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Home , Hypokalemia

DISEASEOF THE MONTH

Hypokalemia-Consequences , Causes , and Correction

I. DAVID WEINER and CHARLES S. WINGO Division of Nephrology, and Transplantation, University of Florida College of , 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 to sudden death. The correction of hypokabemia 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 . 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 . 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 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 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 , 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). -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 , can Hypokalemia impairs both 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 (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 (16). Pa- increases 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- 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 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 of hypokabemia is the development of in states of potassium deficiency. Under these conditions, mild , 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 -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 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 , KtATPase, which results in increased enzyme activity and or stool volume, such as , 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 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 at 4#{176}Cconfirms 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 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 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 . 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 of all extremities, which may Drugs persist from 6 to 24 h (36). A genetic defect in a dihydropyr- idine-sensitive calcium channel has been determined to cause diuretics certain cases of this disorder (42). Carbonic anhydrase inhib- thiazide diruetics itors ( 250 mg four times daily), beta blockers, or loop diuretics 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 channels and, hence, cellular potassium exit (16). aminoglycosides Hormones aldosterone Non-Renal Potassium L05s glucocorticoid-remediable hypertension Both the skin and the 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 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, deficiency intravascular volume depletion is present also, leading to sec- Other less common causes ondary hyperabdosteronism, stimulation of renal potassium ex- cretion, and further worsening of the potassium deficit (43). carbonic anhydrase inhibitors Prolonged loss of gastric contents, whether from 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 , 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 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). 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 -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 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 1f3-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 gene, the rate-limiting , 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 . 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- tassium wasting and is frequently a complication of diuretic use is required, assessment of sodium intake should be pre- 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, , surreptitious di- potassium-sparing diuretics amiloride, , 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 . In the latter condition, either Correction potassium bicarbonate or 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 , particularly in patients with known cated. I I 86 Journal of the American Society of Nephrology

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