cell

to potassium

the

transporters

involved

principal

cell

secretion.

and

basolateral

is actively

gradient

potassium

sium

channel.

sodium

reabsorption

voltage.

Because

is codependent

on Cl

generates

this

luminal
An

sium,

most

sponse

a basolateral

could

cell,

increased

CCD

A-

and

B-type

to

resulting

modeled

reabsorption
principal
secretes

contributing

occurs
cell

through

potassium

protons

com-

reabsorb

pro-

and

reabsorbs

deficiency

exit

present
may

transporter,

can

exit

presumably

the cell

via

a potas-

HKct,

in the

the OMCD

IMCD

Re-

do

(34,35).

on

not

to

potassium

to hypokalemia
This
A

CCD

the

HKa1
extent
opposite

under
or potas-

appears
cell,

to occur

e.g. , luminal

and basolateral

potassium

duct:

and the

clinically.

transport

isoforms

inwith

H-K-ATPase,

HtKtATPase

two

the

expansion,

potassium.

a greater

whereas

the

the

a basolaterab

to

sodium
reabfor potassium

hypokalemia,
in combination

is observed

reabsorb

collecting
CCD,

to the apical

of apical
HKt
provide
a new model
inhibition
of H-

volume

in response

at least

regulated
in the

that

by an apical
via

previously,
be

potassium

similar

uptake

In re-

potassium

exchanger

reabsorption,

but
can

potassium

apical

deprivation,

and

potassium

across

the

homeostasis.

(3 1). In
activity,

pressure

conditions,

mechanisms

noted

transport.

OMCD

via

potas-

potassium

CF7HCO3

for

to net NaCl

sium

of normal

is recycled

and

that

necessary.

to potassium

WKtATPase
H-K-ATPase

blood

The

(3 1 ). In the presence
net

duct.

mechanism

when

CCD amiloride-insensitive
that sodium
can substitute

substituting

lead

acidification

potassium

collecting

a sensitive

contribute

reduces
suggesting
CCD
CCD

normal

secre-

also

by the apical

sodium

to urinary

in little

barium-sensitive

on the
creased

secretion,
the rate of sodium
rate of potassium
secretion.
which

reabsorbed

or

electro-

are

H4KtATPase

to potassium

charge

the

provides

reabsorption

HtKATPase
(3 1 ). Parallel
operation
ATPase
and apical Cl/HCO3
exchange
for active
KC1 reabsorption.
Additionally,
K-ATPase
sorption,

Electrogenic

respectively),

of

potas-

CCD,

reabsorption

membrane,

secretion.

(32,33).

apical

that

B cell,

those

via

an

the

potassium,

potassium

indicates

increases

the

in the cortical

our laboratories
and those of others
provide
strong
evidence
for an apical
H-K-ATPase
in this cell
We have also shown
that there is coupling
of chloride

reabsorption

electro-

via

and

from

apical

its

(urine)

of

Potassium

different

cell

(A cell

remainder

buminab

principal

the

lumen-negative

charge

for potassium
regulates
the

potassium.

cesses
tion.

cells

the

negative

into

potassium

This

potassium

may

sults from
functional

60 to 70%
for

down

fluid

transport

studies
show
that the B cell, generally
believed
to
bicarbonate
secretion
and recovery
from
metabolic

alkabosis,

The

(20).

active

Recent
mediate

1 summarizes

comprising

secreted

luminal

evidence

to the

intercalated

the

ducts
(30,31).

transport.

up

Additional

chemical
gradient
reabsorption
also
In contrast

and

into

secretion

prise

taken

of potassium

channel

allows

all of which

Figure

to be responsible

Na-K-ATPase

chemical

collecting

in the CCD,

cell,

sium

potassium,

potassium

numerous

1. Model

Figure

Instead,

potassium

homeostasis.

is believed

Potassium

reabsorbs

reabsorb

are present

and

is the collecting

medullary

in CCD

is the most

CCD,

and

inner

types

contribute

(30).

however

secretes

by

tubule
of potassium

regulation

respectively)

may

followed

regulation

segments,

and

and IMCD,

little

potassium

both

is the urine.

gbomerulus,
by the proximal

Relatively

in these

excretion

the
85%

site for renal

(3 1 ). The

of the

at

of approximately

loop

duct

population

(28,29).

The

can

development

and contribute

hypertension

is

preferences

Notably,
African
Americans
less potassium,
which may

potassium

and

in

on the

space

that

barge.

deficit
can

foods

Peritubular

3.5 to 3.0 mEq/

potassium

of potassium

of physiologic

incidence

states

from

1 181

level.

is very

mEq/liter

intake

of marked
hypokalemia.
monby eat diets containing
state

body

depending

range

small

pseudohypokalemia

most

dietary

In the

a result,
potassium

and Treatment

Lumen

mEq.

in

variation,

As

below)

to 2.0

to 800

potas-

serum

potassium

a total

a decrease

notably

in hypokalemic

discussed

in serum

tissues,

in intracellular
brain.

the

(excluding

be

indicates

mEq,

body

will

the

deficit

loss

a decrease

biter typically

as
affect

potassium

redistribution,

example,

such

potassium

certain

reduction

minimally

the

from

rapid

others,

losses

Conversely,

depletion,

a more

Diagnosis

channel

(20).

of HtKtATPase
and

HKa2

by

(20).

HKa1

hypokalemia
appears

As

are

to be true

than
in

I I 82

Journal

Despite

the

of the American

presence

porters

in the

level

is generally

Society

of active

CCD,

OMCD,

not

potassium

and

lower

of Nephrology

reabsorptive

IMCD,

than

the

Little potassium
is excreted
ditions
because
of a low stool
sium

concentration.

or stool

volume,

be excreted

by

content

do not

because
small.

the basal

increase

renal

may
re-

and

increase

fecal

this

route.

Decreases

affect
of stool

the

potassium

potassium

The

accurate

treatment
of

the

either
with normal
Normal
total body
potassium
lular

of

cause.

or decreased
potassium

redistribution

space.

Total

from

body

hypokalemia

is normally

broad

groups

loss,

be

correct
associated

depletion

can

intracel-

result

white

from

losses.
We suggest
that the
hypokabemia
consider
four

plasma
potassium
of the storage

artifact

this

artifact,

More

98%
fluid,

mia.

most
Insulin

potassium

if present

level. The
procedure

in

large

enough
stored
for
in a low

apparent
hypokalemia
and is referred
to as

most common
underlying
disleukemia.
Rapid
separation
of
at 4#{176}C
confirms
the diagnosis,

prevents

inappropriate

of total

body

predominantly

insulin,
common

aldosterone,
cause

activates
uptake

sympathomimetic
dobutamine,
and

directly

stimulate

the

stimulate

insulin

release,

potassium

potassium

is present
muscle

and

Acute

the
This

en-

sympathomimetics,

are
hypokale-

which
insulin

in the
cells,

of potassium
to alter
Certain
hormones,

of redistribution-induced

from

hyperkabemia.

tration,
chronically
do not typically

high
cause

as a result

of Nat
activity

results

administration

cellular

ischemia

of potassium

acute

increases

and

the

risk

mia,

is

important

asthma

therapy.

impairment

Patients
decreased

might

not

setting

of

may develop
wheezing,

sympathetic

tone,

arrhythmia

insulin
bevels,
hypokalemia;

to acute

insulin

cell

oral
the

in

for

or cell

from

granulocyte

ment

of refractory

anemia

with
acute

contractile

more seriously,
air movement,
improvement

periods,

providing

anemia

redistribution

can

to the

cause

can also

rapid

intracellular

movement
space.

and

paralysis

(16,36).

reported.

Most

distribution,

(40).
and

sudden

Both

although

resultant

in some

death

factor

treatment

familial

cases
an

treat-

of pernicious

cell production

individuals

has

can
resulted

(41).

secondary
to redistribution
can be a result of hypokalemic

hereditary

documented.
In Asians
dition
associated
with

The

Rapid

high-grade
can result

colony-stimulating
or the initial

hypokalemia.

contain
approximately
stimulation
of either

macrophage

Rarely,
hypokalemia
hanced
cellular
uptake

in

states.
Cells
consequently,
production

hypokabemia

in arrhythmias

ability.

of potassium

the extra-

vitamin

death.

agonists
or
hypokale-

cell production
can occur
in acute
leukemia
and
lymphomas.
Acute
stimulation
of cell production

cause

as occur in insubinomas,
the mechanism
of this

prolonged
of severe

as a result

from

as a

or from
Cellular
then in-

Another
clinical
concern
is premature
3-agonists.
These
patients
frequently

intake

hypertrophy

muscle

acute

whether

sudden

as an overall

development

of potassium

in active

adminis-

and

CO2 retention,
or, even
as a result
of decreased

condition.
involving

have
for

respiratory

be misinterpreted

the patients
labor therapy
do

ventricular

slim-

Myocardial

of the asthma
patient
with 3-adrenergic
can bead to potassium
redistribution,

and

which

of

also

indirectly

Sympathomimetic-induced

hypokalemia

and

agonists,
dothree agents

first

theophylbine

(36,37).
to

commonly

uptake

whereas

leading

ischemia

produces

extrato intracellular
space,
problem
is most
frequently

In contrast

and

to extracellular
below,
aldoThus hyperof the combined

agents,
,-adrenergic
theophylbine.
The

uptake

redistribution

Hypokabemia

encountered
in the treatment
of diabetic
ketoacidosis.
Insulininduced
redistribution
of potassium
is the physiologic
principle
underlying
the administration
of insulin
with glucose
to pawith

includes
pamine,

treatment.

in skeletal

NaKtATPase,
(37).

rapid
potassium
shifts
resulting
in hypokalemia.

tients

hypokalemia

of

slowly

production
enzyme

the transport
of potassium
from the intracellular
space (37-39).
In addition,
as will be discussed
sterone
also regulates
renal potassium
transport.
causes

more

crease

abling
small changes
in the distribution
the extracellular
concentration
markedly.
the

the

in increased

occur from acute anabolic

130 mEq/biter
of potassium;

than

particularly

stimulates

results

uptake

much

redistribution,

potassium

Redistribution
intracellular

Aldosterone

but

loss.

renal

up extraceblubar
potassium
when
at room
temperature,
resulting

and

of effects,

redistribu-

cellular

pseudohypokalemia,

pseudohypokalemia
(36). The
ease state is acute myelogenous
the plasma
or storing
the sample
avoids

induces

and

cells,

measured

responsiveness

direct result of the ischemia,

decreased
cardiac
output,
either the pain or the anxiety
related
to the ischemia.
potassium
redistribution
leading
to hypokalemia
can

blood

can take
periods

a variety

which

Treatment
theophylbine

numbers,
prolonged
is an

insulin.

myocardial

to the

end-organ

Aldosterone

through

the extracellular

Pseudohypokalemia
Abnormal

potassium

decreased

diabetes
may contribute
to the hyperby altering
the distribution
of potas-

the intra- and extracellular

space.
clinically
common
cause of potassium

is aldosterone.

ulates

potassium

of etiologies:
potassium

can

tion

total body potassium

content.
with hypokalemia
is a result of

either renal or extrarenal

potassium
clinician
evaluating
a patient
with
extrarenal

requires

Hypokabemia

The

effects
of redistribution
and stimulation
of renal
potassium
clearance.
The final major hormonal
cause of potassium
redistribution

Causes
identification

sium between
A second,

aldosteronism

to hypokalemia

excretion

is unknown.

to insulin
in adult-onset
kalemia
frequently
seen

KtATPase,

potassium

in stool

response

escape

than

potassium

hyperkalemia,

failure
can cause adaptive
changes
in
such that as much as 20 to 30 mEq/d

materially
level

stool

failure

as diarrhea,

excretion.
Chronic
renal
stool potassium
content,
can

that

as chronic
such

This

potassium
in the CCD.

in the stool under

normal
convolume
and a low stool potas-

Conditions

such

potassium

15 to 20 mEqlliter.

reflect
both water reabsorption,
which
exceeds
absorption,
and persistent
potassium
secretion

concentration,

trans-

urinary

and

follow

X-binked

sporadic

cases

an autosomab
recessive

form

there is a high frequency

thyrotoxicosis
( 16). Attacks

with enperiodic
have

been

dominant
has

been

of this confrequently

Hypokalemia:

commence

during

characterized
persist

the

night

by flaccid

or

6 to 24 h (36).

from

idine-sensitive

the

paralysis

calcium

early

morning

A genetic

channel

defect

has

been

Finally,

hypokalemia

and

explained

and,

Non-Renal
Both the

action

hence,

cellular

Potassium
skin and

the

amounts

of

net fluid

loss from

these

Occasionally,

intravascular

and

further

Prolonged
nasogastric

suctioning,

this

loss

exertion

lead

to hypokalemia.

Other

potassium

tuna,
cation

which
increases
potassium
excretion
both directly,
to balance
the negative
charge
of bicarbonate
ions,

indirectly,

through

Metabolic

alkabosis

stimulation

of

results

urinary

leading
to worsening
of intravascular
stimulation
of the renin-angiotensin-aldosterone
dition,
by

potassium

acid-base

reabsorption
status.

potassium

excretion

metabolic

by

increasing

probably
by direct suppression
Diarrhea,
whether
secretory

duct

alkabosis

secretion

concern

image

body

needed

to confirm

anosis
tives,

and

cobi
such

may

also

screening

abuse
for

The

former

who

have

been

using

cascara

and

aloe,

for

and

diuretics
will

(44).
may

reveal

anthracene

more

abuse,
Patients
of over-

diuretics

the diagnosis.

in patients
as senna,

and

urine

renal

reabsorption.
of laxative

gastrointestinal
potassium
loss.
may deny the condition
because

about

and
In ad-

is affected

can cause
profound
with laxative
abuse
Sigmoidoscopy

than

be

mellaxa-

4 months

If phenolphthabein

laxatives
are being used, alkalinization
of the stool to pH 9 will produce
a pink color. If magnesiumor phosphate-containing
cathartics,
such as magnesium
citrate
or sodium
phosphate,
are suspected,
direct
measurement
of
(45).

these

compounds

in the

stool

can

confirm

the

The

Potassium
most

diagnosis.

potassium
endogenous
sic

renal

loss. This
hormone
defects.

cause
can occur
production

Table

of hypokalemia

is excess

renal

either
because
of medications,
or, in rare conditions,
intrin-

1 summarizes

these

necrosis

syndrome

syndrome

Drugs.
Many
medications
can cause
renal potassium
wasting,
including
diuretics
and some antibiotics.
Both thiazide
and loop diuretics
factored
for their
potent
diuretics

causes.

increase
natriuretic

urinary
effect,

potassium
thiazide

kabiuretic
agents
(46).
In
have a shorter
pharmacologic

potassium

conservation

during

part

excretion;
when
diuretics
are more

this is because
half-life,
enabling

periods

between

drug

loop
renal
adminis-

tration,
but may also reflect
their
convoluted
tubule
with secondary

site of action
in the distal
effects
on flow to the pri-

mary

in

site

except
ing

of

potassium

by

increasing

delivery,
and
determinants
also

induce

ondary

CCD

luminal

intravascular

volume

kalemia

is both

dosecan

of mechanisms.

bin analogues,
increase
distal
thereby

drug

potassium

may

treatment
urinary

resulting

excretion.

in sec-

stimulation

of

and

excretion

hypokalemia

Polyene

renal
hypo-

duration-related.
potassium

penicillin

potassium
induce

sodium

of diuretic-induced

High-dose

urinary
that

diuretics,

luminal

excretion

by

some

penicil-

such as carbenicillin,
oxacilbin,
and
tubular
delivery
of a non-reabsorbable

increasing

is another

further

incidence

and

increase

rate,

All

potassium-wast-

which
are the primary
by the CCD.
They
may
contraction,

and
The

CCD.

induce

flow

luminal
electronegativity,
of potassium
secretion

secretion.

the

diuretics,

hyperaldosteronism

potassium

renal

secretion

the potassium-sparing

Antibiotics

Loss

common

inhibitors

syndrome

Liddles

variety

Renal

anhydrase

Gitelmans

as a
and

increases

potassium

of potassium
or as a result

causes

excretion,

depletion
system.

by the collecting

Thus

common

Bartters

in bicarbona-

sodium

volume

tubular
acidosis
alkabosis

leukemia
diuretic
phase of acute tubular
Intrinsic
renal transport
defects

fluids

renal

acidosis

deficiency

less

carbonic
toluene

or
part

body

tubular

cisplatin

(43).

A small

these

hypertension
states

of proximal
renal
phase
of metabolic

Magnesium

ex-

vomiting

renal

treatment
correction

to sec-

potassium

from

because

distal

contain
5 to 8 mEqfliter
potassium.
More importantly,
concomitant alkabosis
and intravascular
volume
depletion
contribute
to
loss.

analogues

B icarbonaturia

loss
cases,

deficit

whether

is direct

penicillin
B

glucococorticoid-excess

in hot,

leading

of the potassium

can

potassium

and

amphotericin

conditions,

of renal

contents,

diuretics

penicillin

be

net potassium

also,

stimulation

of gastric

osmotic
antibiotics

transport

severe
potassium
In most of these

is present

worsening

loss

diuretics

aminoglycosides

can

limiting

as prolonged

depletion

can

diruetics

loop

potassium

normal

is small,

such

thiazide

(16).

tract

Under

organs

hyperabdosteronism,

cretion,

of

potassium.

loss

Hormones
aldosterone
glucocorticoid-remediable

or chronic
diarrhea.
to hypokabemia
(43).

volume

ondary

exit

potassium

diuretics

with

effect

to block

L05s
gastrointestinal

in cases

dry environments
can occur,
leading

latter

of renal

1 183

Drugs

to cause

in connection

potassium

1. Causes

anhydrase
inhibbeta blockers,
or

The

of barium

Table

and Treatment

may

in a dihydropyr-

reported

known

significant
boss.

been

intoxication.

by the

channels

has

barium

are

which

determined

certain
cases of this disorder
(42). Carbonic
itors (acetazolamide
250 mg four times daily),
spironolactone
may prevent
attacks.
chboroquine

and

of all extremities,

Diagnosis

antibiotics,

(47).
via

ampiciblin,
anion,
Cisplatin

an increase

such

as ampho-

in

I I 84

Journal

the American

of

Society

of Nephrology

tericin
B, create
cation
channels
in the apical
collecting
duct cells, which
increases
potassium
results

in potassium

result from
presumably

wasting

but

(see

may

below)

exposure,

which

cessive
hyperplasia,

there

can

hydroxybase

or I 7a-hydroxylase,

or direct

most
such

to stimulation
inhibition

antibiotics

by

not

and

inhibition

cause

pentamidine,

17a-hydroxylase

hy-

leading

most

it

quently
the

leads

kidney

cell

apical

effects

increase

potassium

luminab
channels

movement

from

fluid.
and
cell

sorption

can

sorptive

capacity

intake,

secretion.

in the
than

the

gradient

rate

can

of

be

because

cytoplasm

particularly

secretion

primary

or

results

in cases
sodium-retaining

hypokalemia

II levels
may

oral

intake,

the

occur

will

typically

in a variety

diuretic

use,

involve

vomiting,

renin-angiotensin-aldosterone

lignant

aldosteronism
activation
gests

that

of

below).
mg

of

an-

defects

lead

to excessive

In gbucocorticoid-remediable

of
in ma-

(ACTH)-regulated

of the

aldosterone

gene

synthase

is linked

gene,

sugto

aldosterone

the

proan adre-

to the

with

exceed

of

chewing

to-

with

is

and

in

potas-

lysozymuria

Gitebmans

magnesium

daily,

This

cisplatin-induced

with
with

times

defi-

(36).

hypokabemia

and

ca-

magnesium

associated

in individuals
four

such

the metabolic

hypokalemia

diuretic-induced

hypokalemia

and

not

drugs,

This can occur

or in the ectopic

Concomitant

of aminoglycoside-

show that these

known
as either
Patients

contributes

aldosteronism,

carbenoxobone,

may

in

syndrome
oxide,

serve

understanding
of renal solute
transport.
scribed
the association
of hypokabemia,
perreninemia,
and metabolic
alkabosis

with

at an early

as decreased

system

significantly

(54). Some

can

Supplementation

coding

rate-limiting

enzyme
for aldosterone
synthesis
(52).
Aldosterone
synthase
is
no longer
regulated
by the renin-angiotensin
system,
and ex-

patients
Bartters

Bartters
age

250

to correct

with

In

1962,

to

both

Bartter

hypomagnesemia,
(57).
Recent

can be divided
into two
syndrome
or Gitebmans
syndrome

severe

are hypercalciuric

volume

depletion.

sium

channel,

and

ROMK,

both

of which

reabsorption
(59).
hypomagnesemia,
presents

at a later

are

and present
This

necessary

condition
Na-K-2C1
potasfor

Gitelmans
syndrome
and milder
clinical

age.

This

syndrome

de-

hystudies

groups
now
syndrome.

appears
to be a result of defects
in either
the renal
cotransporter
gene, NKCC2
(58), or the ATP-sensitive

tations

redistribution

cortisol

correction

by mouth

the

renin-angiotensin-aldosterone

dehydrogenase
which
does

the magnesium
and potassium
deficiency.
Intrinsic
renal defects.
Intrinsic
renal defects
beading to
hypokalemia
are rare but have led to important
advances
in our

contrib-

occur

cases

500

Activation

as may

true

(see

(49),

potassium

nocorticotropin

sequence

system,

particularly

Henle sodium
hypocalciuria,

the hypokalemia.
Rarely,
genomic
duction.

diarrhea.

prevent

renovascubar
hypertension
(50), and
tumors
(5 1 ), can also lead to secondary
hyperwith subsequent
hypokalemia.
The secondary

hypertension

renin-secreting

or

such

in

Glucocor-

for the mineralofrom binding

to

1 1 f3-HSDH,
allowing
cortisol
to
effects
in the distal nephron
(55).

depletion.

may

the

hyperabdosteronism.

of conditions,

Magnesium

renal

synthesis,

giotensin

circulating

leukemia,

elevated

(found

as mineralo-

hypertension.

of 1 l3-HSDH
and cause hypokalemia.
in severe
cases of Cushings
disease
syndrome
(56).

acute

gland
This

pacity
either
ACTH

wasting,

effects

involving

acid

bacco,
and licorice),
inhibit
exert minerabocorticoid-bike

metabolism,

characteristics.

function

and

receptor

sium

the vasculature
to neurohumoral
regulators
Because
angiotensin
II regulates
adrenal
conditions

glucocorticoids

hypokalemia

glycerrhetinic

1 1 f3-hy-

production,
In contrast,

hormone

minerabocorticoid

certain

ute by sensitizing
of blood
pressure.
aldosterone

sex

of sexual

bind

reab-

secondary.

also

inhibits

and
a p0-

be recognized

in increased
androgen
of men and women.

1 1/3-hydroxysteroid
cortisol
to cortisone,

to the

1 1f3-

hypotha-

production.

enzyme
converts

reab-

of hypertension
may

can

steroid

the

ciency

by

condition

sex

such as cortisol,
have a high affinity
receptor
but are normally
prevented

Na
CCD

normal

is to enhance

of the

but the associated

the

with

potassium

either

for

potassium

(3 1 ),

conditions,

adrenal
either

hormone
(CRH)
secretion
1 1-deoxycorticosterone,

development

causing

of

in excess

because
(1 l-HSDH)

to the

on apical
increases

IMCD

of aldosterone

hyperaldosteronism
predominantly

and

segments,

net effect

or transepithe-

Although

OMCD

of these

the

aldosterone,

charge

rare

ticoids,
corticoid

as

These

on

deficiency

Infrequently,

CCD.

electrochemical

actions

potassium
clearance.
Hyperabdosteronism
Primary

the

in

transport,

in the

Thus
aldosterone,
via
basolateral
NatKtATPase,

is less

Thus

the

site

NatKtAlPase

absorption

cell

potassium

fre-

effect

cell responsible
for
increases
principal

principal

occur

ho-

or

potassium

the net luminal-negative

increases

potassium

is the primary

basolateral

sodium

which

principal

(48),

CCD

regulates

conductance,

electrogenic

voltage.

Na

The

aldosterone

sodium
and

CCD.

body

production

CCD
principal
cell is the CCD
secretion
(30,3 1 ). Aldosterone

activity,
hal

total

abdosterone

to hypokalemia.
where

and the
potassium

regulating

excess

in

In congenital
absence

resulting
of

effects

to incomplete

Under

hormone

ensures.

congenital

deficiency
results
to early viribization

and

cause

channels

the

(53). This

associated

corticoids,

and

sodium

the

the

important

apical

can

production
is

mineralocorticoid

by

droxylase
leading

reabsorption.

hypokabemia,

tent

CCD.
Endogenous
hormones.
Endogenous
hormones
are very
important
causes
of hypokalemia.
Aldosterone
is perhaps
the
meostasis,

of

depletion

of potassium

do

as trimethoprim

perkalemia

of magnesium

abdosterone

lamic
corticotropin-releasing
persistent
adrenal
synthesis

either
in the presence
or absence
of
mechanism
is not completely
under-

The

rebate

(36)

However,
some,

Tobuene

of
and

sniffing
certain
glues, can also cause hypokalemia,
by renal potassium
wasting
(2). Aminoglycosides

can cause
hypokalemia
overt nephrotoxicity.
stood

(36).

membrane
secretion

loop

of

features
manifes-

appears

to be

a result
of mutations
in the thiazide-sensitive
NaC1 cotransporter (60). Both Bartters
syndrome
and Gitelmans
syndrome
are associated
pbetion
drome
alkalosis,

with

due to renal
is associated
and

This condition
principal
cell

hypotension

and

sodium-wasting.
with hypertension,

suppressed

renin

intravascular
In contrast,
hypokalemia,

and

appears
to be a result
apical
sodium
channel,

aldosterone

volume

de-

Liddles
synmetabolic
levels

(61).

of defects
in the CCD
ENaC,
leading
to an

Hypokalemia:

increased
subsequent

open probability,
excessive
sodium
volume
expansion,
hypertension,

of renin

and aldosterone

because

increased

luminal

(62).

CCD

sodium

electronegativity

dient

for

last

distal

renal

bicarbonate

delivery

of distal

beads

major

renal

tubular

cause

acidosis.

of renal

with

gra-

In each

sium

acidosis

secretion.

may

either

distal

reflect

tubular

therapy

Certain

medication

primary

de-

reabsorption.

Approach

due

to potassium

responsible

for

Second,

uptake

the

consider

by abnormal

reported

whether

reduction

leukocytes,
in

redistribution

serum

is not

of potassium

from

the

accounts
for the hypokalemia.
is present,
the hypokalemia

probably
represents
total body
from either skin, gastrointestinal

potassium
(GI) tract,

boss.

Excessive

prolonged

potassium

exertion

is high.

This

under

most

either

diarrhea,

in hot,

diagnosis

can

GI

vomiting,

Occasionally,

patients

from

diarrhea

to be confirmed

acidosis

Finally,

use,

suction,

reluctant

and

frequently

admit

cause

hypokalemia

of diuretic

renal

po-

per

di-

syndrome

hour

may

against

risks
the

the patient

associated
risks

with

of therapy

is determined.

hypokabemia
when

Usually,

the

must

appropriate

the primary

be

approach

short-term

to

risks

are cardiovascular,
and the most important
is the proarrhythmogenic
effect of hypokalemia.
In contrast,
the primary
risk of
overaggressive
replacement
is the development
of hyperkabemia with resultant
ventricular
fibrillation.
Occasionally,
incorrect therapy
of hypokalemia
of the hypokabemia.
Conditions
requiring
causes
include
severe
undergo

emergent

can lead
emergent
hypokalemia

surgery,

to paradoxical

worsening

therapy
are rare. The classic
in a patient
preparing
to

particularly

in patients

with

known

and

the

risk

versus

oral

to take

oral

to function

exist

intravenous

appropn-

about

the speed

of

be given

intrave-

route,

replace-

(IV)

response.

In nondiabetic

insulin
the

KC1

extra-

concentrations

be

of KC1

might

be

provided

hypokalemia
Patients

re-evaluated
is required,

the

assessment

Excessive

If this

potassium-sparing

may

is required,

with

is not

KCI

other

enzyme

to avoid
with

oral
be

diuretics.

If continual

intake

oral

drug

can

of the

and

except

condition,

should

blockers

spi-

ther-

in all patients

renal

assist

use

replacement

latter

citrate

beta

be pre-

triamterene,

In the

minimizes

reasons,

should

diuretic-induced

concomitant

When

preferred

inhibitors

then

should

for

case

or potassium

salt of potassium

veIling

the

acidosis.

bicarbonate

fluid,

successfully

amiloride,

is the

barge

saline

accentuates

be considered.

metabolic

for

need

intake

diuretics

ronolactone

par-

If

saline.

hypokalemia

of sodium

sodium

paradox-

cases,

parenteral

be treated

diuretic-induced

to reconsider

can

In most

normal

of

As a result,

solution.

can

with

in-

redistribution

normal

in half

can

dextrose

as DW

to the

of a hypertonic

with
therapy

space.

(64).
in

added

administered

administration

IV

cause

such

levels

are

catheter

administration

intracellular

solutions

potassium

should

can

per

40 mEq

replacement

patients,

which
to the

in glucose

serum

KCI

formed.

levels,

mEqIL

then

a central

However,
if possible.

fluids

of 0.25

is necessary,

through

monitoring.

from

indicated

average

for potassium

lower

use

an

used

providing

KC1

by

replacement

orally

potassium

ically

rapid

be administered

serum

chloride

balanced

the

patient

KC1 can

be administered

potassium

Correction

via

may

cases,

level

infarction,
paralysis,
may be unable
to take

parenterab

creases

apy

to be considered.

as myocardial
the patient

to increase

ECO

the

those
The

can

hypokabemia.

ureterosig-

surreptitious

or Gitelmans

If more

(63).

Usually

potassium

and

bevel

hour

therapy.

of diuretic
include
renal

ketoacidosis,

Bartters

use.

given

potassium

disease

causes

aldosteronism,

need

of the stool.

of renal

When

of parenteral
of the

or questions

be repeated

to reduce

of the 01 tract

In these

can

of

potas-

can be given safely at a rate of 10 mEq KCI per hour. One

has found
that 20 mEq KCI per hour causes
the serum

enteral

self-in-

or hepatic

is frequently
a complication
of renal
potassium
loss
diabetic

loss
from

may

nously.

affect

history

to

testing

a result
cardiac

is a common

primary

either

the

occurs

safely

absorption.

The

or a 01 fistula.

to

or direct
from

(RTA),

moidostomy.

from

loss

potassium

01 tract

should

from

sweat

use, and the diagnosis

is most

syndrome

wasting
and
Rarer
causes

tubular

need

be

results

the ability

yen-

serum

dose

necessary

ability

pa-

significant

of the serum

the choice

on the

ately. In many cases, such

and hepatic
encephabopathy,

continuous

resulting
potassium

where
made

nasogastric
may

skin

potassium

Hypomagnesemia-induced

tassium
useage.

uretic

readily

hyperaldosteronism

or a nephrotic
loss.

be

tract

catharctic

loss

the

environments

by sigmoidoscopy

potassium

Secondary

from

dry

conditions.

duced
Renal

loss

depletion
or renal

are

conditions,

and

This

monitoring

(ECG)

the

of 5 to 10 mEq

to increase

3.0 mEq/liter.

continuous

is dependent

ment
study

potassium.

extra- to the intracellular

space
If neither
of this possibilities

above

Close,

be used

and

and

administration

may

1 185

treatment,

infarction

cases,

15 to 20 mm

of hyperkalemia.
In most other

In approaching
the patient
with hypokabemia,
we recommend using the approach
outlined
above.
Figure
2 summarizes
our diagnostic
algorithm.
First,
ensure
that pseudohypokalemia,

myocardial

In such

to a level

oral

Diagnostic

an acute

and Treatment

or on digitalis

the electrocardiogram

or treatment

case,

potassium

tubular

from

acidosis,

disease

ectopy.

KC1 over

potassium

can result

tubular

increases

renal

in potassium

tient

artery

tricular

to increased

electrochemical

Bicarbonaturia

alkabosis,

of proximal

fects

reabsorption

occurs

coronary

as needed.

The

is bicarbonaturia.

cases

wasting

secretion.

Bicarbonaturia.
metabolic

potassium

and an increased

potassium

wasting

Renal

reabsorption,
and
and suppression

Diagnosis

either

be used.

potassium

The

bosses.

If

or angiotensin-con-

in maintaining

potassium

levels.
Finally,

ing

and

patients,

hypomagnesemia

to renal

to potassium

correction

of the hypokalemia

does

(65).

Patients

is corrected

duced

hypokabemia,

duced

hypokabemia

cated.

lead

refractoriness

hypomagnesemia

checked

can

and

replacement

unexplained
should

magnesium

have

potassium

hypokalemia,
their

replacement

serum
therapy

(36).
not occur
with

wast-

In these
until

the

diuretic-in-

or diuretic-inmagnesium

bevels

begun

if mdi-

I I 86

Journal

of

the American

Society

of Nephrology

b
hi

hi

E
0
ci

hi

hi

0
E

bi

hi

0
hi

0
hi

C
C

hi

hi

hi
0

hi

ci

ci

C
E
ci)

ci
0

E
N
V

ci)

hi
hi
C,)

Figure

2. Diagnostic

evaluation

of hypokalemia.

hi

Hypokalemia:

Note
reduced

added
in proof:
A recent meta-analysis
concluded
potassium
intake
may play an important
role

that
in the

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genesis

of hypertension

Bran-

lateral

cati

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