A Practical and Pathophysiologic Approach to Hypokalemia · A Practical and Pathophysiologic...

Review Article

14 Hong Kong J Nephrol • April 2008 • Vol 10 • No 1

Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei,Taiwan.Correspondence to: Dr. Shih-Hua Lin, Division of Nephrology, Department of Medicine, Tri-Service General Hospital,No. 325, Section 2, Cheng-Kung Road, Taipei 114, Taiwan.Fax: (+886) 2-87927134; E-mail: [email protected]

A Practical and Pathophysiologic Approach to Hypokalemia

Shih-Hua Lin

Hypokalemia is not an isolated disease but an associated finding in a vast number of different diseases; it posesa great challenge in correct diagnosis and proper management. Hypokalemia usually arises from a shift ofpotassium (K+) into cells and/or a net loss of K+. Besides a detailed history and physical examination,measurement of K+ excretion rate with freshly-voided and/or 24-hour urine and assessment of blood acid-basestatus can help discriminate between the various causes of hypokalemia. In patients with a low rate of K+

excretion, hypokalemia can be due to an acute shift of K+ into cells, intestinal/sweating K+ loss, or prior renalK+ excretion. In patients with a high rate of K+ excretion, there may be either increased flow rate or increasedK+ secretion, seen with fast sodium (Na+) or slow chloride (Cl–) disorders, in the cortical collecting ducts(CCD). An increased flow rate in the CCD arises from increased osmole excretion (whether solutes orelectrolytes). Patients with fast Na+ disorders have a high extracellular fluid (ECF) volume and thus high bloodpressure associated with a state of high mineralocorticoid activity. Measurement of renin activity, aldosterone,and cortisol levels in plasma helps distinguish between the causes. Patients with slow Cl– disorders usuallyhave low to normal ECF volume and blood pressure and are usually associated with abnormal acid-base states.In patients with metabolic alkalosis, urine Na+ and Cl– excretion rate reveal the basis for renal Na+ wasting anddistinguish it from non-renal Na+ loss. In patients with hyperchloremic metabolic acidosis, an assessment ofthe ammonium excretion rate (NH4

+) separates those with renal tubular acidosis (low NH4+ excretion) from

those with other causes. The treatment of hypokalemia depends on the degree and timing of hypokalemia,clinical manifestations, underlying causes, and potential risks from associated conditions. [Hong Kong J Nephrol2008;10(1):14–26]

Key words: acid-base, aldosterone, ammonium, blood pressure, hypokalemia, renin, urine electrolyte

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Hong Kong J Nephrol • April 2008 • Vol 10 • No 1 15

Practical and pathophysiologic approach to hypokalemia

INTRODUCTION

Potassium (K+), a major intracellular cation, functionsin critically maintaining the osmotic equilibrium of thecell and the electrical gradient across the cell membrane.Most of the cellular K+ in the body (~50 mmol/kg, 98%)resides primarily in the skeletal muscles (3,000 mmol),red blood cells (300 mmol), and liver (200 mmol). Incontrast, the total K+ content in the extracellular fluid(ECF) is very low (< 1 mmol/kg, approximately 2%)and similar to the daily dietary K+ intake and renalexcretion of K+. Plasma K+ concentration represents afunction of total body K+ and the distribution betweenintracellular fluid (ICF) and ECF stores. Hypokalemiausually arises from redistribution of K+ from ECF toICF stores and/or a consequence of total body K+

depletion. The most significant effects of hypokalemiaare on the cardiovascular, neuromuscular, renal andmetabolic functions (Table 1) [1–6]. In addition,hypokalemia is also associated with increased mortality,likely due to the profound effects on arrhythmogenesis,blood pressure, and cardiovascular morbidity.

Hypokalemia is the most common electrolyteabnormality encountered in clinical practice. Oneshould understand that hypokalemia per se is not aspecific disease but an associated finding in a largenumber of different diseases. The rapid identificationof its underlying causes with appropriate managementis still challenging. Although several articles abouthypokalemia have been extensively reviewed [7–12],

I discuss a more practical and pathophysiologicapproach to hypokalemia and introduce some importantconcepts in managing hypokalemia in this review.

K+ HOMEOSTASIS

K+ concentration in the ICF is close to 35-fold greaterthan that in the ECF. Renal excretion in response to aK+ load is relatively slow (approximately 50% withinthe first 4 hours). To avoid retained K+ in the ECF andthe ensuing hyperkalemia, there must be sensitiveregulatory mechanisms to dampen plasma K+

concentration before complete renal K+ excretion. Themechanisms regulating the distribution of K+ betweenthe ICF and ECF are known as the internal K+ balancein contrast to the external balance of renal K+ excretion.Derangements in either the internal balance (e.g. K+

shift) or external balance (e.g. K+ wasting) can resultin hypokalemia [13,14].

Regulation of K+ between ICF and ECFThe movement of K+ ions across cell membranes hastwo requirements: (1) a driving force; (2) a K+ ionchannel in that membrane (Figure 1).

Driving force: The force driving K+ shift into cellsis the more negative voltage in cells. This is created byNa-K-ATPase. Na-K-ATPase extrudes three sodiumions (Na+) for every two K+ ions that enter cells, thusproducing a net export of positively charged ions [15].

Table 1. Clinical signs and symptoms of hypokalemia

Cardiovascular● ECG changes: flattened or inverted T waves, prominent U wave, depressed, prolonged QT interval● Arrhythmias: atrial tachycardia with or without block, premature ventricular contraction, ventricular tachycardia and/or fibrillation,

torsades de pointes, atrioventricular block or dissociation● Hypertension

Neurologic/neuromuscular● Neurologic: paresthesia, decreased deep tendon reflexes● Skeletal muscle: cramp, myalgia, rhabdomyolysis, weakness, paralysis● Gastrointestinal tract: reduced gastrointestinal motility (nausea, vomiting, constipation, paralytic ileus)● Genitourinary tract: hypomotility with dilatation of bladder (hypotonic bladder)

Renal● Metabolic alkalosis due to increased HCO

3– reabsorption and ammoniagenesis in the proximal tubule, decreased urinary citrate excretion,

increased H+ secretion in the cortical collecting duct● Impaired medullar concentration● Renal cystic disease, interstitial scarring, and renal insufficiency● Increased renal stone formation

Metabolic● Decreased insulin release with hyperglycemia● Impaired end-organ sensitivity to insulin with carbohydrate intolerance● Inhibited aldosterone secretion, but stimulated renin secretion● Worsened hepatic encephalopathy

S.H. Lin


Because impermeable ICF anions (macromolecularphosphates such as RNA, DNA, phospholipids) cannotfollow the Na+ movement, a negative intracellularvoltage is generated. The main hormones that increasethe activity of Na-K-ATPase include

2-adrenergic

agonists, insulin and thyroid hormone [15,16]. Increasesin the concentration of Na+ inside cells can also activateNa-K-ATPase. For instance, insulin stimulates amembrane Na+/H+ exchanger (NHE) [17], thus helpingprevent hyperkalemia when K+ is ingested incarbohydrate-rich food. Metabolic alkalosis also affectsthe NHE and causes K+ shift into cells.

K+ channels: K+ channels are a diverse andubiquitous family of membrane-spanning proteins thatselectively conduct K+ ions across the cell membranealong its electrochemical gradient in both excitable andnon-excitable cells [18]. There are several differenttypes of K+ channels. These K+ channels share thecommon features of a water-filled permeation poreallowing K+ ions to flow across the cell membrane, aselectivity filter that specifies K+ as the permeant ionspecies, and a gating mechanism that serves to switchbetween open and closed channel conformations [19].Some of these channels are regulated by voltage, othersby ligands such as calcium ions (Ca2+) and metabolitessuch as adenosine triphosphate (ATP). Because K+ ionsdo not reach diffusion equilibrium, control of the open-probability of K+ channel regulates the transmembranevoltage. K+ channels are inhibited by barium and otherdrugs [20]. Closure or opening of them may not only

alter the membrane potential but also acutely affect theplasma K+ concentration.

Renal handling of K+

K+ is freely filtered in the glomerulus. Most of thefiltered K+ is reabsorbed by the proximal tubule andthe loop of Henle. The final amount of K+ excreted inthe urine is primarily controlled by the late distalconvoluted tubule, the connecting tubule, and thecortical collecting duct (CCD) [14,21]. Two factorsinfluence the rate of excretion of K+: the flow rate inthe terminal CCD and the net secretion of K+ byprincipal cells in the CCD which raises the luminalconcentration of K+ ([K+]

CCD) (Figure 2). There is an

interplay between the magnitudes of the flow rate inthe CCD and the [K+]

CCD that permits the kidney to

excrete all the K+ that is ingested in steady state [22].The flow rate in the CCD: The flow rate in the CCD

is directly proportional to the rate of excretion ofosmoles and can be expressed as the urine osmoleexcretion rate divided by plasma osmolality (Uosm ×volume/plasma osm) because urine osmolality in theterminal CCD is equal to the plasma osmolality whenantidiuretic hormone (ADH) is present [23]. While therate of flow in the CCD is high during a water diuresis,the rate of K+ excretion need not be elevated, even withmineralocorticoid effects, because ADH must bepresent to have high rates of K+ secretion [24]. Usingspot urine, the flow rate in the CCD can be indirectlyrepresented by Uosm/Ucreatinine (see below).

Figure 1. K+ homeostasis: the internal balance of K+. The circledepicts the cell membrane. Na+/K+-ATPase, NHE, and K+ channelsare three major elements controlling K+ shift. The Na+/K+-ATPasepumping Na+ out of cells in exchange for two K+ entering cellscauses a large internal negative voltage and is activated by

2-

adrenergics, insulin and thyroid hormone. Also, insulin, byactivating NHE, causes the electroneutral entry of Na+ into cells,and thereby the net exit of positive voltage via the Na+-K+-ATPase.K+ exiting cells through K+ channels is responsible for generatingthe majority of the resting membrane potential.

Figure 2. Fast Na+ and slow Cl– in CCD. The barrel-shapedstructures represent the terminal CCD. The reabsorption of Na+

faster than Cl– (right panel) or Cl– slower than Na+ (left) in theCCD creates the lumen negative voltage that drives the net secretionof K+. Fast Na+ disorders cause ECF volume expansion and highblood pressure whereas slow Cl– disorders lead to diminished ECFvolume and low to normal blood pressure.



[K+]CCD

: K+ secretion in the CCD depends on the K+

channel conductance of the apical membrane (primarilyrenal outer-medullary K [ROMK]) driven by theelectrogenic reabsorption of Na+ (a lumen-negativetransepithelial voltage) via epithelial Na+ channels(ENaC) [10,14]. Blood aldosterone and luminalbicarbonate are two major factors enhancing K+

secretion in the CCD [22,25]. Aldosterone action leadsto an increase in the activity of ENaC by activatingvarious serum and glucocorticoid-regulated kinases(SGK) which phosphorylate the ubiquitin ligase Nedd-4-2 and reduce its interaction with ENaC as well aschannel-activating proteases (CAP 1-3) which activateENaC by increasing its open-probability [26]. Theconcentration of HCO

3– and/or an alkaline luminal pH

appear to exert a decrease in the apparent permeabilityof Cl– and/or an increase in ROMK open probability inthe CCD, although the mechanism has not been fullyvalidated. There are two ways to generate morenegativity in the lumen of the CCD and thus drive K+

secretion via the ROMK channel. When Na+ isreabsorbed faster than Cl– (fast Na+ disorders) or Cl– isreabsorbed slower than Na+ (fast Na+ disorders), thelumen of the CCD becomes more negatively charged(electrogenic) and drives K+ secretion via the ROMKchannel [24]. The [K+] in the CCD can be estimated bycalculating the transtubular potassium gradient (TTKG)as {(urine/plasma [K+])/(urine/plasma osmolality)} [27,28]. The TTKG is a semiquantitative index that reflectsthe driving force of K+ secretion in the CCD because itadjusts for plasma K+ concentration and for waterreabsorption in the medullary collecting ducts [27]. ATTKG that is greater than 3 in the presence ofhypokalemia indicates fast Na+ or slow Cl– disorders(electrogenic), whereas a TTKG that is less than 3indicates that Na+ is not reabsorbed faster than Cl–

(electroneutral) as seen with extrarenal or former renalK+ loss. Of note, TTKG cannot be calculated if the urineosmolality is appreciably less than the plasmaosmolality.

Opening of K+ channels are crucial for K+ secretionin the CCD. Although many types of K+ channels havebeen identified in renal tubules, the ROMK channel

(Kir 1.1; secretory K+, small K+, or SK channel) (a low-conductance 35 pS) and large-conductance (140 pS),Ca2+-activated K+ channels (BK, maxi-K+ channels) aretwo particularly important channels [29,30]. Openingof ROMK is primarily driven by a lumen-negativetransepithelial voltage. Maxi-K+ channels are stimulatedas a result of increased intracellular Ca2+ when flowrate to the CCD is increased. The importance of maxi-K+ channels in renal K+ secretion is further supportedby the finding that patients with Bartter’s syndrome,due to inactivation mutations of ROMK in the ascendinglimb of Henle’s loop and distal tubules, do not havehyperkalemia but hypokalemia [31]. Mutations ofROMK decrease NaCl and flow reabsorption in thethick ascending limb, resulting in increased distaldelivery of NaCl and fluid to the CCD which increasesflow-stimulated K+ secretion via maxi-K+ channelsdespite the loss of functional ROMK in the CCD [32].

ASSESSMENT OF URINE K+ EXCRETION RATE

A major branch point in hypokalemic pathophysiologyis the renal K+ excretion response during hypokalemia.The 24-hour urine and/or spot urine have been used toassess renal K+ excretion rate. However, 24-hour urinecollection can be cumbersome to the patient and isfrequently erroneous because of inaccurate timing,collection and calculation. More importantly, it isimplausible to collect urine for 24 hours duringemergency situations and in states of acute K+ shift intocells. Furthermore, KCl, volume expansion, or drugsaffecting K+ excretion (e.g. diuretics) may interfere withthe validity of the 24-hour urinary K+ collection. Weprefer a spot (timed) urine collection prior to therapyas a fast and practical alternative. Nevertheless, 24-hoururine, if collected properly, can provide additionalinformation such as how much K+ is needed to replacea K+ deficit and the state of K+ balance from calculationof K+ input and output. Five spot urine indices of renalresponse to hypokalemia have been used: urine K+

concentration, fractional excretion of K+, TTKG, K+/Cr ratio and Uosm/Cr (Table 2) [33–38].

Table 2. Tests used to assess the K+ excretion rate for hypokalemia

Test Unit Expected Pitfalls

24-hr urine mmol/d < 15 Inaccurate or incomplete collections, K+ shift, drugs

Spot urineRandom urine [K+] mmol/L None Polyuria or oligouriaFractional excretion of K+ % < 3% Need nomogram if renal function impairmentK+ to creatinine ratio mmol/mmol < 1.5 Renal failure, muscle mass, volume depletion, severe rhabdomyolysisTTKG < 3 Low urine osmolalityOsmolality to creatinine ratio mosm/mmol 120–150 As in K+/Cr ratio

S.H. Lin


CAUSES OF HYPOKALEMIA

Based on the urinary K+ excretion rate in response tohypokalemia, the etiology of hypokalemia can besimply divided into two groups: those with a low K+

excretion rate and those with a high K+ excretion rate.

Disorders with a low urine K+ excretion rateLow urine K+ excretion can be caused by an increasedtranscellular shift of K+ or excessive loss of K+ fromthe intestinal tract or sweat glands. In contrast to eithermetabolic acidosis or alkalosis commonly found ingastrointestinal or sweat K+ loss as a result of aconcomitant bicarbonate (HCO

3–) or chloride (Cl–) loss,

an acid-base imbalance is usually not prominent inpatients with increased intracellular shift of K+ [35,39].This is because ECF K+ content is relatively small andevery K+ entering cells is exchanged for H+ or Na+ outof cells to maintain electroneutrality. However, theamount of H+ that enters the ECF compartment and isbuffered by HCO

3– is minute compared to the ECF

HCO3

– content. Accordingly, the simultaneousassessments of blood acid-base state also helpsdiscriminate the causes of hypokalemia with low urineK+ excretion rate (Figure 3).

As a whole, increased shift of extracellular K+ intocells can occur acutely in a number of highly stressfulconditions associated with increased catecholaminesor hyperinsulinemia via the activation of membraneNa-K-ATPase or NHE activity [40,41]. Bariumintoxication and chloroquine overdose causehypokalemia via the direct closure of cellularmembrane K+ channels [42,43]. We would like to

clarify the clinical definition of hypokalemic periodicparalysis (HPP) which has been used with confusionin many causes of hypokalemia with paralysis. HPPis specifically used for any hypokalemic disorderscaused by an acute shift of K+ into cells in contrast tonon-HPP where there is a large total body deficit ofK+ [44]. Within the HPP subgroups, the most commonare thyrotoxic periodic paralysis (TPP) in Asia [45,46] and familial periodic paralysis (FPP) due to genemutations encoding the dihydropyridine-sensitivevoltage-gated Ca2+ channel 1-subunit (CACNA1S)and tetradoxin-sensitive voltage-gated Na+ channel

-subunit (SCN4A) of skeletal muscle in Westerncountries [47,48].

Any cause of gastrointestinal K+ loss and excessivesweating can lead to hypokalemia with low urinary K+

excretion. Of note, metabolic alkalosis and/or acidosisis usually present as mentioned above. Furthermore,other electrolyte excretion rates, such as Na+, Cl–,divalent ions, and osmoles, are frequently low prior totherapy [35]. However, sometimes, patients withgastrointestinal or sweat loss may have high urine K+

excretion because concomitant Na+ loss with secondaryhyperaldosteronism, metabolic alkalosis withbicarbonaturia, hypomagnesemia, and coexistingintrinsic renal disorders all contribute to renal K+

wasting [49,50].

Disorders with a high urine K+ excretion rateHypokalemia due to renal K+ wasting is chronic andusually related to disorders with either increased flowrate to the CCD or increased K+ in the CCD (fast Na+

or slow Cl–).

Figure 3. Algorithm for theapproach to hypokalemia witha low urine K+ excretion.



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S.H. Lin


Increased urine flow rate to CCDFlow rate to the CCD is enhanced when osmoleexcretion rate is increased. Increased osmole excretionrate can be caused by increased excretion of electrolytes(diuretics or tubular defects) or non-electrolytes(mannitol, glucose, urea) [27,28] (Figure 4).

Increased [K+] in the CCDFast Na+ disorders: Because Na+ reabsorption in theCCD is augmented, ECF volume is usually expandedand thus blood pressure is high, as in states ofmineralocorticoid excess [51]. In this setting,measurement of plasma renin activity, aldosterone andcortisol concentration helps narrow the differentialdiagnosis of fast Na+ disorders [12,28,52] (Figure 4).Plasma renin activity and aldosterone levels are highin patients with a renin-secreting tumor, renal vasculars t e n o s i s , m a l i g n a n t h y p e r t e n s i o n , a n dpheochromocytoma. High plasma aldosterone levels butlow plasma renin activity indicates primaryhyperaldosteronism which can be caused by bilateraladrenal hyperplasia, adrenal adenoma/carcinoma,glucocorticoid-remediable aldosteronism or others [53].In contrast, low plasma aldosterone level and reninactivity represents pseudohyperaldosteronism [54].Based on the plasma cortisol concentration, threesubgroups can be readily divided. Patients with highplasma cortisol concentrations may have ectopicadrenocorticotropic hormone, Cushing’s syndrome orexogenous hydrocortisone administration [55,56]. Lowplasma cortisol concentration suggests the diagnosisof congenital adrenal hyperplasia due to either 17 -hydrolyase or 11 -hydroxylase deficiency [57]. Anormal plasma cortisol level has been found in thefollowing causes: 11-deoxycorticosterone (DOC)producing adenoma, autosomal dominant Liddle’ssyndrome due to a gain of function mutation in theC-terminal part of the or subunit of ENaC, andfailure of the 11 -hydroxysteroid dehydrogenase-2(11 -HSDH-2) to remove cortisol resulting in apparentmineralocorticoid excess from either a hereditary defectdue to a homozygous deficiency of 11 -HSDH-2 orlicorice ingestion (inhibition) [51,58–60].

Because aldosterone synthesis and secretion can beinhibited by hypokalemia itself, the effect ofhypokalemia should be taken into consideration wheninterpreting plasma aldosterone concentration [61]. Onemust also be concerned about the effect ofantihypertensive drugs such as angiotensin-convertingenzyme inhibitors (ACEIs), angiotensin II (AII)antagonists, and beta-blockers which may influenceplasma renin activity and aldosterone concentrations.Diuretics (thiazides or loop diuretics) prescribed tohypertensive patients can cause or aggravatehypokalemia and metabolic alkalosis while mimickingthe clinical and laboratory finding of mineralocorticoid

excess. To differentiate a diuretic-induced hypokalemiafrom a true mineralocorticoid excess state, withdrawalof diuretics coupled with replacement of the K+ deficitcan be employed. Once plasma K+ level is normal, stopK+ supplementation. If hypokalemia recurs, excessmineralocorticoid state is more likely than a diuretic-induced hypokalemia.

Slow Cl– disorders: Because Cl– reabsorption in theCCD is diminished, ECF volume is usually contractedand thus blood pressure is relatively low to normal.Because intracellular K+ loss is often accompanied byECF HCO

3– or Cl– loss, slow Cl– disorders can have

either hyperchloremic metabolic acidosis orhypochloremic metabolic alkalosis (Figure 4).

H y p e rc h l o r e m i c m e t a b o l i c a c i d o s i s :Hyperchloremic metabolic acidosis provides animportant diagnostic clue for the presence of apathophysiologic process involving both K+ depletionand direct or indirect loss of HCO

3–. Estimating the

urine NH4

+ concentration unveils the basis of metabolicacidosis associated with K+ depletion [62]. Theexcretion of NH

4+ is low in patients with renal tubular

acidosis (RTA), whereas this excretion is not depressedin simple gastrointestinal loss of NaHCO

3 [63]. Because

direct measurement of urine NH4

+ concentration isusually unavailable in most laboratories, an indirectestimate of NH

4+ can be obtained from the urine anion

gap (Na+ + K+ – Cl–) or osmolar gap (measured –calculated urine osmolality/2). Positive urine net chargeand osmolar gap < 100 mosm/kgH

2O are indicative of

low urine NH4

+ excretion, pointing to the diagnosis ofRTA [64]. RTA can be proximal or distal in origin.Intravenous NaHCO

3 loading at a rate of 2–3 mmol/

kg/hr can be administered to separate proximal fromdistal RTA. Fractional excretion of bicarbonate(FE

HCO3–) as an index of proximal tubule H+ secretion

at plasma bicarbonate close to 24 mmol/L is > 15% inproximal RTA, whereas urine-blood carbon dioxidegradient ( U-B P

CO2), an index of distal renal tubule

H+ secretion in the alkaline urine (pH > 7.4) is less than25 mmHg in distal RTA [65]. The causes for patientswho do not have a low NH

4+ excretion rate include

gastrointestinal loss of HCO3–, chronic toluene abuse,

treatment of diabetic acidosis with insulin, and ureteraldiversion [66,67].

Hypochloremic metabolic alkalosis: Metabolicalkalosis is diagnostically useful in patients with severeKCl depletion. An assessment of urine Na+ and Cl– mayreveal the basis for renal tubular electrolyte disordersand distinguish it from non-renal Na+ loss. Lowexcretion of Na+ and Cl– indicate remote vomiting,remote or yesterday’s diuretics, Cl–-losing diarrhea (e.g.congenital chloridorrhea), or excessive sweating [68].Low urine Na+ but high Cl– excretion in the presenceof hypokalemia and metabolic alkalosis suggestslaxative abuse or some chronic diarrhea states with



chronic stimulation of renal NH4

+ excretion. Conditionsof high Na+ excretion but low Cl– suggests the presenceof an anion that is not reabsorbed. If the urine is alkaline(pH > 7), vomiting and/or ingestion of bases is the likelycause. If the urine is not alkaline, intake or generationof anions that are poorly reabsorbed by the kidney islikely [69]. A high urine Na+ and Cl– excretion in thepresence of ECF volume depletion is indicative of therecent use of diuretics, intrinsic renal disease or thelack of signaling to stimulate NaCl reabsorption.Inherited or acquired renal tubular disorders such asGitelman’s syndrome, Bartter’s syndrome, and relatedmedication-induced disorders, such as fromaminoglycosides, cisplatin, diuretics, and foscarnet, areoften the diagnosis [70–72]. The evaluation of urinedivalent Mg2+ and Ca2+ excretion helps to localize theexact tubular defect. A high urine Ca2+ and Mg2+

excretion is universally present in lesions of the loopof Henle, whereas low urine Ca2+ and high Mg2+

excretion is invariably found in lesions of the distalconvoluted tubule [73–75]. A differential diagnosis ofGitelman’s syndrome and different subtypes of Bartter’s

syndrome is shown in Table 3. It is important todiscriminate Gitelman’s syndrome from Bartter’ssyndrome because nonsteroidal anti-inflammatory drugsare usually ineffective and not needed in treating patientswith Gitelman’s syndrome based on the relatively normalurinary prostaglandin E

2 excretion [76], unlike Bartter’s

syndrome with abnormally higher prostaglandin E2

excretion, especially in antenatal type [77].

MANAGEMENT

The management of hypokalemia incorporates theacuity of illness, magnitude of K+ deficit, K+

preparations, risks of therapy, and special associatedconditions.

Medical emergencyThe major emergencies include cardiac arrhythmias andrespiratory failure. There are two notes of caution whentreating patients with profound hypokalemia in amedical emergency. First, the aim of therapy is to get

Table 3. Differential diagnosis of Gitelman’s syndrome (GS) or Bartter’s syndrome (BS)-like inherited renal electrolyte disorders

GS aBS/HPS cBS BSND ADH

OMIM 263800 241200 602023 602522 601189602023 600359

Inheritance AR AR AR AR ADAR

Gene locus 16q 15q15-21 1p36 1p31 3q13.3-211p36 11q24

Gene SLC12A3 SLC12A1 CLCNKB BSND CASRCLCNKB KCNJ1

Protein NCC Na+-K+-2Cl– CLC-Kb Barttin CASRCLC-Kb ROMK

ClinicalAge at onset Variable Neonatal Variable Neonatal InfancyNephrocalcinosis No Yes Rare No YesRenal stones No Yes or no No No Yes

LaboratoryBlood pHPlasma K+ to to toPlasma Mg2+ N or N or NPlasma Ca2+ N N N NUrine Mg2+ N or N or NUrine Ca2+ Variable N or to

OMIM = online Mendelian Inheritance in Man; aBS/HPS = antenatal Bartter’s syndrome/hyperprostaglandin E syndrome; cBS = classicBartter’s syndrome; BSND = antenatal Bartter’s syndrome with sensorineural deafness; ADH = autosomal dominant hypoparathyroidism;AR = autosomal recessive; AD = autosomal dominant; CASR = calcium sensing receptor.

S.H. Lin


the patient out of danger, not to immediately correctthe entire K+ deficit. Enough K+ must be given to raisethe plasma K+ quickly to a safe range (~3.0 mmol/L)and the total body K+ deficit should then be replacedmore slowly [78]. Since large doses and highconcentrations of K+ might be needed, a central venouscatheter and cardiac monitor are essential for aggressivetreatment. Second, the infusion should not containglucose or HCO

3– because this might aggravate the

degree of hypokalemia by increasing redistribution ofK+ from ECF into ICF space [79].

Magnitude of K+ deficitBalance studies in K+-deprived normal subjects showthat when plasma K+ concentration decreases from 4to 3 mmol/L, there is a mean K+ deficit of 350 mmol. Afurther reduction in plasma K+ concentration from 3 to2 mmol/L is associated with an additional 400 mmolK+ deficit [13]. Given the degree of K+ loss, an estimatedamount of K+ supplement should be provided. The oralroute is preferred if bowel sounds are present. When aperipheral intravenous route is used, the K+

concentration should not be > 40 mmol/L. The rate ofK+ administration should not be > 60 mmol/hr in allbut emergency settings. However, one must know thatthere is no useful quantitative relationship betweenplasma K+ and total body K+ deficit because there mayalso be shift of K+ into cells such as in the presence ofcoexisting volume depletion, metabolic alkalosis, andincreased -adrenergic activity.

K+ preparationsThree kinds of K+ salts are available to replace bodyK+ deficit: KCl, KHCO

3 (K+ citrate or organic anion),

and K+ phosphate. KCl is needed in hypokalemicpatients with K+ deficit and hypochloremic metabolicalkalosis, whereas KHCO

3 or K+ citrate is preferred in

patients with K+ deficit and hyperchloremic metabolicacidosis. KHCO

3 or K+ citrate also has the significant

effect of reducing calcium excretion in patients withmetabolic acidosis. Because the administration ofHCO

3– may lead to a shift of K+ into cells, KCl should

be given initially and alkali should be withheld unlessthere are ongoing and large losses of HCO

3–. K+

phosphate may be needed when there is concomitantdeficit of K+ and phosphate such as in the condition ofrapid anabolism, little oral intake, gastrointestinaldisorders, and preexisting cellular K+ phosphate loss(e.g. diabetic or alcoholic ketoacidosis) [80].

Risks of therapyIn hypokalemic patients with acute increased shift K+

into cells, body K+ stores are normal. Aggressive KCltherapy may be associated with a potential risk ofrebound hyperkalemia, due to K+ rapidly released fromcells when the K+ shift resolves [38,44,45]. With

prolonged hypokalemia, the CCD may becometemporarily hyporesponsive to the kaliuretic effect ofaldosterone [81]. Hyperkalemia may develop,especially when K+ supplementation is given with K+-sparing diuretics and if other conditions compromisingK+ excretion are present. These conditions include renalfailure, diabetes mellitus and the simultaneous use ofACEIs, AII receptor blockers, beta-blockers ornonsteroidal anti-inflammatory drugs [82]. However,a recent retrospective study reported that total parenteralnutrition as a source of K+, magnesium supplementationwhich may reduce kaliuresis, and hematologicmalignancy causing cell lysis contribute to subsequenthyperkalemia in one of every six patients withhypokalemia [83].

Special associated settingsHPP due to transcellular shift of K+: In patients withHPP, acute intravenous or oral KCl administration canhasten recovery and prevent cardiac arrhythmia andrespiratory arrest. However, caution must be exercisedbecause KCl therapy is associated with the developmentof rebound hyperkalemia on recovery. One interestingbut still less-appreciated finding is a further fall inplasma K+ concentration in some patients with TPPduring KCl therapy. This paradoxical hypokalemia mayt r igger phys ic ians to admin i s te r more K+

supplementation to correct the hypokalemia, leadingto marked rebound hyperkalemia. From retrospectiveand case-controlled studies, rebound hyperkalemia(> 5.0 mmol/L) has been reported to occur in close to30–70% of patients with TPP if > 90 mmol KCl wasgiven within 24 hours or at a rate of 10 mmol/hr [84,85]. We suggest that KCl supplementation be kept low(< 10 mmol/hr) unless there are cardiopulmonarycomplications. An alternative therapeutic option in TPPis high-dose nonselective beta-blockers to suppressadrenergic activity and inhibit insulin secretion, basedon the implication of hyperadrenergic activity andhyperinsulinemia in the pathogenesis of TPP [86,87].Nonselective beta-blockers may not only reverse anacute episode of TPP without the development ofrebound hyperkalemia but also prevent or amelioratefuture paralytic attacks [88].

Associated with chronic hyponatremia: K+ may beimportant in cerebral recovery following hyponatremiabecause the cellular uptake of K+ is a critical responseto increasing extracellular tonicity. Hypokalemia is aparamount risk factor for osmotic demyelinationsyndrome (ODS) following the correction of chronichyponatremia [89]. It has been reported that 89% ofpatients who developed ODS presented with initialhypokalemia and that their K+ level did not normalizewith serum Na+ correction [90]. Normalizing thehypokalemia either before, or at least concomitant withthe plasma Na+ correction would be a prudent and



logical approach. There are many benefits of KClsupplementation over NaCl, including the reduction ofarrhythmia related to hypokalemia, the Na+ gain in theECF and volume expansion if K+ enters the cells, andreduced risk of ODS during correction of chronichyponatremia [89]. Nevertheless, the administration ofdesmopressin is warranted to prevent or reduce a largerwater diuresis with a rapid and unwanted rise in plasmaNa+ concentration if aggressive KCl or NaCl therapycauses ECF volume expansion with the resultantinhibition of ADH release [91].

Associated with volume depletion: Because volumedepletion can cause an increase in -adrenergic activityand reduce the extracellular K+ shift into cells, plasmaK+ concentration is often misleadingly high [92]. Whenvolume status is restored in parallel with a reduction in

-adrenergic activity, there will be a further fall inplasma K+ concentration, leading to a paradoxicalworsening of hypokalemia even wi th KClsupplementation, similar to that found during K+

supplementation in the acute phase of HPP.Associa ted wi th magnes ium defic iency:

Hypokalemia is frequently associated with magnesiumdeficiency. It is estimated that > 50% of clinicallysignificant hypokalemia has concomitant magnesiumdeficiency. Concomitant magnesium deficiencyexacerbates hypokalemia and renders it refractory totreatment with K+ supplementation [93]. Micropuncturestudies have shown that magnesium decreases distalK+ secretion [94]. In patch clamp studies, a decrease inintracellular magnesium caused by magnesiumdeficiency may release the magnesium-mediatedinhibition of ROMK channels and thus increase K+

secretion [95]. However, an increased Na+ delivery toCCD or elevated aldosterone may be required foraggravating K+ wasting in magnesium deficiency dueto the fact that magnesium deficiency alone does notnecessarily cause hypokalemia [96]. Correction ofmagnesium deficiency may help in the correction ofhypokalemia and prevention of cardiac arrhythmia [97].

Associated with severe metabolic acidosis: Becauseinorganic rather than organic acidosis causes the effluxof intracellular K+ in exchange with extracellular H+

and thus raises plasma K+ concentration, the degree ofK+ deficit is underestimated in hypokalemic patientswith severe hyperchloremic metabolic acidosis [98].One may be misled to correct the plasma HCO

3– first

because the low HCO3

– concentration appears moredramatic than the K+ concentration in this setting.Actually, the risk of profound hypokalemia is muchgreater than severe metabolic acidosis and should becorrected first. In fact, there have been case reports ofcatastrophic acute respiratory failure and ventriculararrhythmia from exacerbation of hypokalemia as aresult of aggressive alkali therapy before K+

supplementation.

Hypokalemia associated with hereditary renaltubular defects: A common clinical observation is thathypokalemia is difficult to correct in patients withhereditary renal tubular disorders such as Gitelman’ssyndrome or Bartter’s syndrome, even with large K+

supplements. Because of chronic hypokalemia, luminalK+ channels in the CCD might be downregulated [99].KCl supplements transiently raise the plasma K+

concentration, which may not only augment theinsertion of K+ channels into the luminal membrane ofthe CCD but also exert a loop diuretic-like effect, thusinducing a prompt kaliuresis [100]. While maintainingin a subnormal plasma K+ concentration, to administerKCl in multiple small doses instead of infrequent largedoses may be a better way to avoid raising the plasmaK+ concentration to the normal range for even transientperiods.

Associated with a low lean mass: Because cellularK+ primarily resides in the skeletal muscle, total bodyK+ depends upon the lean muscle mass. For the samedegree of hypokalemia, K+ supplementation should berelatively less in patients with low lean mass. If thesame amount of K+ replacement is given to patientswith low lean mass as to those with normal/high leanmass, iatrogenic hyperkalemia may develop.

CONCLUSION

Hypokalemia caused by a multitude of etiologies isoften associated with cardiovascular, neuromuscular,renal and metabolic disturbances. It usually arises fromderangements of internal K+ shift or external K+ balance.Apart from detailed history and careful physicalexamination, the measurement of urine K+ excretionrate by spot and/or 24-hour urine, and assessment ofblood acid-base status will help to discriminate thecauses of hypokalemia. The treatment of hypokalemiainvolves weighing the degree and timing ofhypokalemia with clinical manifestations, underlyingcauses, associated conditions and risks during therapy.Prompt diagnosis with appropriate management ofhypokalemia avoids unnecessary examination and direcomplications related to hypokalemia.

ACKNOWLEDGMENTS

This work was supported by a grant from the Chen-Han Foundation for Education.

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