DISEASEOF THE MONTH

Hypokalemia-Consequences , Causes , and Correction

I. DAVID WEINER and CHARLES S. WINGODivision of Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, and

Gainesville Veterans Administration Medical Center, Gainesville, Florida.

Hypokalemia is one of the most commonly encountered fluid

and electrolyte abnormalities in clinical medicine. It can be an

asymptomatic finding identified only on routine electrolyte

screening, or it can be associated with symptoms ranging from

mild weakness to sudden death. The correction of hypokabemia

can be simple, but if inappropriately performed can lead to

worsening symptoms, and even death.

The purpose of this article is to discuss the management of

hypokalemia in sufficient detail to allow practitioners to care

for patients who have this condition. We shall discuss the

epidemiology of hypokalemia and its consequences on renal

and extrarenal tissues and shall briefly discuss the physiology

of potassium handling and the differential diagnosis of hypo-

kalemia. Finally, we shall consider the important factors that

should influence therapy and shall provide general recommen-

dations for patient management. Space limitations preclude

extensive reference to many of the primary sources of infor-

mation; thus, comprehensive reviews are frequently cited.

EpidemiologyThe occurrence of hypokalemia is strongly dependent on the

patient population. In otherwise healthy adults not receiving

any medications, less than 1 % will develop hypokalemia, as

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 conservation in

states of potassium depletion. The presence of spontaneous

hypokabemia in otherwise healthy adults who are not receiving

any medications should suggest the possibility of underlying

disease and indicate the need to search for an etiology.

Most cases of hypokalemia occur in the setting of specific

disease states. Patients receiving diuretics are at the highest

risk, with as many as 50% developing serum potassium levels

of less than 3.5 mEq/liter ( 1 ). As we will later discuss, thiazide

diuretics are more likely to cause hypokabemia than “1oop” or

osmotic diuretics. Individuals with secondary hyperaldosteron-

ism, whether due to congestive heart failure, hepatic insuffi-

ciency, or nephrotic syndrome, constitute a second group at

high risk. Finally, those patients with diseases that alter renal

potassium conservation through interaction with salt delivery

Correspondence to Dr. Charles S. Wingo, P.O. Box 100224, Division ofNephrology, Hypertension and Transplantation. University of florida Collegeof Medicine, Gainesville, FL 32610.

to the cortical collecting duct (CCD) are also at high risk for

hypokalemia.

ConsequencesPotassium deficiency alters the function of several organs

and most prominently affects the cardiovascular system, neu-

robogic system, muscles, and kidneys (2). These effects ulti-

mately determine the morbidity and mortality related to this

condition. Unfortunately, the correlation between degree of

potassium deficiency and adverse side-effects is poor, possibly

because the occurrence of side-effects is related to both the

potassium deficiency and the underlying disease state. Overall,

children and young adults tolerate more severe degrees of

hypokalemia with less risk of severe side-effects than the

elderly.

Cardiovascular

Two major side-effects of hypokalemia affect the cardiovas-

cular system: hypokalemia-related hypertension and hypokab-

emia-induced ventricular arrhythmias. Both contribute to in-

creased morbidity and mortality.

Hypokalemia contributes to hypertension in many patients

(3) but is frequently unrecognized as an important factor that

may produce or worsen this serious health problem. Several

lines of evidence reveal that potassium deficiency can increase

blood pressure. Cross-sectional studies show that bow-potas-

sium diets, especially in the presence of a high sodium intake,

are linked with the prevalence of hypertension (3). This asso-

ciation is most marked in African Americans. Epidemiologic

and prospective studies confirm this association in both healthy

volunteers and in essential hypertensive patients (4). The an-

tihypertensive effect of thiazide diuretics is reduced by hypo-

kalemia and enhanced by potassium repletion (5). Finally,

blood pressure may be more highly sodium-dependent in the

presence of hypokalemia (3). Thus evidence strongly indicates

that hypokalemia contributes to hypertension.

The mechanism of hypokalemia-induced hypertension is not

completely clear. One component of this type of hypertension

appears to be salt retention (4). Hypokalemia leads to intravas-

cular volume expansion as a result of renal NaC1 retention.

Hypokalemia may also potentiate the hypertensive effects of

various neurohumoral agents (6,7).

Ventricular arrhythmias are a second cardiovascular side-

effect of hypokabemia. Several prospective studies show that

hypokalemia predisposes patients to the development of a

variety of ventricular arrhythmias, including ventricular fibril-

lation (8). Patients at the highest risk for arrhythmias, the

I 180 Journal of the American Society of Nephrology

elderly and those patients with underlying ischemic heart dis-

ease, appear to have the highest risk for hypokalemia-related

complications (9, 10). Diuretic-induced hypokalemia is of par-

ticular concern because the incidence of sudden death in hy-

pertensive individuals treated with the thiazide diuretic hydro-

chborothiazide is greater than that in matched control subjects

( I 1 ). The effect is dose-related and is decreased by the con-

comitant use of potassium-sparing diuretics ( 1 1).

Hormonal

Hypokalemia impairs both insulin release and end-organ

sensitivity to insulin, resulting in worsening hyperglycemia in

diabetic patients ( I 2, 13). Hyperglycemia and diabetes meblitus

are major public health concerns in industrialized nations.

Because increasing evidence suggests that end-organ compli-

cations from diabetes mellitus are related to the degree of

hyperglycemia (14, 15), treatment of hypokalemia may de-

crease the devastating effects of diabetes meblitus.

Muscular

Potassium depletion can result in several muscular-related

complications ( 16). Hypokabemia can hyperpolarize skeletal

muscle cells, impairing their ability to develop the depobariza-

tion necessary for muscle contraction. It can also reduce blood

flow to skeletal muscles. The reduced blood flow can predis-

pose patients to rhabdomyolysis (I 7), especially when vigor-

ous exercise is combined with impaired blood-flow regulation.

The combination of these effects frequently leads to muscle

weakness, easy fatigabibity, cramping, and myalgias (16). Pa-

ralysis, although uncommon, can occur in cases of profound

potassium deficiency (16).

Acid-Base

Hypokalemia can profoundly affect systemic acid-base ho-

meostasis through its effects on multiple components of renal

acid-base regulation. The most common abnormality is meta-

bolic alkabosis. Hypokalemic metabolic alkabosis results from

the effects of hypokabemia on several components of net acid

excretion. The most direct effects include stimulation of prox-

imal tubule HCO1 reabsorption and ammoniagenesis (18,19);

collecting duct proton secretion, possibly via stimulation of

both the gastric (HKa1) and cobonic (HKa,) isoforms of H�-

KtATPase (20); and decreasing urinary citrate excretion.

Hypokalemia may produce these widespread effects on renal

acid-base homeostasis because of intracellular acidification

(2 1 ). Hypokabemia also inhibits abdosterone secretion (22),

which possibly minimizes such effects on acid-base homeosta-

sis. In rare cases, severe hypokabemia leads to respiratory

muscle weakness and the development of respiratory acidosis.

In patients with hypokalemia as a result of renal tubular aci-

dosis, the concomitant development of respiratory acidosis can

be life-threatening.

Polvuria

Another complication of hypokabemia is the development of

mild polyuria, averaging 2 to 3 liters per day (2). The polyuria

is related to both increased thirst and mild nephrogenic diabe-

tes insipidus (23). Increased thirst is associated with increased

central nervous system levels of angiotensin II, a hormone that,

besides its other effects, regulates thirst. Hypokalemia also

impairs the kidney’s ability to concentrate the urine maximally

(2). This appears to occur because hypokalemia causes defec-

tive activation of renal adenylate cyclase. preventing antidi-

uretic hormone-stimulated un nary concentration (24).

Renal Cystic Disease

Hypokabemia, in association with hyperaldosteronism, can

lead to renal cystic disease. These cysts appear to arise in the

collecting duct epithebium and are frequently associated with

interstitial scarring (25). Correcting the hypokalemia leads to

cyst regression (25). The mechanism of cyst development is

unclear. Hypokalemia beads to increased ammoniagenesis and

medubbary ammonia accumulation, which may activate the

complement system. It has been postulated that hypokalemia,

by leading to activation of complement in the medublary inter-

stitium, beads to interstitial fibrosis (26). Consistent with this

hypothesis is the observation that bicarbonate supplementation,

by inhibiting ammoniagenesis, decreases the interstitial fibro-

sis associated with hypokalemia; this effect is independent of

changes in serum potassium (26).

Hepatic Encephalopathv

Hypokalemia can contribute to the development, or worsen

the symptoms, of hepatic encephabopathy. One toxin that

causes hepatic encephabopathy is ammonia, and hypokalemia

increases proximal tubule ammoniagenesis (19). Approxi-

mately 50% of proximal tubule ammonia production is re-

turned to the systemic circulation via the renal veins. In hepatic

insufficiency, the increased systemic burden of ammonia re-

subting from increased renal ammoniagenesis can be sufficient

to cause the development or worsen the symptoms of hepatic

encephabopathy (27).

Physiology of Potassium HomeostasisSerum potassium concentration is a balance between intake,

excretion, and distribution between the intra- and extracellular

space. The average daily potassium intake in a typical Western

diet is 70 mEq. Under normal conditions, excretion equals

intake, with approximately 90% of potassium excreted in the

urine and the vast majority of the remainder in the stool.

Distribution of potassium between the intra- and extracelbubar

space plays an important role in potassium homeostasis.

Most potassium is present in the intracellular space. Intra-

cellular potassium averages 120 to 140 mEq/liter, largely as a

result of active potassium uptake by Na4-K�-ATPase. Ap-

proximately 98% of total body potassium is present in the

intracellular space. Consequently, small changes in the distri-

bution of potassium between the intra- and extracellular fluid

spaces result in proportionally large changes in extracelluar

potassium concentration. The large intracellular potassium

store functions to minimize changes in extracellular potassium

in states of potassium deficiency. Under these conditions,

potassium shifts from the intra- to the extracellular fluid,

apparently to reduce changes in the transmembrane potassium

Lumen Peritubular space

Na�

K�

H�

K�

K�

H

HCO3

Figure 1. Model of potassium transport in the cortical collecting duct.

Hypokalemia: Diagnosis and Treatment 1 181

gradient. With potassium depletion, certain tissues, notably

muscle, exhibit a more rapid reduction in intracellular potas-

sium than do others, such as the brain. As a result, small

potassium losses minimally affect the serum potassium level.

Conversely, the potassium deficit in hypokalemic states that

result from potassium loss (excluding pseudohypokalemia and

redistribution, as will be discussed below) is very barge. For

example, a decrease in serum potassium from 3.5 to 3.0 mEq/

biter typically indicates a total body potassium deficit of 100 to

300 mEq, and a decrease to 2.0 mEq/liter can indicate a total

body deficit of 600 to 800 mEq.

Potassium is present in most foods in varying amounts.

Although the typical dietary intake averages 70 mEq/d, there is

considerable variation, depending on the dietary preferences of

the individual. In the absence of other factors, the body can

adapt to a wide range of potassium intake without development

of marked hypokalemia. Notably, African Americans com-

monby eat diets containing less potassium, which may induce a

state of physiologic potassium deficiency and contribute to the

incidence and severity of hypertension in this population

(28,29).

The primary mechanism of potassium excretion is the urine.

Potassium is freely filtered at the gbomerulus, followed by

reabsorption of approximately 85% by the proximal tubule and

the loop of Henle (30). Relatively little regulation of potassium

reabsorption occurs in these segments, however (30). Instead,

the primary site for renal potassium regulation is the collecting

duct (3 1 ). The CCD both secretes and reabsorbs potassium,

whereas the outer and inner medullary collecting ducts

(OMCD and IMCD, respectively) reabsorb potassium (30,31).

At least three cell types are present in the CCD, all of which

may contribute to potassium homeostasis. Figure 1 summarizes

the transporters involved in CCD potassium transport. The

principal cell is the most numerous cell, comprising 60 to 70%

of the CCD, and is believed to be responsible for potassium

secretion. Potassium is actively taken up into the cell via a

basolateral Na�-K�-ATPase and secreted down its electro-

chemical gradient into the luminal fluid (urine) via an apical

potassium channel. Additional evidence indicates that potas-

sium secretion is codependent on Cl secretion. Electrogenic

sodium reabsorption generates a lumen-negative charge or

voltage. Because this negative charge increases the electro-

chemical gradient for potassium secretion, the rate of sodium

reabsorption also regulates the rate of potassium secretion.

In contrast to the principal cell, the CCD A- and B-type

intercalated cells (A cell and B cell, respectively), which com-

prise the remainder of the CCD, are modeled to reabsorb

luminal potassium. Potassium reabsorption occurs through pro-

cesses different from those of principal cell potassium secre-

tion. An apical H4�KtATPase secretes protons and reabsorbs

buminab potassium, contributing to urinary acidification and

potassium reabsorption (3 1 ). In the presence of normal potas-

sium, most reabsorbed potassium is recycled across the apical

membrane, resulting in little net potassium transport. In re-

sponse to potassium deprivation, potassium can exit the cell via

a basolateral barium-sensitive transporter, presumably a potas-

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

allows active potassium reabsorption when necessary.

Recent studies show that the B cell, generally believed to

mediate bicarbonate secretion and recovery from metabolic

alkabosis, may also contribute to potassium homeostasis. Re-

sults from our laboratories and those of others provide strong

functional evidence for an apical H�-K�-ATPase in this cell

(32,33). We have also shown that there is coupling of chloride

reabsorption by the apical CF7HCO3 exchanger to the apical

HtK��ATPase (3 1 ). Parallel operation of apical H��Kt

ATPase and apical Cl�/HCO3 exchange provide a new model

for active KC1 reabsorption. Additionally, inhibition of H�-

K�-ATPase reduces CCD amiloride-insensitive sodium reab-

sorption, suggesting that sodium can substitute for potassium

on the CCD W�KtATPase (3 1). In hypokalemia, the in-

creased CCD H�-K�-ATPase activity, in combination with

sodium substituting for potassium on the H�-K�-ATPase,

could lead to net NaCl reabsorption, volume expansion, and the

increased blood pressure that is observed clinically.

The OMCD and IMCD do not transport potassium under

normal conditions, but in response to hypokalemia or potas-

sium deficiency can reabsorb potassium. This appears to occur

via mechanisms similar to the CCD A cell, e.g. , luminal

potassium uptake by an apical HtKtATPase and basolateral

potassium exit via a basolaterab potassium channel (20). As

noted previously, at least two isoforms of HtKtATPase are

present in the collecting duct: HKa1 and HKa2 (20). HKa1

may be regulated to a greater extent by hypokalemia than

HKct, in the CCD, whereas the opposite appears to be true in

the OMCD (34,35).

I I 82 Journal of the American Society of Nephrology

Despite the presence of active potassium reabsorptive trans-

porters in the CCD, OMCD, and IMCD, the urinary potassium

level is generally not lower than 15 to 20 mEqlliter. This may

reflect both water reabsorption, which exceeds potassium re-

absorption, and persistent potassium secretion in the CCD.

Little potassium is excreted in the stool under normal con-

ditions because of a low stool volume and a low stool potas-

sium concentration. Conditions that increase stool potassium

concentration, such as chronic renal failure and hyperkalemia,

or stool volume, such as diarrhea, increase fecal potassium

excretion. Chronic renal failure can cause adaptive changes in

stool potassium content, such that as much as 20 to 30 mEq/d

can be excreted by this route. Decreases in stool potassium

content do not materially affect the response to hypokalemia

because the basal level of stool potassium excretion is normally

small.

CausesThe accurate treatment of hypokalemia requires correct

identification of the cause. Hypokabemia can be associated

either with normal or decreased total body potassium content.

Normal total body potassium with hypokalemia is a result of

potassium redistribution from the extracellular to the intracel-

lular space. Total body potassium depletion can result from

either renal or extrarenal potassium losses. We suggest that the

clinician evaluating a patient with hypokabemia consider four

broad groups of etiologies: pseudohypokalemia, redistribution,

extrarenal potassium loss, and renal potassium loss.

Pseudohypokalemia

Abnormal white blood cells, if present in large enough

numbers, can take up extraceblubar potassium when stored for

prolonged periods at room temperature, resulting in a low

measured plasma potassium level. The apparent hypokalemia

is an artifact of the storage procedure and is referred to as

“pseudohypokalemia” (36). The most common underlying dis-

ease state is acute myelogenous leukemia. Rapid separation of

the plasma or storing the sample at 4#{176}Cconfirms the diagnosis,

avoids this artifact, and prevents inappropriate treatment.

Redistribution

More than 98% of total body potassium is present in the

intracellular fluid, predominantly in skeletal muscle cells, en-

abling small changes in the distribution of potassium to alter

the extracellular concentration markedly. Certain hormones,

particularly insulin, aldosterone, and sympathomimetics, are

the most common cause of redistribution-induced hypokale-

mia. Insulin activates Na��KtATPase, which results in active

potassium uptake (37). Acute insulin administration produces

rapid potassium shifts from the extra- to intracellular space,

resulting in hypokalemia. This problem is most frequently

encountered in the treatment of diabetic ketoacidosis. Insulin-

induced redistribution of potassium is the physiologic principle

underlying the administration of insulin with glucose to pa-

tients with hyperkabemia. In contrast to acute insulin adminis-

tration, chronically high insulin bevels, as occur in insubinomas,

do not typically cause hypokalemia; the mechanism of this

“escape” is unknown. The decreased end-organ responsiveness

to insulin in adult-onset diabetes may contribute to the hyper-

kalemia frequently seen by altering the distribution of potas-

sium between the intra- and extracellular space.

A second, clinically common cause of potassium redistribu-

tion is aldosterone. Aldosterone induces cellular uptake of

potassium through a variety of effects, but much more slowly

than insulin. Aldosterone stimulates the production of Nat

KtATPase, which results in increased enzyme activity and

the transport of potassium from the intracellular to extracellular

space (37-39). In addition, as will be discussed below, aldo-

sterone also regulates renal potassium transport. Thus hyper-

aldosteronism causes hypokalemia as a result of the combined

effects of redistribution and stimulation of renal potassium

clearance.

The final major hormonal cause of potassium redistribution

includes sympathomimetic agents, �,-adrenergic agonists, do-

pamine, dobutamine, and theophylbine. The first three agents

directly stimulate the cellular uptake of potassium and also

stimulate insulin release, whereas theophylbine indirectly slim-

ulates potassium uptake (36,37). Sympathomimetic-induced

redistribution leading to hypokalemia is important in acute

myocardial ischemia and acute asthma therapy. Myocardial

ischemia commonly increases sympathetic tone, whether as a

direct result of the ischemia, decreased cardiac output, or from

either the pain or the anxiety related to the ischemia. Cellular

potassium redistribution leading to hypokalemia can then in-

crease the risk of ventricular arrhythmia and sudden death.

Treatment of the asthma patient with 3-adrenergic agonists or

theophylbine can bead to potassium redistribution, hypokale-

mia, and impairment of respiratory muscle contractile ability.

Patients may develop CO2 retention, or, even more seriously,

decreased wheezing, as a result of decreased air movement,

which might be misinterpreted as an overall improvement in

the patient’s condition. Another clinical concern is premature

labor therapy involving �3-agonists. These patients frequently

do not have oral intake for prolonged periods, providing a

setting for the development of severe hypokalemia.

Hypokabemia as a result of potassium redistribution can also

occur from acute anabolic states. Cells contain approximately

130 mEq/biter of potassium; consequently, stimulation of either

cell hypertrophy or cell production can cause rapid movement

of potassium from the extra- to the intracellular space. Rapid

cell production can occur in acute leukemia and high-grade

lymphomas. Acute stimulation of cell production can result

from granulocyte macrophage colony-stimulating factor treat-

ment of refractory anemia or the initial treatment of pernicious

anemia with vitamin 2 (40). The resultant cell production can

cause acute hypokabemia and in some individuals has resulted

in arrhythmias and sudden death (41).

Rarely, hypokalemia secondary to redistribution with en-

hanced cellular uptake can be a result of hypokalemic periodic

paralysis (16,36). Both familial and sporadic cases have been

reported. Most hereditary cases follow an autosomab dominant

distribution, although an X-binked recessive form has been

documented. In Asians there is a high frequency of this con-

dition associated with thyrotoxicosis ( 16). Attacks frequently

Hypokalemia: Diagnosis and Treatment 1 183

commence during the night or the early morning and are

characterized by flaccid paralysis of all extremities, which may

persist from 6 to 24 h (36). A genetic defect in a dihydropyr-

idine-sensitive calcium channel has been determined to cause

certain cases of this disorder (42). Carbonic anhydrase inhib-

itors (acetazolamide 250 mg four times daily), beta blockers, or

spironolactone may prevent attacks.

Finally, hypokalemia has been reported in connection with

chboroquine and barium intoxication. The latter effect can be

explained by the known action of barium to block potassium

channels and, hence, cellular potassium exit (16).

Non-Renal Potassium L05s

Both the skin and the gastrointestinal tract can transport

significant amounts of potassium. Under normal conditions,

net fluid loss from these organs is small, limiting net potassium

boss. Occasionally, in cases such as prolonged exertion in hot,

dry environments or chronic diarrhea. severe potassium loss

can occur, leading to hypokabemia (43). In most of these cases,

intravascular volume depletion is present also, leading to sec-

ondary hyperabdosteronism, stimulation of renal potassium ex-

cretion, and further worsening of the potassium deficit (43).

Prolonged loss of gastric contents, whether from vomiting or

nasogastric suctioning, can lead to hypokalemia. A small part

of this potassium loss is direct because these body fluids

contain 5 to 8 mEqfliter potassium. More importantly, concom-

itant alkabosis and intravascular volume depletion contribute to

renal potassium loss. Metabolic alkabosis results in bicarbona-

tuna, which increases potassium excretion both directly, as a

cation to balance the negative charge of bicarbonate ions, and

indirectly, through stimulation of urinary sodium excretion,

leading to worsening of intravascular volume depletion and

stimulation of the renin-angiotensin-aldosterone system. In ad-

dition, potassium reabsorption by the collecting duct is affected

by acid-base status. Thus metabolic alkabosis increases renal

potassium excretion by increasing potassium secretion and

probably by direct suppression of potassium reabsorption.

Diarrhea, whether secretory or as a result of laxative abuse,

can cause profound gastrointestinal potassium loss. Patients

with laxative abuse may deny the condition because of over-

concern about body image and may also abuse diuretics (44).

Sigmoidoscopy and urine screening for diuretics may be

needed to confirm the diagnosis. The former will reveal mel-

anosis cobi in patients who have been using anthracene laxa-

tives, such as senna, cascara and aloe, for more than 4 months

(45). If phenolphthabein laxatives are being used, alkalinization

of the stool to pH 9 will produce a pink color. If magnesium-

or phosphate-containing cathartics, such as magnesium citrate

or sodium phosphate, are suspected, direct measurement of

these compounds in the stool can confirm the diagnosis.

Renal Potassium Loss

The most common cause of hypokalemia is excess renal

potassium loss. This can occur either because of medications,

endogenous hormone production or, in rare conditions, intrin-

sic renal defects. Table 1 summarizes these causes.

Table 1. Causes of renal potassium loss

Drugs

diuretics

thiazide diruetics

loop diuretics

osmotic diuretics

antibiotics

penicillin and penicillin analogues

amphotericin B

aminoglycosides

Hormones

aldosterone

glucocorticoid-remediable hypertension

glucococorticoid-excess states

B icarbonaturia

distal renal tubular acidosis

treatment of proximal renal tubular acidosis

correction phase of metabolic alkabosis

Magnesium deficiency

Other less common causes

cisplatin

carbonic anhydrase inhibitors

toluene

leukemia

diuretic phase of acute tubular necrosis

Intrinsic renal transport defects

Bartter’s syndrome

Gitelman’s syndrome

Liddle’s syndrome

Drugs. Many medications can cause renal potassium

wasting, including diuretics and some antibiotics. Both thiazide

and loop diuretics increase urinary potassium excretion; when

factored for their natriuretic effect, thiazide diuretics are more

potent kabiuretic agents (46). In part this is because loop

diuretics have a shorter pharmacologic half-life, enabling renal

potassium conservation during periods between drug adminis-

tration, but may also reflect their site of action in the distal

convoluted tubule with secondary effects on flow to the pri-

mary site of potassium secretion in the CCD. All diuretics,

except the potassium-sparing diuretics, induce potassium-wast-

ing by increasing CCD luminal flow rate, luminal sodium

delivery, and luminal electronegativity, which are the primary

determinants of potassium secretion by the CCD. They may

also induce intravascular volume contraction, resulting in sec-

ondary hyperaldosteronism and further stimulation of renal

potassium secretion. The incidence of diuretic-induced hypo-

kalemia is both dose- and treatment duration-related.

Antibiotics can increase urinary potassium excretion by a

variety of mechanisms. High-dose penicillin and some penicil-

bin analogues, such as carbenicillin, oxacilbin, and ampiciblin,

increase distal tubular delivery of a non-reabsorbable anion,

thereby increasing urinary potassium excretion (47). Cisplatin

is another drug that may induce hypokalemia via an increase in

renal potassium excretion. Polyene antibiotics, such as ampho-

I I 84 Journal of the American Society of Nephrology

tericin B, create cation channels in the apical membrane of

collecting duct cells, which increases potassium secretion and

results in potassium wasting (36). Tobuene exposure, which can

result from sniffing certain glues, can also cause hypokalemia,

presumably by renal potassium wasting (2). Aminoglycosides

can cause hypokalemia either in the presence or absence of

overt nephrotoxicity. The mechanism is not completely under-

stood but may rebate to stimulation of magnesium depletion

(see below) (36) or direct inhibition of potassium reabsorption.

However, most antibiotics do not cause hypokabemia, and

some, such as trimethoprim and pentamidine, can cause hy-

perkalemia by inhibition of apical sodium channels in the

CCD.

Endogenous hormones. Endogenous hormones are very

important causes of hypokalemia. Aldosterone is perhaps the

most important hormone regulating total body potassium ho-

meostasis, and excess abdosterone production or effect fre-

quently leads to hypokalemia. The CCD is the primary site in

the kidney where aldosterone regulates potassium transport,

and the CCD principal cell is the CCD cell responsible for

potassium secretion (30,3 1 ). Aldosterone increases principal

cell apical sodium conductance, basolateral NatKtAlPase

activity, and electrogenic sodium absorption in the CCD. These

effects increase the net luminal-negative charge or transepithe-

hal voltage. which increases the electrochemical gradient for

potassium movement from the principal cell cytoplasm to the

luminab fluid. Thus aldosterone, via actions on apical Na�

channels and basolateral NatKtATPase, increases CCD

principal cell potassium secretion. Although potassium reab-

sorption can occur in the OMCD and IMCD (3 1 ), the reab-

sorptive capacity of these segments, particularly with normal

Na intake, is less than the rate of potassium secretion by the

CCD. Thus the net effect of aldosterone is to enhance renal

potassium clearance.

Hyperabdosteronism can be either primary or secondary.

Primary hyperaldosteronism results in cases of hypertension

(48), predominantly because of the sodium-retaining effects of

aldosterone, but the associated hypokalemia may also contrib-

ute by sensitizing the vasculature to neurohumoral regulators

of blood pressure. Because angiotensin II regulates adrenal

gland aldosterone synthesis, conditions involving elevated an-

giotensin II levels will typically involve hyperabdosteronism.

This may occur in a variety of conditions, such as decreased

oral intake, diuretic use, vomiting, or diarrhea. Activation of

the renin-angiotensin-aldosterone system, as may occur in ma-

lignant hypertension (49), renovascubar hypertension (50), and

renin-secreting tumors (5 1 ), can also lead to secondary hyper-

aldosteronism with subsequent hypokalemia. The secondary

activation of the renin-angiotensin-aldosterone system sug-

gests that potassium redistribution significantly contributes to

the hypokalemia.

Rarely, genomic defects lead to excessive aldosterone pro-

duction. In gbucocorticoid-remediable aldosteronism, an adre-

nocorticotropin (ACTH)-regulated gene is linked to the coding

sequence of the aldosterone synthase gene, the rate-limiting

enzyme for aldosterone synthesis (52). Aldosterone synthase is

no longer regulated by the renin-angiotensin system, and ex-

cessive abdosterone production ensures. In congenital adrenal

hyperplasia, there is the congenital absence of either 1 1f3-

hydroxybase or I 7a-hydroxylase, resulting in excess hypotha-

lamic corticotropin-releasing hormone (CRH) secretion and

persistent adrenal synthesis of 1 1 -deoxycorticosterone, a p0-

tent mineralocorticoid (53). This condition can be recognized

by the associated effects on sex steroid production. 1 1 f3-hy-

droxylase deficiency results in increased androgen production,

leading to early viribization of men and women. In contrast,

17a-hydroxylase deficiency inhibits sex hormone metabolism,

leading to incomplete development of sexual characteristics.

Under rare conditions, glucocorticoids function as mineralo-

corticoids, causing hypokalemia and hypertension. Glucocor-

ticoids, such as cortisol, have a high affinity for the mineralo-

corticoid receptor but are normally prevented from binding to

it because the enzyme 1 1 /3-hydroxysteroid dehydrogenase

(1 l�-HSDH) converts cortisol to cortisone, which does not

bind to the minerabocorticoid receptor (54). Some drugs, such

as glycerrhetinic acid (found in carbenoxobone, chewing to-

bacco, and licorice), inhibit 1 1 f3-HSDH, allowing cortisol to

exert minerabocorticoid-bike effects in the distal nephron (55).

Infrequently, circulating cortisol can exceed the metabolic ca-

pacity of 1 l3-HSDH and cause hypokalemia. This can occur

either in severe cases of Cushing’s disease or in the ectopic

ACTH syndrome (56).

Magnesium depletion. Concomitant magnesium defi-

ciency may prevent correction of hypokalemia (36). This is

particularly true with diuretic-induced hypokabemia and in

certain cases of aminoglycoside- and cisplatin-induced potas-

sium wasting, hypokalemia associated with lysozymuria in

acute leukemia, and in individuals with Gitebman’s syndrome

(see below). Supplementation with magnesium oxide, 250 to

500 mg by mouth four times daily, may serve to correct both

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. In 1962, Bartter de-

scribed the association of hypokabemia, hypomagnesemia, hy-

perreninemia, and metabolic alkabosis (57). Recent studies

show that these patients can be divided into two groups now

known as either Bartter’s syndrome or Gitebman’s syndrome.

Patients with Bartter’s syndrome are hypercalciuric and present

at an early age with severe volume depletion. This condition

appears to be a result of defects in either the renal Na-K-2C1

cotransporter gene, NKCC2 (58), or the ATP-sensitive potas-

sium channel, ROMK, both of which are necessary for loop of

Henle sodium reabsorption (59). Gitelman’s syndrome features

hypocalciuria, hypomagnesemia, and milder clinical manifes-

tations and presents at a later age. This syndrome appears to be

a result of mutations in the thiazide-sensitive NaC1 cotrans-

porter (60). Both Bartter’s syndrome and Gitelman’s syndrome

are associated with hypotension and intravascular volume de-

pbetion due to renal sodium-wasting. In contrast, Liddle’s syn-

drome is associated with hypertension, hypokalemia, metabolic

alkalosis, and suppressed renin and aldosterone levels (61).

This condition appears to be a result of defects in the CCD

principal cell apical sodium channel, ENaC, leading to an

Hypokalemia: Diagnosis and Treatment 1 185

increased open probability, excessive sodium reabsorption, and

subsequent volume expansion, hypertension, and suppression

of renin and aldosterone (62). Renal potassium wasting occurs

because increased CCD sodium reabsorption beads to increased

luminal electronegativity and an increased electrochemical gra-

dient for potassium secretion.

Bicarbonaturia. The last major cause of renal potassium

wasting is bicarbonaturia. Bicarbonaturia can result from either

metabolic alkabosis, distal renal tubular acidosis, or treatment

of proximal renal tubular acidosis. In each case, distal tubular

bicarbonate delivery increases potassium secretion. Certain

cases of distal renal tubular acidosis may reflect primary de-

fects in potassium reabsorption.

Diagnostic ApproachIn approaching the patient with hypokabemia, we recom-

mend using the approach outlined above. Figure 2 summarizes

our diagnostic algorithm. First, ensure that pseudohypokal-

emia, due to potassium uptake by abnormal leukocytes, is not

responsible for the reported reduction in serum potassium.

Second, consider whether redistribution of potassium from the

extra- to the intracellular space accounts for the hypokalemia.

If neither of this possibilities is present, the hypokalemia

probably represents total body potassium depletion resulting

from either skin, gastrointestinal (GI) tract, or renal potassium

boss. Excessive potassium loss from the skin results from

prolonged exertion in hot, dry environments where sweat loss

is high. This diagnosis can be readily made from the history

under most conditions. GI tract potassium loss occurs from

either diarrhea, vomiting, nasogastric suction, or a 01 fistula.

Occasionally, patients may be reluctant to admit to self-in-

duced diarrhea from catharctic use, and the diagnosis may need

to be confirmed by sigmoidoscopy or direct testing of the stool.

Renal potassium loss is most frequently a result of diuretic use.

Secondary hyperaldosteronism from cardiac or hepatic disease

or a nephrotic syndrome is a common cause of renal potassium

loss. Hypomagnesemia-induced hypokalemia causes renal po-

tassium wasting and is frequently a complication of diuretic

useage. Rarer causes of renal potassium loss include renal

tubular acidosis (RTA), diabetic ketoacidosis, and ureterosig-

moidostomy. Finally, primary aldosteronism, surreptitious di-

uretic use, and either Bartter’s or Gitelman’s syndrome may

need to be considered.

CorrectionThe risks associated with hypokabemia must be balanced

against the risks of therapy when the appropriate approach to

the patient is determined. Usually, the primary short-term risks

are cardiovascular, and the most important is the proarrhyth-

mogenic effect of hypokalemia. In contrast, the primary risk of

overaggressive replacement is the development of hyperkabe-

mia with resultant ventricular fibrillation. Occasionally, incor-

rect therapy of hypokalemia can lead to paradoxical worsening

of the hypokabemia.

Conditions requiring emergent therapy are rare. The classic

causes include severe hypokalemia in a patient preparing to

undergo emergent surgery, particularly in patients with known

coronary artery disease or on digitalis treatment, and the pa-

tient with an acute myocardial infarction and significant yen-

tricular ectopy. In such cases, administration of 5 to 10 mEq of

KC1 over 1 5 to 20 mm may be used to increase serum potas-

sium to a level above 3.0 mEq/liter. This dose can be repeated

as needed. Close, continuous monitoring of the serum level and

the electrocardiogram (ECG) are necessary to reduce the risk

of hyperkalemia.

In most other conditions, the choice of parenteral versus oral

therapy is dependent on the ability of the patient to take oral

medication and the ability of the 01 tract to function appropn-

ately. In many cases, such as myocardial infarction, paralysis,

and hepatic encephabopathy, the patient may be unable to take

oral potassium safely or questions may exist about the speed of

01 tract absorption. In these cases, KC1 can be given intrave-

nously. When given via the intravenous (IV) route, replace-

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

study has found that 20 mEq KCI per hour causes the serum

potassium bevel to increase by an average of 0.25 mEqIL per

hour (63). If more rapid replacement is necessary, then 40 mEq

per hour can be administered through a central catheter with

continuous ECO monitoring. However, replacement therapy

should be administered orally if possible.

The parenterab fluids used for potassium administration can

affect the response. In nondiabetic patients, IV dextrose in-

creases serum insulin levels, which can cause redistribution of

potassium from the extra- to the intracellular space. As a result,

providing KC1 in glucose solutions such as D�W can paradox-

ically lower serum potassium levels (64). In most cases, par-

enteral KCI should be provided in normal saline. If barge

concentrations of KC1 are added to the parenteral fluid, then

KC1 might be administered in half normal saline to avoid

administration of a hypertonic solution.

Usually hypokalemia can be treated successfully with oral

therapy. Patients with diuretic-induced hypokalemia should be

re-evaluated to reconsider the need for diuretics. If continual

use is required, assessment of sodium intake should be pre-

formed. Excessive sodium intake accentuates diuretic-induced

hypokabemia. If this is not the case concomitant use of the

potassium-sparing diuretics amiloride, triamterene, and spi-

ronolactone may be considered. When oral replacement ther-

apy is required, KCI is the preferred drug in all patients except

those with metabolic acidosis. In the latter condition, either

potassium bicarbonate or potassium citrate should be used. The

chloride salt of potassium minimizes renal potassium bosses. If

indicated for other reasons, beta blockers or angiotensin-con-

veIling enzyme inhibitors can assist in maintaining potassium

levels.

Finally, hypomagnesemia can lead to renal potassium wast-

ing and refractoriness to potassium replacement (36). In these

patients, correction of the hypokalemia does not occur until the

hypomagnesemia is corrected (65). Patients with diuretic-in-

duced hypokabemia, unexplained hypokalemia, or diuretic-in-

duced hypokabemia should have their serum magnesium bevels

checked and magnesium replacement therapy begun if mdi-

cated.

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I I 86 Journal of the American Society of Nephrology

Figure 2. Diagnostic evaluation of hypokalemia.

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Hypokalemia: Diagnosis and Treatment I 187

Note added in proof: A recent meta-analysis concluded that

reduced potassium intake may play an important role in the

genesis of hypertension (Whelton PK, He J, Cutler IA, Bran-

cati FL, Appel LI, Follmann D, Klag MI: Effects of oral

potassium on blood pressure: Meta-analysis of randomized

controlled clinical trials. JAMA 277: 1624-1632, 1997).

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