DISEASEOF

THE

MONTH

Hypokalemia-Consequences
I. DAVID
Division

Causes
S. WINGO

and Correction
of Florida College of Medicine, and

WEINER
of Nephrology,

and
Administration

CHARLES
and

Hypertension

Transplantation,

University

Gainesville

Veterans

Medical

Center,

Gainesville,

Florida.

Hypokalemia and electrolyte asymptomatic screening, mild weakness can be simple,

is one finding or it can

of the most identified

commonly only with on

encountered medicine. routine

fluid

to the cortical hypokalemia.

collecting

duct

(CCD)

are

also

at high

risk

for

abnormalities be associated

in clinical

It can be an electrolyte ranging from to

symptoms

Consequences
Potassium deficiency alters the function of several system, effects organs neuultiand most prominently affects robogic system, muscles, and mately determine the condition. Unfortunately, potassium because potassium children hypokalemia elderly. morbidity the the cardiovascular kidneys (2). These

to sudden death. The but if inappropriately

correction of hypokabemia performed can lead

worsening symptoms, and even death. The purpose of this article is to discuss hypokalemia in sufficient detail to allow for patients who have this condition. epidemiology and extrarenal of potassium kalemia. should dations extensive mation; Finally, influence for thus, patient reference

the management of practitioners to care We shall discuss the

and mortality related to this correlation between degree of

of hypokalemia and its consequences on renal tissues and shall briefly discuss the physiology handling and the differential diagnosis of hypofactors that recommenpreclude of inforcited. we shall consider therapy and shall management. to many of the reviews the important provide general Space primary limitations sources

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, and young with adults less risk tolerate of severe more severe side-effects degrees than of the

Cardiovascular
Two major cular system: emia-induced
creased morbidity is frequently reveal

comprehensive

are frequently

side-effects of hypokalemia affect hypokalemia-related hypertension ventricular

and

the cardiovasand hypokabto inpatients

factor can that

arrhythmias.
mortality.

Both

contribute in many

Epidemiology
The occurrence patient population. any medications, of hypokalemia is strongly dependent on the In otherwise healthy adults not receiving less than 1 % will develop hypokalemia, as

Hypokalemia
(3) but

contributes or worsen this

that

to hypertension
as an

unrecognized

important

may
lines

produce
of evidence

serious
potassium

health show

problem. that (3).

Several
increase

defined by a serum potassium level of less than 3.5 mEq/liter. This very low frequency of hypokalemia is a testament to two factors: the adequacy of potassium in the typical Western diet, and potent mechanisms for renal potassium states of potassium depletion. The presence hypokabemia in otherwise healthy adults who
any medications should suggest the possibility

deficiency

blood sium ciation

pressure. diets, with

Cross-sectional the prevalence marked

studies

bow-potasintake, assoThis

especially

in the presence in African

of a high Americans.

sodium

conservation in of spontaneous are not receiving

of underlying

are linked

of hypertension

is most

Epidemiologic

and prospective volunteers and tihypertensive kalemia and blood pressure presence that hypokalemia

studies confirm this association in both healthy in essential hypertensive patients (4). The aneffect of thiazide diuretics is reduced by hypoenhanced by potassium repletion (5). Finally, may be more highly sodium-dependent in the (3). Thus evidence strongly indicates contributes to hypertension. hypertension is not type of hypertension leads NaC1 to intravasretention. effects of
side-

disease Most
disease

and cases
states.

indicate
Patients

the

need
receiving

to search occur
diuretics

for in the serum later

an etiology. setting
are at

of hypokalemia as 50%

of specific
the highest

risk,

with

as many

developing

potassium discuss,

levels thiazide or

of hypokalemia

of less than diuretics osmotic

3.5 mEq/liter

( 1 ). As we will

are more likely to cause hypokabemia diuretics. Individuals with secondary

than 1oop hyperaldosteron-

The mechanism completely clear. appears cular

various

of hypokalemia-induced One component of this (4). potentiate

agents are (6,7). a second

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

high risk. Finally, those patients

heart failure, hepatic constitute a second

with diseases that

insuffigroup at
alter renal

to be salt retention volume expansion may also

Hypokalemia of renal the

as a result

Hypokalemia
Ventricular

hypertensive
cardiovascular

potassium

conservation

through

interaction

with

salt

delivery

neurohumoral arrhythmias

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

P.O. Box 100224, Division of University of florida College

effect of hypokabemia. hypokalemia predisposes

variety of ventricular

Several prospective patients to the

arrhythmias, including

studies show development

ventricular

that of a
fibril-

lation

(8).

Patients

at the

highest

risk

for

arrhythmias,

the

I 180

Journal

of the American

Society

of Nephrology

elderly
ease, ticular

and
appear concern

those

patients
the

with
highest the

underlying
risk for of

ischemic
hypokalemia sudden

heart

dis-

tes

insipidus

(23). other kidneys of

Increased

thirst regulates

is associated thirst. hypokalemia cyclase. concentration

with Hypokalemia

increased

to have (9, 10). because is greater

hypokalemia-related is of pardeath in hy-

central
besides impairs (2). tive uretic This

nervous
its the activation

system
effects,

levels
ability

of angiotensin
to concentrate the

II, a hormone
urine preventing (24). maximally

that,
also defecantidi-

complications

Diuretic-induced incidence

pertensive
chborothiazide

individuals

treated
than

with
that

the thiazide
in matched

diuretic
control

hydrosubjects

appears

to occur renal

because adenylate un nary

causes

( I 1 ). The effect is dose-related comitant use of potassium-sparing

Hormonal Hypokalemia
sensitivity diabetic patients

and

is decreased by the diuretics ( 1 1).

con-

hormone-stimulated

Renal
impairs
to insulin,

Cystic
to renal

Disease
in association
cystic disease. These

Hypokabemia, both insulin release and end-organ

in lead resulting in worsening hyperglycemia

with and are

hyperaldosteronism,
cysts appear to arise

can
in the

collecting interstitial
cyst unclear.

duct

epithebium (25).
(25). The beads

frequently the
of which cyst

associated leads
development may activate

with to
is and the

( I 2, 13). Hyperglycemia health evidence

mellitus

and diabetes in industrialized that

related

meblitus nations. complidegree of

scarring
Hypokalemia ammonia

Correcting
mechanism to increased

hypokalemia
ammoniagenesis

are
cations crease

major
from the

public increasing
diabetes

concerns suggests
are

regression

Because

end-organ
to meblitus. the

medubbary

accumulation,

hyperglycemia

(14, 15),
devastating

treatment
effects

of

hypokalemia

may

de-

complement by leading
stitium, hypothesis beads

system. to activation
to

It has

been
fibrosis that

postulated
(26). bicarbonate

that
Consistent

hypokalemia, interwith this

of diabetes

of complement

in the medublary
supplementation,

interstitial observation hypokalemia; potassium

Muscular Potassium complications depletion can result in several muscular-related

is the

by inhibiting
sis associated changes

ammoniagenesis,
with

decreases
this (26). effect

the interstitial
is independent

fibroof

( 16). impairing

Hypokabemia their ability

can

hyperpolarize

skeletal

muscle

cells,

to develop

the depobariza-

in serum

tion necessary flow to skeletal

pose ous patients exercise

for muscle muscles.

to rhabdomyolysis is combined

contraction. The reduced

(I 7), impaired with

It can also reduce blood blood flow can predisespecially blood-flow when vigorregulation.

Hepatic
the
causes increases

Encephalopathv
can of contribute hepatic
tubule circulation increased

Hypokalemia symptoms,
hepatic proximal

to the development, encephabopathy.

is ammonia, ammoniagenesis

or worsen toxin
hypokalemia Approxi-

One
and (19).

that

The
ralysis,

combination easy
although deficiency

of these fatigabibity,
uncommon, (16).

effects cramping,
can

frequently and
occur

leads myalgias
of

to muscle (16).
profound

encephabopathy

weakness,
potassium

Pa-

in cases

mately
turned insufficiency,

50%
to the

of proximal
systemic the

tubule
systemic

ammonia
via the renal burden

production
veins. of ammonia

is reIn hepatic re-

Acid-Base
Hypokalemia
meostasis acid-base through regulation.

subting can
its

from

increased (27).

renal

ammoniagenesis or worsen

can

be sufficient of hepatic

profoundly
effects The most on

affect
multiple common

systemic
components abnormality

acid-base

ho-

to cause

the development

the symptoms

of renal is meta-

encephabopathy

bolic alkabosis. Hypokalemic the effects of hypokabemia excretion. The most imal tubule HCO1 collecting both KtATPase Hypokalemia acid-base
(2 1 ). which sis. In

metabolic on several

alkabosis components

results from of net acid of prox(18,19); of of Hexcretion. on renal

Physiology
Serum excretion,
space. diet is The 70

of Potassium
potassium concentration and distribution between
average mEq. daily Under potassium normal

Homeostasis
is a balance the intraintake conditions,

direct effects reabsorption secretion, and

include stimulation and ammoniagenesis possibly (HKa,) urinary widespread of intracellular abdosterone
on acid-base leads to

between intake, and extracellular

Western equals excretion

in a typical

duct

proton (HKa1) and

via

stimulation isoforms

the gastric (20);

cobonic these

intake, urine space Most cellular result

Distribution

with and plays

approximately the vast majority

of potassium

90% of
between

of potassium the
the

excreted in
and

in the the stool.

decreasing

citrate effects

remainder
intra-

may

produce

extracelbubar

homeostasis Hypokabemia
possibly rare cases,

because also inhibits

such severe

acidification secretion (22),

homeostarespiratory

an important averages potassium

role

in potassium in the

homeostasis. space. largely Intraas a Ap-

potassium potassium of active

is present

intracellular by Na4-K-ATPase.

minimizes

effects

120 to 140 mEq/liter, uptake

hypokabemia

muscle weakness In patients with

dosis, the

and the development of respiratory acidosis. hypokalemia as a result of renal tubular acidevelopment of respiratory acidosis can

concomitant

proximately 98% intracellular space. bution of potassium

spaces potassium result in

of total body potassium is present in the Consequently, small changes in the distribetween the intra- and extracellular fluid
proportionally The deficiency. large large changes intracellular in extracelluar potassium

be life-threatening. Polvuria Another

mild polyuria, is related

concentration.

store complication
averaging increased to both

functions
states of

to minimize
potassium

changes

in extracellular
Under these

potassium
conditions,

of hypokabemia
2 to 3 liters thirst and mild

is the development per day (2). The polyuria

diabenephrogenic

of

in

potassium apparently

shifts from the to reduce changes

intrato the extracellular fluid, in the transmembrane potassium

Hypokalemia:

Diagnosis

and Treatment

1 181

gradient. muscle, sium potassium Conversely, than

With exhibit do losses the as

potassium a more others, rapid such

depletion, reduction as affect deficit the

certain

tissues,

notably potassmall level. states barge. that

Lumen

Peritubular

space

in intracellular brain. As a result, potassium

Na

minimally potassium

the

serum

in hypokalemic

result example, 300 body

from

potassium
will

loss
be

(excluding
discussed

pseudohypokalemia
below) is very

and
For

redistribution,

a decrease indicates and

is

in serum a total to 800

in

potassium body mEq/liter

foods

from can
in

3.5 to 3.0 mEq/ deficit indicate of 100 to a total

amounts.

biter typically mEq, deficit

Potassium

potassium

a decrease of 600
present

to 2.0 mEq.
most

varying

H K
is
of

Although
considerable

the typical
variation,

dietary absence

intake

averages
on the

70 mEq/d,
dietary preferences

there body

depending of potassium

the
adapt

individual.
to a wide

In the
range

of other
intake

factors,
without

the

can

development

of marked hypokalemia. monby eat diets containing state of physiologic

and

Notably, African Americans less potassium, which may deficiency

hypertension

cominduce a to the

potassium
severity of

and contribute
in this

incidence (28,29).

population

HCO3
primary
is

The
Potassium

mechanism
freely filtered of approximately

of potassium
at the 85%

excretion
gbomerulus,

is the urine.
followed by

reabsorption the loop

by the proximal little regulation however

tubule
of potassium

and

Figure

1. Model

of potassium

transport

in the cortical

collecting

duct.

of Henle occurs

(30).

Relatively

reabsorption

in these

segments,

(30).

Instead,
sium channel (20). This provides a sensitive mechanism that

the primary duct whereas (OMCD At least

may contribute

site for renal CCD outer cell both and types the three

potassium secretes inner

regulation and medullary reabsorb

is the collecting potassium, ducts (30,31). collecting potassium allows Recent mediate
alkabosis,

(3 1 ). The

reabsorbs

active

potassium

reabsorption

when

necessary.

and IMCD,

respectively)

are present
homeostasis.

in the CCD,
Figure

all of which
1 summarizes

studies show that the B cell, generally believed to bicarbonate secretion and recovery from metabolic
may also contribute to potassium homeostasis. Re-

to potassium

the

transporters cell CCD, and

Potassium

involved is the most is believed

in CCD numerous

potassium cell,
taken

transport. for
into the via

The

sults from functional

(32,33).

principal of the
secretion.

comprising
up

60 to 70% potassium
cell via a

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 by the apical CF7HCO3 exchanger to the apical of apical HKt provide a new model inhibition of Hsodium reabfor potassium the inwith

to be responsible and secreted

fluid

reabsorption

is actively into the luminal

basolateral
chemical potassium

Na-K-ATPase
gradient channel. Additional

down
(urine) indicates

its
an that

electroapical potas-

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

evidence

sium
sodium

secretion
reabsorption

is codependent
generates

on Cl
a

secretion. increases

Electrogenic
charge or

CCD amiloride-insensitive that sodium can substitute (3 1). In activity,

potassium that on

lumen-negative

voltage.

Because

this

negative

charge

the

electro-

on the creased
sodium

WKtATPase H-K-ATPase
for pressure

hypokalemia, in combination
the H-K-ATPase,

chemical gradient reabsorption also In contrast intercalated

prise the

for potassium regulates the principal and

the of from

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

are

substituting

could
increased

to net NaCl
blood

reabsorption, IMCD do not

volume transport
This A

expansion,
clinically.

and the under or potasto occur

to the cells

CCD
modeled

A-

and which
to

B-type comprosecrereabsorb

is observed

(A cell

B cell,
CCD, of

respectively), occurs
cell protons

The normal
sium via

OMCD conditions,
deficiency

and
can

potassium
appears cell,

remainder

but
similar via

in response
potassium. to the

to hypokalemia
CCD potassium

luminal
cesses tion. An

potassium.
different apical

Potassium
those H4KtATPase

reabsorption
principal secretes

through
and

reabsorb

potassium

mechanisms

e.g. , luminal

reabsorbs

potassium and
potassium

uptake
exit

by an apical
a basolaterab

HtKtATPase isoforms HKa1

extent opposite

and basolateral
channel (20). As

buminab potassium
sium, sponse

potassium, reabsorption
reabsorbed most

contributing
potassium

to urinary
is recycled

acidification of normal
across the

(3 1 ). In the presence in little

deprivation,

potasapical

noted present
may HKct,

previously, in the
be regulated in the CCD,

at least collecting
to whereas

two duct:

of HtKtATPase and
by

are (20). HKa1

than in

HKa2
appears

membrane, a basolateral

resulting
to potassium

net

potassium
potassium can

transport.
exit

In revia

a greater the

hypokalemia to be true

the cell

barium-sensitive

transporter,

presumably

a potas-

the OMCD

(34,35).

I I 82

Journal

of the American

Society

of Nephrology

Despite porters

the in the

presence CCD,

of active OMCD, and

potassium IMCD, the

reabsorptive urinary

transpotassium

escape

is unknown.

The

decreased

end-organ

responsiveness

level

is generally

not

lower

than

15 to 20 mEqlliter.

This

may re-

to insulin in adult-onset kalemia frequently seen sium between A second, tion than
potassium

diabetes may contribute to the hyperby altering the distribution of potasredistribuuptake

more slowly

reflect both water reabsorption, which exceeds absorption, and persistent potassium secretion Little potassium is excreted ditions because of a low stool
sium concentration. Conditions

potassium in the CCD.

the intra- and extracellular space. clinically common cause of potassium Aldosterone
a variety

in the stool under normal convolume and a low stool potasthat increase stool potassium

is aldosterone.
through

induces
but

cellular
much

of

of effects,

insulin.

Aldosterone which results

stimulates in increased

the

production enzyme

of Nat activity and

concentration, or stool volume,

such

as chronic such

renal

failure increase

and

hyperkalemia, fecal potassium

KtATPase,

as diarrhea,

excretion. Chronic renal stool potassium content, can content because small. be excreted do not the basal by level this materially

failure can cause adaptive changes in such that as much as 20 to 30 mEq/d route. affect of stool Decreases the response potassium in stool excretion potassium is normally to hypokalemia

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

to extracellular below, aldoThus hyperof the combined

effects of redistribution and stimulation of renal potassium clearance. The final major hormonal cause of potassium redistribution includes pamine, sympathomimetic dobutamine, and stimulate insulin potassium ischemia
commonly

Causes
The
identification

agents, ,-adrenergic theophylbine. The uptake whereas (36,37). theophylbine

is

first

agonists, dothree agents and also slimin whether acute as a

accurate
of

treatment
the cause.

of

hypokalemia
can

requires
be

correct
associated

directly stimulate ulates myocardial

ischemia redistribution

the release, uptake

leading

cellular

of potassium indirectly
important

Hypokabemia

either with normal Normal total body potassium lular space. redistribution Total

or decreased potassium from body

total body potassium content. with hypokalemia is a result of the extracellular depletion to the can intracelfrom result

Sympathomimetic-induced asthma therapy.

tone,

to

hypokalemia

and
increases

acute

Myocardial or from Cellular then indeath.

potassium

sympathetic

either renal or extrarenal potassium clinician evaluating a patient with broad extrarenal groups of etiologies: potassium loss, and renal

losses. We suggest that the hypokabemia consider four redistribution, loss. potassium

pseudohypokalemia,

direct result of the ischemia, decreased cardiac output, either the pain or the anxiety related to the ischemia. potassium redistribution leading to hypokalemia can crease the risk of ventricular arrhythmia and sudden Treatment theophylbine of the asthma patient with 3-adrenergic can bead to potassium redistribution,
impairment of respiratory muscle contractile

Pseudohypokalemia Abnormal numbers, prolonged measured

is an artifact

agonists or hypokaleability.

white can take periods

blood

cells,

if present

in

large

enough stored for in a low

mia,

and

up extraceblubar potassium when at room temperature, resulting level. The procedure

Patients decreased which

may develop wheezing, might condition. involving oral

the

CO2 retention, or, even as a result of decreased as an overall

more seriously, air movement, improvement in

plasma potassium of the storage

apparent hypokalemia and is referred to as

be misinterpreted

pseudohypokalemia (36). The ease state is acute myelogenous the plasma or storing the sample avoids this artifact, and prevents

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

the patients labor therapy do not have

for setting

Another clinical concern is premature 3-agonists. These patients frequently for prolonged
of severe

intake as a result

periods,
hypokalemia.

providing can also

development

Hypokabemia

of potassium states. Cells consequently,

redistribution

Redistribution More intracellular than 98% fluid, of total predominantly body potassium in skeletal is present muscle cells, in the en-

occur from acute anabolic 130 mEq/biter of potassium; cell hypertrophy from or cell of potassium the extra-

contain approximately stimulation of either cause rapid movement space. Rapid high-grade can result factor cell production has treatcan resulted with enperiodic
have been

production to the

can

intracellular

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

of potassium to alter Certain hormones, sympathomimetics, hypokaleresults in active produces which

cell production can occur in acute leukemia and lymphomas. Acute stimulation of cell production from ment anemia cause granulocyte of refractory with acute vitamin hypokabemia
and sudden

insulin, common
activates uptake

aldosterone, cause
(37). NaKtATPase, Acute

and

are

macrophage anemia
2

colony-stimulating or the initial treatment individuals The resultant

(41).

most
Insulin

of redistribution-induced
insulin administration

of pernicious

(40). and

potassium

in some

rapid potassium shifts resulting in hypokalemia.

from

the This

extrato intracellular space, problem is most frequently

in arrhythmias

death

encountered in the treatment of diabetic ketoacidosis. Insulininduced redistribution of potassium is the physiologic principle underlying the administration of insulin with glucose to patients with hyperkabemia. high cause In contrast insulin bevels, hypokalemia; to acute insulin administration, chronically do not typically as occur in insubinomas, the mechanism of this

Rarely, hypokalemia hanced cellular uptake

paralysis (16,36). Both

secondary to redistribution can be a result of hypokalemic

familial and sporadic cases

reported. distribution,

Most

hereditary although an

cases

follow

an autosomab recessive form

dominant has been of this confrequently

X-binked

documented. In Asians dition associated with

there is a high frequency thyrotoxicosis ( 16). Attacks

Hypokalemia:

Diagnosis

and Treatment

1 183

commence

during

the

night

or

the

early

morning

and

are

Table

1. Causes Drugs
diuretics thiazide

of renal

potassium

loss

characterized
persist from idine-sensitive

by flaccid
calcium

paralysis
channel

of all extremities, defect

been has determined

which

may

6 to 24 h (36).

A genetic

in a dihydropyrto cause

certain cases of this disorder (42). Carbonic itors (acetazolamide 250 mg four times daily), spironolactone may prevent attacks.
Finally, hypokalemia has been reported

anhydrase inhibbeta blockers, or

in connection with

diruetics

loop osmotic antibiotics

diuretics diuretics and penicillin B analogues

chboroquine explained channels and,

and by the

barium known

intoxication. action cellular potassium

The exit

latter (16).

effect

can

be

penicillin amphotericin
aminoglycosides

of barium

to block

potassium

hence,

Non-Renal Both the

significant

Potassium skin and

amounts of

the

L05s gastrointestinal
Under

Hormones aldosterone glucocorticoid-remediable tract

normal

hypertension
states acidosis

can

transport
conditions,

glucococorticoid-excess

potassium.

B icarbonaturia
distal renal tubular

net fluid
boss.

loss from

these

organs
such

is small,

limiting

net potassium
exertion in hot,

Occasionally,

in cases

as prolonged

dry environments can occur, leading

intravascular ondary volume

or chronic diarrhea. to hypokabemia (43).

depletion is present stimulation

severe potassium In most of these

also, of renal leading potassium

loss cases,
to secex-

treatment correction
Magnesium

of proximal renal phase of metabolic

deficiency

tubular acidosis alkabosis

Other

less

common anhydrase

causes inhibitors

hyperabdosteronism,

cisplatin

cretion, nasogastric of this

and

further loss suctioning,

worsening of gastric can loss lead

of the potassium contents, whether because from these to hypokalemia.

deficit A small body

(43). or part fluids

Prolonged

vomiting

carbonic toluene

potassium

is direct

contain 5 to 8 mEqfliter potassium. More importantly, concomitant alkabosis and intravascular volume depletion contribute to renal tuna, cation
indirectly,

leukemia diuretic phase of acute tubular Intrinsic renal transport defects Bartters
Gitelmans

necrosis

syndrome
syndrome

potassium

loss.

Metabolic

alkabosis

results

in bicarbonaas a and and In adrenal and

which increases potassium excretion both directly, to balance the negative charge of bicarbonate ions,
through stimulation of urinary sodium excretion,

Liddles

syndrome

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

by potassium

volume

depletion system. duct

increases secretion

potassium
status. excretion

reabsorption
Thus by

by the collecting
metabolic increasing alkabosis potassium

is affected

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

acid-base

increase natriuretic

urinary effect,

potassium thiazide part

excretion; when diuretics are more loop renal

adminis-

probably by direct suppression Diarrhea, whether secretory can cause profound with laxative abuse concern needed
anosis tives, (45).

of potassium or as a result

reabsorption. of laxative

abuse, Patients of over(44).

may be

kabiuretic agents (46). In have a shorter pharmacologic

conservation during periods

this is because half-life, enabling

between drug

gastrointestinal potassium loss. may deny the condition because image

urine who cascara

about

body
and

and

may The
been aloe,

also
for

abuse

diuretics will
than

tration, but may also reflect their convoluted tubule with secondary
mary site by of potassium CCD secretion luminal

site of action in the distal effects on flow to the priin flow the CCD. rate, All luminal diuretics, sodium

Sigmoidoscopy

screening have and

diuretics anthracene

to confirm
cobi such in patients as senna,

the diagnosis.

former
using for more

reveal

mellaxa-

except
ing

the potassium-sparing
increasing

diuretics,

induce

potassium-wast-

4 months

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
these compounds in the stool can confirm the diagnosis.

If phenolphthabein

delivery, and determinants

also induce

luminal electronegativity, of potassium secretion

intravascular volume

which are the primary by the CCD. They may

contraction, resulting in sec-

ondary
potassium

hyperaldosteronism
secretion. The

and
incidence

further

stimulation

of

renal
hypoby a

of diuretic-induced

kalemia variety

is both

dosecan

and

treatment
urinary

duration-related.
potassium excretion

Antibiotics

increase

of mechanisms.

High-dose

penicillin

and

some

penicil-

Renal
The

Potassium
most common loss. This hormone defects.

Loss
cause can occur production of hypokalemia is excess renal either because of medications, or, in rare conditions, intrinthese causes.

bin analogues, increase distal thereby

is another

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

that may

ampiciblin, anion, Cisplatin

in

potassium endogenous
sic

increasing
drug

potassium
induce

excretion
via

(47). such

hypokalemia

an increase

renal

Table

1 summarizes

renal

potassium

excretion.

Polyene

antibiotics,

as ampho-

I I 84

Journal

of

the American

Society

of Nephrology

tericin B, create cation channels in the apical collecting duct cells, which increases potassium results in potassium wasting (36). Tobuene exposure, result from presumably

membrane secretion which

of and can

cessive
hyperplasia,

abdosterone
there

production
is the

ensures. resulting of

In congenital
absence of either

adrenal
1 1f3-

congenital

hydroxybase

or I 7a-hydroxylase,

in excess

hypothaand a p01 1 f3-hy-

sniffing certain glues, can also cause hypokalemia, by renal potassium wasting (2). Aminoglycosides The either in the presence or absence of mechanism is not completely underof magnesium of potassium not cause sodium pentamidine, hypokabemia, can channels cause in depletion reabsorption. and hythe inhibition do and of apical

lamic corticotropin-releasing persistent adrenal synthesis tent

by

hormone (CRH) secretion 1 1-deoxycorticosterone, condition

steroid

can cause hypokalemia overt nephrotoxicity. stood (see some, However, such perkalemia but below) may (36) most by rebate

mineralocorticoid
the associated effects

(53). This
on sex

can

be recognized production, In contrast, metabolism, as mineraloGlucocor-

production.

to stimulation

or direct antibiotics inhibition

droxylase leading leading Under

corticoids,

deficiency results to early viribization deficiency conditions, to incomplete rare

causing

in increased androgen of men and women. inhibits sex hormone function

hypertension.

17a-hydroxylase

as trimethoprim

development glucocorticoids
and hypokalemia

of sexual

characteristics.

CCD. Endogenous hormones. Endogenous hormones are very important causes of hypokalemia. Aldosterone is perhaps the most quently the and the potassium cell effects
hal potassium

ticoids, corticoid
it

such as cortisol, have a high affinity receptor but are normally prevented the enzyme converts
acid

for the mineralofrom binding to dehydrogenase which does drugs,

chewing

important
and

hormone
excess

regulating
abdosterone

total CCD

body

potassium
or effect

hofre-

meostasis,

production

because (1 l-HSDH) bind

as

1 1/3-hydroxysteroid cortisol to cortisone, receptor

in (found carbenoxobone,

not such
to-

leads

to hypokalemia. where aldosterone

The

is the primary potassium

site transport,

in

to the
glycerrhetinic

minerabocorticoid

(54). Some

kidney

regulates

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

and

cell responsible for increases principal NatKtAlPase

in the CCD. gradient cytoplasm These for to the

bacco, and licorice), inhibit exert minerabocorticoid-bike Infrequently, pacity either ACTH
ciency

1 1 f3-HSDH, allowing cortisol to effects in the distal nephron (55). can exceed the metabolic caThis can occur or in the ectopic magnesium
(36).

apical

conductance,
sodium increases from the the

basolateral
absorption electrochemical cell

circulating

cortisol

activity,

electrogenic which movement

increase
voltage.

the net luminal-negative

principal

charge

or transepithe-

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

Magnesium
may

Concomitant
of hypokalemia

defiThis is

luminab channels
principal

fluid. and
cell

Thus aldosterone, via basolateral NatKtATPase,

potassium secretion.

actions

on apical increases
potassium

Na CCD
reab-

particularly certain
sium

true cases

with
hypokalemia

diuretic-induced and
associated

hypokabemia cisplatin-induced
with lysozymuria

and potas-

in
in

Although

of aminoglycosideand in individuals with daily, four times

sorption sorptive
Na intake,

can

occur
is less

in the of these
than the

OMCD segments,
rate of

and

IMCD particularly

(3 1 ), with
secretion

the

reabnormal
by the

wasting,

capacity Thus the

acute (see 500

leukemia, below). mg by mouth

with may

Gitebmans oxide, serve

syndrome 250 to both

potassium

Supplementation

magnesium

CCD.

net effect can

because

of aldosterone be either

is to enhance primary or

renal

to correct

potassium clearance. Hyperabdosteronism Primary

(48),

secondary.
effects of

hyperaldosteronism
predominantly

results
of the

in cases
sodium-retaining

of hypertension may also contrib-

the magnesium and potassium deficiency. Intrinsic renal defects. Intrinsic renal defects beading to hypokalemia are rare but have led to important advances in our understanding of renal solute transport. scribed the association of hypokabemia, perreninemia, and metabolic alkabosis show that these known as either Patients
of

In

1962,

Bartter

de-

aldosterone,

but the associated

hypokalemia

ute by sensitizing of blood pressure. gland

giotensin This oral the may intake,

the vasculature to neurohumoral regulators Because angiotensin II regulates adrenal synthesis,

will use, in a variety

hypomagnesemia, (57). Recent

hystudies

aldosterone
II levels occur diuretic

conditions
involve of conditions, vomiting, or system,

involving
such diarrhea. as may

elevated
as decreased Activation occur

an-

patients Bartters with

can be divided into two syndrome or Gitebmans syndrome are hypercalciuric depletion. This volume

groups now syndrome. and present condition Na-K-2C1 potasfor loop of

typically

hyperabdosteronism.

with

Bartters age

at an early

severe

renin-angiotensin-aldosterone

in ma-

appears to be a result of defects in either the renal cotransporter gene, NKCC2 (58), or the ATP-sensitive
sium channel, ROMK, both of which are necessary

lignant

hypertension

renin-secreting

aldosteronism activation
gests that

renovascubar hypertension (50), and tumors (5 1 ), can also lead to secondary hyperwith subsequent hypokalemia. The secondary (49), renin-angiotensin-aldosterone
redistribution significantly

Henle sodium hypocalciuria,

tations and

reabsorption (59). hypomagnesemia,

presents at a later age.

Gitelmans syndrome and milder clinical

This syndrome appears

features manifesto be

of

the

system
contributes

sugto

potassium

the hypokalemia. Rarely, genomic duction.

nocorticotropin

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

defects
(ACTH)-regulated

lead

to excessive
gene

aldosterone
to the

proan adrecoding

with

hypotension

and

intravascular In contrast, hypokalemia,

volume

de-

In gbucocorticoid-remediable of the aldosterone synthase

aldosteronism,
is linked

due to renal is associated

and

sodium-wasting. with hypertension,

renin and

Liddles synmetabolic
levels (61).

sequence

gene,

the

rate-limiting

suppressed

aldosterone

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

This condition principal cell

appears to be a result apical sodium channel,

of defects in the CCD ENaC, leading to an

Hypokalemia:

Diagnosis

and Treatment

1 185

increased subsequent of renin because luminal

dient for

open probability, excessive sodium volume expansion, hypertension, and aldosterone increased
potassium

reabsorption, and and suppression wasting beads occurs grapotassium from distal
primary

coronary tient
tricular

artery
ectopy.

disease
In such

or on digitalis infarction
administration cases,

treatment, and

and significant serum can

the

payenof

with

an acute

myocardial may

(62). sodium

Renal

potassium

of 5 to 10 mEq

CCD

reabsorption

to increased

KC1 over sium

as needed.

15 to 20 mm above Close,

be used monitoring are

to increase This dose

potaslevel the and risk oral oral

electronegativity The distal tubular

and an increased
secretion.

electrochemical of renal can result acidosis, case,

reflect

to a level

3.0 mEq/liter. (ECG)

be repeated

continuous

of the serum to reduce

Bicarbonaturia. wasting metabolic of proximal bicarbonate

cases of distal

last renal

major tubular

cause

the electrocardiogram of hyperkalemia. In most other therapy medication and

necessary

is bicarbonaturia. alkabosis, renal delivery

renal

Bicarbonaturia acidosis.
acidosis

either tubular Certain

de-

or treatment

conditions, on the the ability

the choice ability

of parenteral of the patient to function

versus

In each potassium
may

is dependent

to take

increases
tubular

secretion.

of the 01 tract as myocardial the patient may cases,

appropn-

fects

in potassium

reabsorption.

ately. In many cases, such and hepatic encephabopathy, oral potassium When safely given 01 tract nously. ment study hour absorption. In these via

infarction, paralysis, may be unable to take exist about (IV) the speed intravereplaceof be given route,

or questions the

Diagnostic

Approach

KC1 can

In approaching the patient with hypokabemia, we recommend using the approach outlined above. Figure 2 summarizes our diagnostic algorithm. First, ensure that pseudohypokalemia, Second, due to potassium for consider the whether uptake reported by abnormal reduction redistribution in leukocytes, serum is not from the responsible potassium.

intravenous

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
bevel to increase by an average of 0.25 mEqIL per

potassium

(63). hour

If more can ECO

rapid

replacement through

is necessary, a central replacement

then catheter

40 mEq with therapy can inof

of potassium

per

be administered monitoring. orally used

levels, extra-

extra- to the intracellular space If neither of this possibilities probably represents total body from either skin, gastrointestinal
boss. is high. Excessive potassium loss

accounts for the hypokalemia. is present, the hypokalemia potassium (GI) tract,
from the made

continuous should The affect

creases potassium providing

However, if possible. for potassium

depletion or renal
skin

resulting potassium
from

be administered parenterab the response.

insulin the in glucose from KC1 serum

fluids

administration IV
space. as DW

results

In nondiabetic
which to the solutions

patients,
can such cause intracellular

dextrose

prolonged under either duced Renal

Secondary

exertion
This diagnosis

in hot,
can

dry
be

environments
readily

where
from

sweat
the

loss from

redistribution As a result, can paradox-

history

most diarrhea, diarrhea

conditions. vomiting,
patients

GI
may

tract nasogastric
be

potassium suction,
to reluctant

loss
admit

occurs
to

or a 01 fistula.
self-in-

ically enteral KC1

lower KCI might

serum should be

potassium be provided are

levels in added

(64). normal normal

In most saline. saline parenteral

cases, If fluid,

parbarge then

Occasionally,

from loss

catharctic is most

use, and the diagnosis or direct frequently

from cardiac

may

need use.

concentrations administration Usually

therapy. Patients

of KC1

to the solution.

to be confirmed potassium

by sigmoidoscopy

testing

of the stool.
disease

administered of a hypertonic can the

in half be treated need

to avoid with
should

a result cause

of diuretic

hyperaldosteronism

or hepatic

hypokalemia
with

successfully
hypokalemia

oral
be

or a nephrotic
loss.

syndrome

is a common

of renal
causes

potassium
renal po-

diuretic-induced

Hypomagnesemia-induced

hypokalemia

re-evaluated use is required, formed.

to reconsider assessment sodium is not

diuretics

for

diuretics. intake

If continual should use

and

tassium useage. tubular

moidostomy.

wasting and Rarer causes acidosis use, and (RTA),

Finally,

is frequently a complication of renal potassium loss diabetic

primary

of diuretic include renal and ureterosigdisurreptitious

of sodium intake the case When drug In the

citrate

be preof the
spi-

Excessive

accentuates concomitant

diuretic-induced

ketoacidosis,
aldosteronism,

hypokabemia.
potassium-sparing

If this may

amiloride, preferred

triamterene,

uretic need

either

Bartters

or Gitelmans

syndrome

may

ronolactone
apy is required,

be considered.
KCI is the

oral latter

replacement condition,
be used.

therexcept either
The

to be considered.

in all patients
should

those

with

metabolic
bicarbonate

acidosis.
or potassium

Correction
The
against

potassium

risks
the

associated
risks of therapy

with

hypokabemia
when the

must

be

balanced
to

chloride indicated
veIling levels. Finally,

salt of potassium for

enzyme

minimizes beta
can assist can lead

renal blockers

potassium

bosses.
potassium wast-

If

appropriate

approach

other

reasons,

or angiotensin-con-

the patient

is determined.

Usually,

the primary

short-term

risks

inhibitors

in maintaining to renal potassium

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 to paradoxical worsening

hypomagnesemia

ing

and

refractoriness correction hypokabemia, hypokabemia and

to potassium of the hypokalemia

is corrected

replacement does Patients serum therapy hypokalemia, their with

(36). not occur

In these until the

patients, duced

hypomagnesemia

(65). have

diuretic-inbevels if mdi-

unexplained should replacement

or diuretic-inmagnesium begun

therapy are rare. The classic in a patient preparing to in patients with known

duced checked cated.

magnesium

surgery,

particularly

I I 86

Journal

of

the American

Society

of Nephrology

b hi

hi
0

E
0 ci
hi

hi

0
bi E

E
C

E
0

hi

0
hi

0
hi

C C

hi

E
V

hi

0
hi
0

hi hi
0

C
ci

ci

C
E
ci)

ci

E
N V

ci)

hi hi C,)

Figure

2. Diagnostic

evaluation

of hypokalemia.

Hypokalemia:

Diagnosis

and Treatment

I 187

Note reduced
genesis cati FL, potassium controlled

added in proof: A recent meta-analysis concluded potassium intake may play an important role
of hypertension Appel on clinical LI, blood (Whelton Follmann pressure: trials. JAMA D, 277: PK, Klag He J, Cutler MI: Effects of 1997). IA, of

that in the
Branoral

18. Sobeimani sium lateral 19. Tizianelbo

M, Bergman increases :HCO3 Na:CO3

IA,

Hosford luminal cotransport

MA, Na /H

McKinney exchange

TD: and cortex.

Potasbaso-

depletion

in rat renal C, Saffioti

J Clin
R, 1991 in meaK+ ac-

Invest 86: 1076-1083, A, Garibotto

1990 G, Robaudo 5, Pontremoli

Meta-analysis 1624-1632,

randomized

Bruzzone
with 20. Wingo chronic

M, Deferrari
potassium CS. Smolka

G: Renal
depletion.

ammoniagenesis
Kidney and structure

in humans

Int 40: 772-778, of H-K-AIPase 1995 in vivo

Al: Function

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