DISEASEOF THE MONTH
Hypokalemia-Consequences , Causes , and Correction
I. DAVID WEINER and CHARLES S. WINGO
Division 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 to the cortical collecting duct (CCD) are also at high risk for
and electrolyte abnormalities in clinical medicine. It can be an hypokalemia.
asymptomatic finding identified only on routine electrolyte
screening, or it can be associated with symptoms ranging from Consequences
mild weakness to sudden death. The correction of hypokabemia Potassium deficiency alters the function of several organs
can be simple, but if inappropriately performed can lead to and most prominently affects the cardiovascular system, neu-
worsening symptoms, and even death. robogic system, muscles, and kidneys (2). These effects ulti-
The purpose of this article is to discuss the management of mately determine the morbidity and mortality related to this
hypokalemia in sufficient detail to allow practitioners to care condition. Unfortunately, the correlation between degree of
for patients who have this condition. We shall discuss the potassium deficiency and adverse side-effects is poor, possibly
epidemiology of hypokalemia and its consequences on renal because the occurrence of side-effects is related to both the
and extrarenal tissues and shall briefly discuss the physiology potassium deficiency and the underlying disease state. Overall,
of potassium handling and the differential diagnosis of hypo- children and young adults tolerate more severe degrees of
kalemia. Finally, we shall consider the important factors that hypokalemia with less risk of severe side-effects than the
should influence therapy and shall provide general recommen- elderly.
dations for patient management. Space limitations preclude
extensive reference to many of the primary sources of infor- Cardiovascular
mation; thus, comprehensive reviews are frequently cited. Two major side-effects of hypokalemia affect the cardiovas-
cular system: hypokalemia-related hypertension and hypokab-
emia-induced ventricular arrhythmias. Both contribute to in-
Epidemiology creased morbidity and mortality.
The occurrence of hypokalemia is strongly dependent on the Hypokalemia contributes to hypertension in many patients
patient population. In otherwise healthy adults not receiving (3) but is frequently unrecognized as an important factor that
any medications, less than 1 % will develop hypokalemia, as may produce or worsen this serious health problem. Several
defined by a serum potassium level of less than 3.5 mEq/liter. lines of evidence reveal that potassium deficiency can increase
This very low frequency of hypokalemia is a testament to two blood pressure. Cross-sectional studies show that bow-potas-
factors: the adequacy of potassium in the typical Western diet, sium diets, especially in the presence of a high sodium intake,
and potent mechanisms for renal potassium conservation in are linked with the prevalence of hypertension (3). This asso-
states of potassium depletion. The presence of spontaneous ciation is most marked in African Americans. Epidemiologic
hypokabemia in otherwise healthy adults who are not receiving and prospective studies confirm this association in both healthy
any medications should suggest the possibility of underlying volunteers and in essential hypertensive patients (4). The an-
disease and indicate the need to search for an etiology. tihypertensive effect of thiazide diuretics is reduced by hypo-
Most cases of hypokalemia occur in the setting of specific kalemia and enhanced by potassium repletion (5). Finally,
disease states. Patients receiving diuretics are at the highest blood pressure may be more highly sodium-dependent in the
risk, with as many as 50% developing serum potassium levels presence of hypokalemia (3). Thus evidence strongly indicates
of less than 3.5 mEq/liter ( 1 ). As we will later discuss, thiazide that hypokalemia contributes to hypertension.
diuretics are more likely to cause hypokabemia than “1oop” or The mechanism of hypokalemia-induced hypertension is not
osmotic diuretics. Individuals with secondary hyperaldosteron- completely clear. One component of this type of hypertension
ism, whether due to congestive heart failure, hepatic insuffi- appears to be salt retention (4). Hypokalemia leads to intravas-
ciency, or nephrotic syndrome, constitute a second group at cular volume expansion as a result of renal NaC1 retention.
high risk. Finally, those patients with diseases that alter renal Hypokalemia may also potentiate the hypertensive effects of
potassium conservation through interaction with salt delivery 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
Correspondence to Dr. Charles S. Wingo, P.O. Box 100224, Division of
Nephrology, Hypertension and Transplantation. University of florida College variety of ventricular arrhythmias, including ventricular fibril-
of Medicine, Gainesville, FL 32610. 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- tes insipidus (23). Increased thirst is associated with increased
ease, appear to have the highest risk for hypokalemia-related central nervous system levels of angiotensin II, a hormone that,
complications (9, 10). Diuretic-induced hypokalemia is of par- besides its other effects, regulates thirst. Hypokalemia also
ticular concern because the incidence of sudden death in hy- impairs the kidney’s ability to concentrate the urine maximally
pertensive individuals treated with the thiazide diuretic hydro- (2). This appears to occur because hypokalemia causes defec-
chborothiazide is greater than that in matched control subjects tive activation of renal adenylate cyclase. preventing antidi-
( I 1 ). The effect is dose-related and is decreased by the con- uretic hormone-stimulated un nary concentration (24).
comitant use of potassium-sparing diuretics ( 1 1).
Renal Cystic Disease
Hormonal Hypokabemia, in association with hyperaldosteronism, can
Hypokalemia impairs both insulin release and end-organ lead to renal cystic disease. These cysts appear to arise in the
sensitivity to insulin, resulting in worsening hyperglycemia in collecting duct epithebium and are frequently associated with
diabetic patients ( I 2, 13). Hyperglycemia and diabetes meblitus interstitial scarring (25). Correcting the hypokalemia leads to
are major public health concerns in industrialized nations. cyst regression (25). The mechanism of cyst development is
Because increasing evidence suggests that end-organ compli- unclear. Hypokalemia beads to increased ammoniagenesis and
cations from diabetes mellitus are related to the degree of medubbary ammonia accumulation, which may activate the
hyperglycemia (14, 15), treatment of hypokalemia may de- complement system. It has been postulated that hypokalemia,
crease the devastating effects of diabetes meblitus. by leading to activation of complement in the medublary inter-
stitium, beads to interstitial fibrosis (26). Consistent with this
Muscular hypothesis is the observation that bicarbonate supplementation,
Potassium depletion can result in several muscular-related by inhibiting ammoniagenesis, decreases the interstitial fibro-
complications ( 16). Hypokabemia can hyperpolarize skeletal sis associated with hypokalemia; this effect is independent of
muscle cells, impairing their ability to develop the depobariza- changes in serum potassium (26).
tion necessary for muscle contraction. It can also reduce blood
flow to skeletal muscles. The reduced blood flow can predis- Hepatic Encephalopathv
pose patients to rhabdomyolysis (I 7), especially when vigor- Hypokalemia can contribute to the development, or worsen
ous exercise is combined with impaired blood-flow regulation. the symptoms, of hepatic encephabopathy. One toxin that
The combination of these effects frequently leads to muscle causes hepatic encephabopathy is ammonia, and hypokalemia
weakness, easy fatigabibity, cramping, and myalgias (16). Pa- increases proximal tubule ammoniagenesis (19). Approxi-
ralysis, although uncommon, can occur in cases of profound mately 50% of proximal tubule ammonia production is re-
potassium deficiency (16). turned to the systemic circulation via the renal veins. In hepatic
insufficiency, the increased systemic burden of ammonia re-
Acid-Base subting from increased renal ammoniagenesis can be sufficient
Hypokalemia can profoundly affect systemic acid-base ho- to cause the development or worsen the symptoms of hepatic
meostasis through its effects on multiple components of renal encephabopathy (27).
acid-base regulation. The most common abnormality is meta-
bolic alkabosis. Hypokalemic metabolic alkabosis results from Physiology of Potassium Homeostasis
the effects of hypokabemia on several components of net acid Serum potassium concentration is a balance between intake,
excretion. The most direct effects include stimulation of prox- excretion, and distribution between the intra- and extracellular
imal tubule HCO1 reabsorption and ammoniagenesis (18,19); space. The average daily potassium intake in a typical Western
collecting duct proton secretion, possibly via stimulation of diet is 70 mEq. Under normal conditions, excretion equals
both the gastric (HKa1) and cobonic (HKa,) isoforms of H- intake, with approximately 90% of potassium excreted in the
KtATPase (20); and decreasing urinary citrate excretion. urine and the vast majority of the remainder in the stool.
Hypokalemia may produce these widespread effects on renal Distribution of potassium between the intra- and extracelbubar
acid-base homeostasis because of intracellular acidification space plays an important role in potassium homeostasis.
(2 1 ). Hypokabemia also inhibits abdosterone secretion (22), Most potassium is present in the intracellular space. Intra-
which possibly minimizes such effects on acid-base homeosta- cellular potassium averages 120 to 140 mEq/liter, largely as a
sis. In rare cases, severe hypokabemia leads to respiratory result of active potassium uptake by Na4-K-ATPase. Ap-
muscle weakness and the development of respiratory acidosis. proximately 98% of total body potassium is present in the
In patients with hypokalemia as a result of renal tubular aci- intracellular space. Consequently, small changes in the distri-
dosis, the concomitant development of respiratory acidosis can bution of potassium between the intra- and extracellular fluid
be life-threatening. spaces result in proportionally large changes in extracelluar
potassium concentration. The large intracellular potassium
Polvuria store functions to minimize changes in extracellular potassium
Another complication of hypokabemia is the development of in states of potassium deficiency. Under these conditions,
mild polyuria, averaging 2 to 3 liters per day (2). The polyuria potassium shifts from the intra- to the extracellular fluid,
is related to both increased thirst and mild nephrogenic diabe- apparently to reduce changes in the transmembrane potassium
Hypokalemia: Diagnosis and Treatment 1 181
gradient. With potassium depletion, certain tissues, notably
Lumen Peritubular space
muscle, exhibit a more rapid reduction in intracellular potas-
sium than do others, such as the brain. As a result, small
Na
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 K
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. H
Potassium is present in most foods in varying amounts. K
Although the typical dietary intake averages 70 mEq/d, there is
considerable variation, depending on the dietary preferences of K
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-
H
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). HCO3
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
Figure 1. Model of potassium transport in the cortical collecting duct.
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
sium channel (20). This provides a sensitive mechanism that
duct (3 1 ). The CCD both secretes and reabsorbs potassium,
allows active potassium reabsorption when necessary.
whereas the outer and inner medullary collecting ducts
Recent studies show that the B cell, generally believed to
(OMCD and IMCD, respectively) reabsorb potassium (30,31).
mediate bicarbonate secretion and recovery from metabolic
At least three cell types are present in the CCD, all of which
alkabosis, may also contribute to potassium homeostasis. Re-
may contribute to potassium homeostasis. Figure 1 summarizes
sults from our laboratories and those of others provide strong
the transporters involved in CCD potassium transport. The
functional evidence for an apical H-K-ATPase in this cell
principal cell is the most numerous cell, comprising 60 to 70%
(32,33). We have also shown that there is coupling of chloride
of the CCD, and is believed to be responsible for potassium
reabsorption by the apical CF7HCO3 exchanger to the apical
secretion. Potassium is actively taken up into the cell via a
HtKATPase (3 1 ). Parallel operation of apical HKt
basolateral Na-K-ATPase and secreted down its electro-
ATPase and apical Cl/HCO3 exchange provide a new model
chemical gradient into the luminal fluid (urine) via an apical
for active KC1 reabsorption. Additionally, inhibition of H-
potassium channel. Additional evidence indicates that potas-
K-ATPase reduces CCD amiloride-insensitive sodium reab-
sium secretion is codependent on Cl secretion. Electrogenic sorption, suggesting that sodium can substitute for potassium
sodium reabsorption generates a lumen-negative charge or on the CCD WKtATPase (3 1). In hypokalemia, the in-
voltage. Because this negative charge increases the electro- creased CCD H-K-ATPase activity, in combination with
chemical gradient for potassium secretion, the rate of sodium sodium substituting for potassium on the H-K-ATPase,
reabsorption also regulates the rate of potassium secretion. could lead to net NaCl reabsorption, volume expansion, and the
In contrast to the principal cell, the CCD A- and B-type increased blood pressure that is observed clinically.
intercalated cells (A cell and B cell, respectively), which com- The OMCD and IMCD do not transport potassium under
prise the remainder of the CCD, are modeled to reabsorb normal conditions, but in response to hypokalemia or potas-
luminal potassium. Potassium reabsorption occurs through pro- sium deficiency can reabsorb potassium. This appears to occur
cesses different from those of principal cell potassium secre- via mechanisms similar to the CCD A cell, e.g. , luminal
tion. An apical H4KtATPase secretes protons and reabsorbs potassium uptake by an apical HtKtATPase and basolateral
buminab potassium, contributing to urinary acidification and potassium exit via a basolaterab potassium channel (20). As
potassium reabsorption (3 1 ). In the presence of normal potas- noted previously, at least two isoforms of HtKtATPase are
sium, most reabsorbed potassium is recycled across the apical present in the collecting duct: HKa1 and HKa2 (20). HKa1
membrane, resulting in little net potassium transport. In re- may be regulated to a greater extent by hypokalemia than
sponse to potassium deprivation, potassium can exit the cell via HKct, in the CCD, whereas the opposite appears to be true in
a basolateral barium-sensitive transporter, presumably a potas- the OMCD (34,35).
I I 82 Journal of the American Society of Nephrology
Despite the presence of active potassium reabsorptive trans- “escape” is unknown. The decreased end-organ responsiveness
porters in the CCD, OMCD, and IMCD, the urinary potassium to insulin in adult-onset diabetes may contribute to the hyper-
level is generally not lower than 15 to 20 mEqlliter. This may kalemia frequently seen by altering the distribution of potas-
reflect both water reabsorption, which exceeds potassium re- sium between the intra- and extracellular space.
absorption, and persistent potassium secretion in the CCD. A second, clinically common cause of potassium redistribu-
Little potassium is excreted in the stool under normal con- tion is aldosterone. Aldosterone induces cellular uptake of
ditions because of a low stool volume and a low stool potas- potassium through a variety of effects, but much more slowly
sium concentration. Conditions that increase stool potassium than insulin. Aldosterone stimulates the production of Nat
concentration, such as chronic renal failure and hyperkalemia, KtATPase, which results in increased enzyme activity and
or stool volume, such as diarrhea, increase fecal potassium the transport of potassium from the intracellular to extracellular
excretion. Chronic renal failure can cause adaptive changes in space (37-39). In addition, as will be discussed below, aldo-
stool potassium content, such that as much as 20 to 30 mEq/d sterone also regulates renal potassium transport. Thus hyper-
can be excreted by this route. Decreases in stool potassium aldosteronism causes hypokalemia as a result of the combined
content do not materially affect the response to hypokalemia effects of redistribution and stimulation of renal potassium
because the basal level of stool potassium excretion is normally clearance.
small. The final major hormonal cause of potassium redistribution
includes sympathomimetic agents, ,-adrenergic agonists, do-
Causes pamine, dobutamine, and theophylbine. The first three agents
The accurate treatment of hypokalemia requires correct directly stimulate the cellular uptake of potassium and also
identification of the cause. Hypokabemia can be associated stimulate insulin release, whereas theophylbine indirectly slim-
either with normal or decreased total body potassium content. ulates potassium uptake (36,37). Sympathomimetic-induced
Normal total body potassium with hypokalemia is a result of redistribution leading to hypokalemia is important in acute
potassium redistribution from the extracellular to the intracel- myocardial ischemia and acute asthma therapy. Myocardial
lular space. Total body potassium depletion can result from ischemia commonly increases sympathetic tone, whether as a
either renal or extrarenal potassium losses. We suggest that the direct result of the ischemia, decreased cardiac output, or from
clinician evaluating a patient with hypokabemia consider four either the pain or the anxiety related to the ischemia. Cellular
broad groups of etiologies: pseudohypokalemia, redistribution, potassium redistribution leading to hypokalemia can then in-
extrarenal potassium loss, and renal potassium loss. crease the risk of ventricular arrhythmia and sudden death.
Treatment of the asthma patient with 3-adrenergic agonists or
Pseudohypokalemia theophylbine can bead to potassium redistribution, hypokale-
Abnormal white blood cells, if present in large enough mia, and impairment of respiratory muscle contractile ability.
numbers, can take up extraceblubar potassium when stored for Patients may develop CO2 retention, or, even more seriously,
prolonged periods at room temperature, resulting in a low decreased wheezing, as a result of decreased air movement,
measured plasma potassium level. The apparent hypokalemia which might be misinterpreted as an overall improvement in
is an artifact of the storage procedure and is referred to as the patient’s condition. Another clinical concern is premature
“pseudohypokalemia” (36). The most common underlying dis- labor therapy involving 3-agonists. These patients frequently
ease state is acute myelogenous leukemia. Rapid separation of do not have oral intake for prolonged periods, providing a
the plasma or storing the sample confirms
at 4#{176}C the diagnosis, setting for the development of severe hypokalemia.
avoids this artifact, and prevents inappropriate treatment. Hypokabemia as a result of potassium redistribution can also
occur from acute anabolic states. Cells contain approximately
Redistribution 130 mEq/biter of potassium; consequently, stimulation of either
More than 98% of total body potassium is present in the cell hypertrophy or cell production can cause rapid movement
intracellular fluid, predominantly in skeletal muscle cells, en- of potassium from the extra- to the intracellular space. Rapid
abling small changes in the distribution of potassium to alter cell production can occur in acute leukemia and high-grade
the extracellular concentration markedly. Certain hormones, lymphomas. Acute stimulation of cell production can result
particularly insulin, aldosterone, and sympathomimetics, are from granulocyte macrophage colony-stimulating factor treat-
the most common cause of redistribution-induced hypokale- ment of refractory anemia or the initial treatment of pernicious
mia. Insulin activates NaKtATPase, which results in active anemia with vitamin 2 (40). The resultant cell production can
potassium uptake (37). Acute insulin administration produces cause acute hypokabemia and in some individuals has resulted
rapid potassium shifts from the extra- to intracellular space, in arrhythmias and sudden death (41).
resulting in hypokalemia. This problem is most frequently Rarely, hypokalemia secondary to redistribution with en-
encountered in the treatment of diabetic ketoacidosis. Insulin- hanced cellular uptake can be a result of hypokalemic periodic
induced redistribution of potassium is the physiologic principle paralysis (16,36). Both familial and sporadic cases have been
underlying the administration of insulin with glucose to pa- reported. Most hereditary cases follow an autosomab dominant
tients with hyperkabemia. In contrast to acute insulin adminis- distribution, although an X-binked recessive form has been
tration, chronically high insulin bevels, as occur in insubinomas, documented. In Asians there is a high frequency of this con-
do not typically cause hypokalemia; the mechanism of this dition associated with thyrotoxicosis ( 16). Attacks frequently
Hypokalemia: Diagnosis and Treatment 1 183
commence during the night or the early morning and are Table 1. Causes of renal potassium loss
characterized by flaccid paralysis of all extremities, which may
persist from 6 to 24 h (36). A genetic defect in a dihydropyr- Drugs
idine-sensitive calcium channel has been determined to cause diuretics
thiazide diruetics
certain cases of this disorder (42). Carbonic anhydrase inhib-
itors (acetazolamide 250 mg four times daily), beta blockers, or loop diuretics
spironolactone may prevent attacks. osmotic diuretics
Finally, hypokalemia has been reported in connection with antibiotics
chboroquine and barium intoxication. The latter effect can be penicillin and penicillin analogues
explained by the known action of barium to block potassium amphotericin B
aminoglycosides
channels and, hence, cellular potassium exit (16).
Hormones
aldosterone
Non-Renal Potassium L05s glucocorticoid-remediable hypertension
Both the skin and the gastrointestinal tract can transport glucococorticoid-excess states
significant amounts of potassium. Under normal conditions, B icarbonaturia
net fluid loss from these organs is small, limiting net potassium distal renal tubular acidosis
boss. Occasionally, in cases such as prolonged exertion in hot, treatment of proximal renal tubular acidosis
dry environments or chronic diarrhea. severe potassium loss correction phase of metabolic alkabosis
can occur, leading to hypokabemia (43). In most of these cases, Magnesium deficiency
intravascular volume depletion is present also, leading to sec- Other less common causes
ondary hyperabdosteronism, stimulation of renal potassium ex- cisplatin
cretion, and further worsening of the potassium deficit (43). carbonic anhydrase inhibitors
Prolonged loss of gastric contents, whether from vomiting or toluene
nasogastric suctioning, can lead to hypokalemia. A small part leukemia
of this potassium loss is direct because these body fluids diuretic phase of acute tubular necrosis
contain 5 to 8 mEqfliter potassium. More importantly, concom- Intrinsic renal transport defects
itant alkabosis and intravascular volume depletion contribute to Bartter’s syndrome
renal potassium loss. Metabolic alkabosis results in bicarbona- Gitelman’s syndrome
tuna, which increases potassium excretion both directly, as a Liddle’s syndrome
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
Drugs. Many medications can cause renal potassium
stimulation of the renin-angiotensin-aldosterone system. In ad-
wasting, including diuretics and some antibiotics. Both thiazide
dition, potassium reabsorption by the collecting duct is affected
and loop diuretics increase urinary potassium excretion; when
by acid-base status. Thus metabolic alkabosis increases renal
factored for their natriuretic effect, thiazide diuretics are more
potassium excretion by increasing potassium secretion and
potent kabiuretic agents (46). In part this is because loop
probably by direct suppression of potassium reabsorption.
diuretics have a shorter pharmacologic half-life, enabling renal
Diarrhea, whether secretory or as a result of laxative abuse,
potassium conservation during periods between drug adminis-
can cause profound gastrointestinal potassium loss. Patients
tration, but may also reflect their site of action in the distal
with laxative abuse may deny the condition because of over-
convoluted tubule with secondary effects on flow to the pri-
concern about body image and may also abuse diuretics (44).
mary site of potassium secretion in the CCD. All diuretics,
Sigmoidoscopy and urine screening for diuretics may be
except the potassium-sparing diuretics, induce potassium-wast-
needed to confirm the diagnosis. The former will reveal mel-
ing by increasing CCD luminal flow rate, luminal sodium
anosis cobi in patients who have been using anthracene laxa-
delivery, and luminal electronegativity, which are the primary
tives, such as senna, cascara and aloe, for more than 4 months
determinants of potassium secretion by the CCD. They may
(45). laxatives
If phenolphthabein are being used, alkalinization
also induce intravascular volume contraction, resulting in sec-
of the stool to pH 9 will produce a pink color. If magnesium-
ondary hyperaldosteronism and further stimulation of renal
or phosphate-containing cathartics, such as magnesium citrate
potassium secretion. The incidence of diuretic-induced hypo-
or sodium phosphate, are suspected, direct measurement of
kalemia is both dose- and treatment duration-related.
these compounds in the stool can confirm the diagnosis.
Antibiotics can increase urinary potassium excretion by a
variety of mechanisms. High-dose penicillin and some penicil-
Renal Potassium Loss bin analogues, such as carbenicillin, oxacilbin, and ampiciblin,
The most common cause of hypokalemia is excess renal increase distal tubular delivery of a non-reabsorbable anion,
potassium loss. This can occur either because of medications, thereby increasing urinary potassium excretion (47). Cisplatin
endogenous hormone production or, in rare conditions, intrin- is another drug that may induce hypokalemia via an increase in
sic renal defects. Table 1 summarizes these causes. 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 cessive abdosterone production ensures. In congenital adrenal
collecting duct cells, which increases potassium secretion and hyperplasia, there is the congenital absence of either 1 1f3-
results in potassium wasting (36). Tobuene exposure, which can hydroxybase or I 7a-hydroxylase, resulting in excess hypotha-
result from sniffing certain glues, can also cause hypokalemia, lamic corticotropin-releasing hormone (CRH) secretion and
presumably by renal potassium wasting (2). Aminoglycosides persistent adrenal synthesis of 1 1-deoxycorticosterone, a p0-
can cause hypokalemia either in the presence or absence of tent mineralocorticoid (53). This condition can be recognized
overt nephrotoxicity. The mechanism is not completely under- by the associated effects on sex steroid production. 1 1 f3-hy-
stood but may rebate to stimulation of magnesium depletion droxylase deficiency results in increased androgen production,
(see below) (36) or direct inhibition of potassium reabsorption. leading to early viribization of men and women. In contrast,
However, most antibiotics do not cause hypokabemia, and 17a-hydroxylase deficiency inhibits sex hormone metabolism,
some, such as trimethoprim and pentamidine, can cause hy- leading to incomplete development of sexual characteristics.
perkalemia by inhibition of apical sodium channels in the Under rare conditions, glucocorticoids function as mineralo-
CCD. corticoids, causing hypokalemia and hypertension. Glucocor-
Endogenous hormones. Endogenous hormones are very ticoids, such as cortisol, have a high affinity for the mineralo-
important causes of hypokalemia. Aldosterone is perhaps the corticoid receptor but are normally prevented from binding to
most important hormone regulating total body potassium ho- it because the enzyme 1 1/3-hydroxysteroid dehydrogenase
meostasis, and excess abdosterone production or effect fre- (1 l-HSDH) converts cortisol to cortisone, which does not
quently leads to hypokalemia. The CCD is the primary site in bind to the minerabocorticoid receptor (54). Some drugs, such
the kidney where aldosterone regulates potassium transport, as glycerrhetinic acid (found in carbenoxobone, chewing to-
and the CCD principal cell is the CCD cell responsible for bacco, and licorice), inhibit 1 1 f3-HSDH, allowing cortisol to
potassium secretion (30,3 1 ). Aldosterone increases principal exert minerabocorticoid-bike effects in the distal nephron (55).
cell apical sodium conductance, basolateral NatKtAlPase Infrequently, circulating cortisol can exceed the metabolic ca-
activity, and electrogenic sodium absorption in the CCD. These pacity of 1 l3-HSDH and cause hypokalemia. This can occur
effects increase the net luminal-negative charge or transepithe- either in severe cases of Cushing’s disease or in the ectopic
hal voltage. which increases the electrochemical gradient for ACTH syndrome (56).
potassium movement from the principal cell cytoplasm to the Magnesium depletion. Concomitant magnesium defi-
luminab fluid. Thus aldosterone, via actions on apical Na ciency may prevent correction of hypokalemia (36). This is
channels and basolateral NatKtATPase, increases CCD particularly true with diuretic-induced hypokabemia and in
principal cell potassium secretion. Although potassium reab- certain cases of aminoglycoside- and cisplatin-induced potas-
sorption can occur in the OMCD and IMCD (3 1 ), the reab- sium wasting, hypokalemia associated with lysozymuria in
sorptive capacity of these segments, particularly with normal acute leukemia, and in individuals with Gitebman’s syndrome
Na intake, is less than the rate of potassium secretion by the (see below). Supplementation with magnesium oxide, 250 to
CCD. Thus the net effect of aldosterone is to enhance renal 500 mg by mouth four times daily, may serve to correct both
potassium clearance. the magnesium and potassium deficiency.
Hyperabdosteronism can be either primary or secondary. Intrinsic renal defects. Intrinsic renal defects beading to
Primary hyperaldosteronism results in cases of hypertension hypokalemia are rare but have led to important advances in our
(48), predominantly because of the sodium-retaining effects of understanding of renal solute transport. In 1962, Bartter de-
aldosterone, but the associated hypokalemia may also contrib- scribed the association of hypokabemia, hypomagnesemia, hy-
ute by sensitizing the vasculature to neurohumoral regulators perreninemia, and metabolic alkabosis (57). Recent studies
of blood pressure. Because angiotensin II regulates adrenal show that these patients can be divided into two groups now
gland aldosterone synthesis, conditions involving elevated an- known as either Bartter’s syndrome or Gitebman’s syndrome.
giotensin II levels will typically involve hyperabdosteronism. Patients with Bartter’s syndrome are hypercalciuric and present
This may occur in a variety of conditions, such as decreased at an early age with severe volume depletion. This condition
oral intake, diuretic use, vomiting, or diarrhea. Activation of appears to be a result of defects in either the renal Na-K-2C1
the renin-angiotensin-aldosterone system, as may occur in ma- cotransporter gene, NKCC2 (58), or the ATP-sensitive potas-
lignant hypertension (49),
renovascubar hypertension (50), and sium channel, ROMK, both of which are necessary for loop of
renin-secreting tumors (5 1 ), can also lead to secondary hyper- Henle sodium reabsorption (59). Gitelman’s syndrome features
aldosteronism with subsequent hypokalemia. The secondary hypocalciuria, hypomagnesemia, and milder clinical manifes-
activation of the renin-angiotensin-aldosterone system sug- tations and presents at a later age. This syndrome appears to be
gests that potassium redistribution significantly contributes to a result of mutations in the thiazide-sensitive NaC1 cotrans-
the hypokalemia. porter (60). Both Bartter’s syndrome and Gitelman’s syndrome
Rarely, genomic defects lead to excessive aldosterone pro- are associated with hypotension and intravascular volume de-
duction. In gbucocorticoid-remediable aldosteronism, an adre- pbetion due to renal sodium-wasting. In contrast, Liddle’s syn-
nocorticotropin (ACTH)-regulated gene is linked to the coding drome is associated with hypertension, hypokalemia, metabolic
sequence of the aldosterone synthase gene, the rate-limiting alkalosis, and suppressed renin and aldosterone levels (61).
enzyme for aldosterone synthesis (52). Aldosterone synthase is This condition appears to be a result of defects in the CCD
no longer regulated by the renin-angiotensin system, and ex- principal cell apical sodium channel, ENaC, leading to an
Hypokalemia: Diagnosis and Treatment 1 185
increased open probability, excessive sodium reabsorption, and coronary artery disease or on digitalis treatment, and the pa-
subsequent volume expansion, hypertension, and suppression tient with an acute myocardial infarction and significant yen-
of renin and aldosterone (62). Renal potassium wasting occurs tricular ectopy. In such cases, administration of 5 to 10 mEq of
because increased CCD sodium reabsorption beads to increased KC1 over 15 to 20 mm may be used to increase serum potas-
luminal electronegativity and an increased electrochemical gra- sium to a level above 3.0 mEq/liter. This dose can be repeated
dient for potassium secretion. as needed. Close, continuous monitoring of the serum level and
Bicarbonaturia. The last major cause of renal potassium the electrocardiogram (ECG) are necessary to reduce the risk
wasting is bicarbonaturia. Bicarbonaturia can result from either of hyperkalemia.
metabolic alkabosis, distal renal tubular acidosis, or treatment In most other conditions, the choice of parenteral versus oral
of proximal renal tubular acidosis. In each case, distal tubular therapy is dependent on the ability of the patient to take oral
bicarbonate delivery increases potassium secretion. Certain medication and the ability of the 01 tract to function appropn-
cases of distal renal tubular acidosis may reflect primary de- ately. In many cases, such as myocardial infarction, paralysis,
fects in potassium reabsorption. and hepatic encephabopathy, the patient may be unable to take
oral potassium safely or questions may exist about the speed of
Diagnostic Approach 01 tract absorption. In these cases, KC1 can be given intrave-
In approaching the patient with hypokabemia, we recom- nously. When given via the intravenous (IV) route, replace-
mend using the approach outlined above. Figure 2 summarizes ment can be given safely at a rate of 10 mEq KCI per hour. One
our diagnostic algorithm. First, ensure that pseudohypokal- study has found that 20 mEq KCI per hour causes the serum
emia, due to potassium uptake by abnormal leukocytes, is not
potassium bevel to increase by an average of 0.25 mEqIL per
responsible for the reported reduction in serum potassium.
hour (63). If more rapid replacement is necessary, then 40 mEq
Second, consider whether redistribution of potassium from the
per hour can be administered through a central catheter with
extra- to the intracellular space accounts for the hypokalemia.
continuous ECO monitoring. However, replacement therapy
If neither of this possibilities is present, the hypokalemia
should be administered orally if possible.
probably represents total body potassium depletion resulting
The parenterab fluids used for potassium administration can
from either skin, gastrointestinal (GI) tract, or renal potassium
affect the response. In nondiabetic patients, IV dextrose in-
boss. Excessive potassium loss from the skin results from
creases serum insulin levels, which can cause redistribution of
prolonged exertion in hot, dry environments where sweat loss
potassium from the extra- to the intracellular space. As a result,
is high. This diagnosis can be readily made from the history
providing KC1 in glucose solutions such as DW can paradox-
under most conditions. GI tract potassium loss occurs from
ically lower serum potassium levels (64). In most cases, par-
either diarrhea, vomiting, nasogastric suction, or a 01 fistula.
enteral KCI should be provided in normal saline. If barge
Occasionally, patients may be reluctant to admit to self-in-
concentrations of KC1 are added to the parenteral fluid, then
duced diarrhea from catharctic use, and the diagnosis may need
KC1 might be administered in half normal saline to avoid
to be confirmed by sigmoidoscopy or direct testing of the stool.
administration of a hypertonic solution.
Renal potassium loss is most frequently a result of diuretic use.
Usually hypokalemia can be treated successfully with oral
Secondary hyperaldosteronism from cardiac or hepatic disease
therapy. Patients with diuretic-induced hypokalemia should be
or a nephrotic syndrome is a common cause of renal potassium
re-evaluated to reconsider the need for diuretics. If continual
loss. Hypomagnesemia-induced hypokalemia causes renal po-
use is required, assessment of sodium intake should be pre-
tassium wasting and is frequently a complication of diuretic
useage. Rarer causes of renal potassium loss include renal formed. Excessive sodium intake accentuates diuretic-induced
tubular acidosis (RTA), diabetic ketoacidosis, and ureterosig- hypokabemia. If this is not the case concomitant use of the
moidostomy. Finally, primary aldosteronism, surreptitious di- potassium-sparing diuretics amiloride, triamterene, and spi-
uretic use, and either Bartter’s or Gitelman’s syndrome may ronolactone may be considered. When oral replacement ther-
need to be considered. apy is required, KCI is the preferred drug in all patients except
those with metabolic acidosis. In the latter condition, either
Correction potassium bicarbonate or potassium citrate should be used. The
The risks associated with hypokabemia must be balanced chloride salt of potassium minimizes renal potassium bosses. If
against the risks of therapy when the appropriate approach to indicated for other reasons, beta blockers or angiotensin-con-
the patient is determined. Usually, the primary short-term risks veIling enzyme inhibitors can assist in maintaining potassium
are cardiovascular, and the most important is the proarrhyth- levels.
mogenic effect of hypokalemia. In contrast, the primary risk of Finally, hypomagnesemia can lead to renal potassium wast-
overaggressive replacement is the development of hyperkabe- ing and refractoriness to potassium replacement (36). In these
mia with resultant ventricular fibrillation. Occasionally, incor- patients, correction of the hypokalemia does not occur until the
rect therapy of hypokalemia can lead to paradoxical worsening hypomagnesemia is corrected (65). Patients with diuretic-in-
of the hypokabemia. duced hypokabemia, unexplained hypokalemia, or diuretic-in-
Conditions requiring emergent therapy are rare. The classic duced hypokabemia should have their serum magnesium bevels
causes include severe hypokalemia in a patient preparing to checked and magnesium replacement therapy begun if mdi-
undergo emergent surgery, particularly in patients with known cated.
I I 86 Journal of the American Society of Nephrology
E
C
b
hi
0
hi
0 0
E
0
hi
ci
hi
0
bi E
I hi
E E
0
0
hi
C 0
hi
C
hi
C E
hi
hi
0
V hi
hi
0
C 0
ci E
ci
C z
E
ci)
ci
0
E
N
V
E
0
ci)
0
hi
hi
C,)
Figure 2. Diagnostic evaluation of hypokalemia.
Hypokalemia: Diagnosis and Treatment I 187
Note added in proof: A recent meta-analysis concluded that 18. Sobeimani M, Bergman IA, Hosford MA, McKinney TD: Potas-
reduced potassium intake may play an important role in the sium depletion increases luminal Na /H exchange and baso-
genesis of hypertension (Whelton PK, He J, Cutler IA, Bran- lateral Na:CO3 :HCO3 cotransport in rat renal cortex. J Clin
Invest 86: 1076-1083, 1990
cati FL, Appel LI, Follmann D, Klag MI: Effects of oral
19. Tizianelbo A, Garibotto G, Robaudo C, Saffioti 5, Pontremoli R,
potassium on blood pressure: Meta-analysis of randomized
Bruzzone M, Deferrari G: Renal ammoniagenesis in humans
controlled clinical trials. JAMA 277: 1624-1632, 1997).
with chronic potassium depletion. Kidney Int 40: 772-778, 1991
20. Wingo CS. Smolka Al: Function and structure of H-K-AIPase in
the kidney [Editorial]. Am J Phvsiol 269: Fl-Fl6, 1995
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