Hyperkalemia in Dialysis Patients

Junaid Ahmed* and Lawrence S. Weisberg²

*Duane L. Waters Hospital, Jackson, Michigan, and ²University of Medicine and Dentistry of New Jersey,Robert Wood Johnson Medical School, Cooper Health System, Camden, New Jersey

ABSTRACT

Serious hyperkalemia is common in patients with end-stagerenal disease (ESRD) and accounts for considerable morbidityand death. Mechanisms of extrarenal disposal of potassium(gastrointestinal excretion and cellular uptake) play a crucialrole in the defense against hyperkalemia in this population. Inthis article we review extrarenal potassium homeostasis and its

alteration in patients with ESRD. We pay particular attentionto the factors that in¯uence the movement of potassium acrosscell membranes. With that background we discuss the emer-gency treatment of hyperkalemia in patients with ESRD. Weconclude with a review of strategies to reduce the risk ofhyperkalemia in this population of patients.

Serious hyperkalemia is common in patients with end-stage renal disease (ESRD), seen in about 10% ofhemodialysis patients (1). One group of investigatorsreported that hyperkalemia was the reason for emer-gency dialysis 24% of the time in their patients withESRD on maintenance hemodialysis (2). Of greatconcern is the attribution of 3±5% of deaths in dialysispatients to hyperkalemia (3,4).In this reviewwewill explain why patients with ESRD

are predisposed to hyperkalemia, describe the adverseconsequences of hyperkalemia, and provide a rationalscheme for the treatment and prevention of hyperkal-emia in this population.

Potassium Pathophysiology in ESRD

The total bodypotassiumcontent is about50mmol/kgof body weight (approximately 3500 mmol for a 70 kgadult), ofwhichonly about 2%(70mmol) is extracellular(5). This uneven distribution re¯ects the large potassiumconcentration gradient between the intracellular(Ki » 150 mmol/L) and extracellular (Ke » 4 mmol/L)¯uid compartments. The Ki:Ke ratio largely determinesthe resting membrane potential of cells. The relationshipbetween Ki and Ke implies that a very small absolutechange in the extracellular potassium concentration willhave amajor e�ect on this ratio and thus on the functionof excitable tissues (muscle and nerve) in particular (6). Itis not surprising therefore that the extracellular potas-sium concentration is tightly regulated. In fact, twoseparate and cooperative systems participate in potas-sium homeostasis. One system regulates external potas-sium balance: the total body parity of potassium

elimination with potassium intake. The other systemregulates internal potassium balance: the distribution ofpotassium between the intracellular and extracellular¯uid compartments. This latter system provides a short-term defense against changes in the serum potassiumconcentration (SK) that might otherwise result fromtotal-body potassium losses or gains.Given that 90±95% of the daily potassium load is

normally excreted through the kidneys, the importanceof extrarenal disposal of potassium (gastrointestinalexcretion and cellular uptake) for patients with ESRDcannot be overestimated. Consider, for example, that theaverage dietary potassium intake of patients undergoingmaintenance dialysis is about 0.75±1.0 mmol/kg bodyweight/day (7). Absorption of ingested potassium fromthe gut into the extracellular ¯uid is nearly complete.Thuswere it not for extrarenal disposal of this potassiumload, the SK would be expected to more than double inthe interdialytic interval, resulting in lethal hyperkalemia.That this is the exception rather than the rule (1) is atestament to the integrity of the extrarenal potassiumdisposal mechanisms in ESRD.Nonetheless, several studies have shown that patients

with ESRD have impaired extrarenal defenses againsthyperkalemia.PatientswithESRDtranslocatemuch lessof an orally administered potassium load into cells thando patients with normal renal function, even whenurinary excretion is taken into account (8,9). Of greatconcern from a clinical standpoint, the higher the initialSK, the lessof apotassium load ismoved into cells (10). Inthe next section we will discuss the mechanisms ofextrarenal potassium disposal in patients with ESRD.

Mechanisms of Extrarenal PotassiumDisposal in ESRD

Gastrointestinal Excretion

Patients with normal renal function eliminate only5±10% of their daily potassium load through the gut. In

Address correspondence to: Lawrence S. Weisberg, MD,Nephrology Division, UMDNJ/Robert Wood JohnsonMedical School, Education and Research Building, Room286, 401 Haddon Ave., Camden, NJ 08103, or e-mail:weisberg@umdnj.edu.

Seminars in DialysisÐVol 14, No 5 (September±October)2001 pp. 348±356

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patients with chronic renal failure, gut elimination ofpotassium increases, and may account for as much as25% of daily potassium elimination (11,12). This gutpotassium adaptation is mediated by increased colonicsecretion, which is two- to threefold higher in patients ondialysis than in patients with normal kidney function(7,12). Aldosterone is known to stimulate potassiumsecretion in the colon, but whether it participates incolonic potassium adaptation in patients with ESRD isquestionable (13). The amount of potassium excretedthrough the gut is roughly proportionate to the stoolvolume. Constipation, which has been reported to occurin 40% of hemodialysis patients (14), may therefore beexpected to predispose such patients to hyperkalemia.Indeed, one study found the 24-hour fecal potassiumexcretion in anephric hemodialysis patients to be lessthan 5 mmol on a 40 mmol/day potassium diet (15).For a patient with ESRDon hemodialysis who ingests

about 60mmol of potassium/day, evenoptimal intestinaleliminationwould still yield a positive potassiumbalanceof about 45 mmol/day. Fortunately, cellular uptakeleaves only 15±20% of this retained potassium in theextracellular space (1,15), thus mitigating the rise in SK.

Cellular Uptake

The distribution of potassium between the intracellu-lar and extracellular ¯uid compartments is determinedphysiologically by the action of Na,K-ATPase ``pumps''and the di�erent conductances of sodium and potassiumacross the cell membrane. In skeletal muscle (the body'ssingle largest intracellular repository of potassium)Na,K-ATPase is regulated by various factors operatingover the long and short term (16).Over the long term, physical inactivity, hypothyroid-

ism, and total body potassium depletion are known todecrease the number of pumps inserted into the mem-brane of skeletal muscle cells. Conversely, physicaltraining and hyperthyroidism increase the density ofpumps (16). The in¯uence of these long-term Na,K-ATPase regulators on potassium tolerance in patientswith ESRD has yet to be demonstrated. There isconsiderable evidence that in uremia, pump density isdecreased and the rate of active sodium and potassiumtransport is reduced. These defects are reversible afterseveral weeks of maintenance dialysis (17). Factors thatregulate Na,K-ATPase over the short term includecatecholamines and insulin (16). It is not surprisingtherefore that these are among the most importantin¯uences on the minute-to-minute changes in thedistribution of potassium across the cell membrane.

Insulin. The e�ect of insulin in stimulating cellularpotassium uptake is completely independent of its e�ecton cellular glucose uptake (18), acting through a separatereceptor and signaling pathway (19). Insulin's e�ect onpotassium is dose dependent from the physiologicthrough the pharmacologic range (20). The e�ect isunaltered by b-adrenergic blockade (21) and is mediatedby activation of Na,K-ATPase (16), apparently byrecruitment of intracellular pump components into theplasmamembrane (22). Somatostatin infusion into dogs

and human beings results in an increase in serumpotassium concentration (23,24), implying that normalbasal insulin secretion is necessary for themaintenance ofnormal transcellular potassium distribution. Further-more, although not conclusively demonstrated, a pre-ponderanceof the evidence supports a role for insulin inahomeostatic feedback loop with potassium, such that amodest increase in extracellular ¯uid potassium concen-tration stimulates pancreatic insulin release, which inturn moves potassium into cells (25).In uremia, insulin-mediated glucose uptake is known

to be impaired (26). In contrast, the potassium-loweringe�ect of insulin is preserved in patients with renal failure(27). When an oral potassium load is administered topatientswithESRD, the increase inSK is signi®cantly lesswhen the potassium is accompanied by oral glucose, ane�ect that is not completely blocked by propranolol (28).This observation suggests that endogenous insulinenhances the cellular disposal of dietary potassium inpatients with ESRD. Conversely, fasting in patients withESRD is associated with a signi®cant, occasionallydrastic (29) increase in SK not seen in patients withnormalkidney function (30), presumablydue toa relativelack of insulin allowing potassium e�ux from cells.

Catecholamines. It has long been recognized thatepinephrine, mainly through its action on liver andskeletal muscle, has a biphasic e�ect on the serumpotassium concentration: an immediate increase fol-lowed by a more sustained decrease (31). The biphasicnature of the response is now understood to be due toepinephrine's stimulation of both a- and b-adrenocep-tors, with a-adrenergic stimulation mediating potassiume�ux from cells and b-adrenergic stimulation mediatingcellular uptake. The b-adrenergic e�ect is independent ofinsulin (32±34) and does not depend on renal excretion(33±35). Speci®callyb2-adrenoceptor activation, throughG-protein-mediated adenylyl cyclase stimulation (36), isresponsible for cellular potassium uptake (37).Endogenous catecholamines appear to participate in

normal potassium homeostasis under two physiologiccircumstances: physical exercise and feeding. The normalexercise-induced increase in serum potassium concen-tration is ampli®ed by treatment with the nonselectiveb-adrenoceptor blocker propranolol [but not the selec-tive b1-adrenoceptor blocker metoprolol (37)] andmitigated by treatment with the a-adrenoceptor blockerphentolamine (38). The sympathetic nervous system isstimulated by feeding and may thus participate in thedisposal of dietary potassium (39). Hyperkalemia itself,however, may not directly stimulate catecholaminerelease. For example, when the serum potassium con-centrationof normal human subjectswas increasedbyanaverage of 0.8 mmol/L by potassium infusion, there wasan insigni®cant increase in plasma epinephrine levels(34). It is quite clear, however, that blockade ofb2-adrenoceptors results in markedly impaired toleranceof an acute potassium load (34), and has been associatedwith sustained hyperkalemia in patients with ESRDingesting normal amounts of potassium (40,41). Theb1-adrenoceptor selectivity of drugs like metoprolol andatenolol is lost at high drug concentrations. It is not

HYPERKALEMIA IN DIALYSIS PATIENTS 349

surprising therefore that hyperkalemia has been reportedwith high doses of such drugs (42).Patients with ESRD are known to manifest abnor-

malities of the autonomic nervous system characterizedin part by end-organ resistance to sympathetic stimula-tion (43). In keeping with those observations, thepotassium-lowering e�ect of epinephrine infusion intopatientswithESRDhas been found tobe heterogeneous,with about 40%of patients showing no response and theremainder showing an exaggerated response (41). Low-dose epinephrine infusion had no e�ect on SK in fastedpatients with ESRD (30,44), whereas it had a signi®canthypokalemic e�ect on fasted normal subjects (30). Thisresistance of patients with ESRD to the hypokalemice�ect of epinephrine appears to be due to a dispropor-tionate a-adrenoceptor e�ect rather than impairedb-adrenoceptor responsiveness (45).

Aldosterone. The low sodium concentration andhigh potassium concentration in the saliva (46) and stool(47)ofpatientswithchronic renal failureare typicalof thee�ect of excess aldosterone. Nonetheless, plasma aldo-sterone levels are normal in many patients with chronicrenal failure (48). The role of aldosterone in enhancingcolonic potassium secretion in ESRD is controversial(13).Whetheraldosteroneis importantforcellularuptakeof potassium in the defense against hyperkalemia in renalfailure is likewise debatable. The sensitivity of adrenalaldosterone secretion to potassium loading seems to beenhanced in renal failure (49), setting the stage for animportant role of aldosterone in potassium tolerancein that condition. Indeed, one study showed thatadrenalectomy (with glucocorticoid replacement) wasassociated with impaired potassium tolerance in insulin-de®cient rats (50), but the possible confounding e�ect ofcatecholaminede®ciencywasnotaddressed in that study.More convincing evidence for an e�ect of aldosterone

oncellularpotassiumuptakecomesfromastudyshowingthat a continuous aldosterone infusion signi®cantlyreduced the ratio of extracellular to total body potassiumin normal and postadrenalectomy dogs (51). Similarly,anephric hemodialysis patients showed a signi®cantlyblunted increase in serum potassium concentration withacute oral potassium loading after DOCA administra-tion, and a signi®cantly exaggerated increase afterspironolactone administration compared with untreatedpatients (15). Of interest, neither drug a�ected theincrease in serum potassium over the long term withmodest dietary potassium intake. In contrast, however,an uncontrolled, unblinded study of chronic mineralo-corticoidadministration tohemodialysispatients showeda reduction in predialysis SK (52). Taken together, thesestudies suggest a role for aldosterone in the short-termand perhaps long-term defense against hyperkalemia.

Acid-Base Balance. Our understanding of thee�ects of acid-base balance on potassium distributionhas undergone considerable revision (53±55) since FennandCobb®rst described the inverse relationship betweenblood pH and SK (56). It is now clear that the directionand magnitude of an acid-base-related change inSK depend on the nature and the duration of thedisturbance. Moreover, a variety of coincidental factors

such as plasma osmolality, circulating hormone levels,and cell integrity may in¯uence the response.The most consistent and pronounced relationship

between changes in pH and SK occurs in acute mineralacidosis, where there is a strong inverse relationshipbetween these two variables, such that SK increases byabout 0.8 mmol/L for each decline of 0.1 pH units (53).Of interest, hypokalemia is seen with prolonged mineralacidosis in patients with normal renal function andre¯ects increased renal potassium excretion (53). Thus inpatients with ESRD, even sustained mineral acidosiswould be expected to result in persistent hyperkalemia.Unlike mineral acidoses, however, even severe acute

organic (high anion gap) acidoses are not usuallyassociated with hyperkalemia (55,57,58), and it is nowgenerally accepted that organic acidoses do not directlya�ect internal potassium balance. Nonetheless, factorscoincident with the acidosis may alter SK. For example,mesenteric ischemia may result in both lactic acidosis(from anaerobic metabolism) and hyperkalemia (frominactivatedNa,K-ATPase and potassium e�ux from thetissues). Even the hyperkalemia so commonly seen inpatients with diabetic ketoacidosis does not result fromthe acidemia, rather it appears to be a consequence of thecharacteristic insulin de®ciency and hyperglycemia (seeHypertonicity below) (58).Respiratory disturbances typically alter SK less than

metabolic disturbances. Alkaloses, respiratory or meta-bolic, have less e�ect on SK than their correspondingacidoses (54). Bicarbonate administration, which wasonce thought to reduce the SK by stimulating cellularpotassiumuptake (59), is nowknown to have very little ifany immediate e�ect on internal potassium balance(44,60). These observations have had a major impact onthe management of hyperkalemia in patients withESRD, as we will discuss later.

Parathyroid Hormone. Hyperparathyroidism, acommon feature of ESRD, appears to impair cellularuptake of potassium. The putative mechanism is via anincrease in intracellular calcium, which might suppressoxidative metabolism and ATP generation, thus redu-cing Na,K-ATPase activity (61). In that light, it isinteresting to note that patients with ESRD showed aslower rate of increase in the SK in the interdialyticinterval when treated with the calcium channel blocker,diltiazem, than with placebo (62).

Hypertonicity. Hypertonicity, as seen with hyper-tonic ¯uid administration (63) or diabetic hyperglycemicstates (64), leads to hyperkalemia probably as a result ofpotassiume�ux fromcells bywayof solventdrag.Lethalhyperkalemia has been attributed to this phenomenon indiabetic patients with ESRD (65).

Exercise. Contractingmuscles release potassium intothe extracellular¯uidat a rate that exceeds the capacityofNa,K-ATPase to pump it back into cells (66). Thusexercise typically is associated with an increase in SK.Exercise-induced hyperkalemia is no greater in healthydialysis patients than in normal controls (67,68), owingperhaps to higher basal and exercise-induced plasmalevels of norepinephrine, insulin, and aldosterone (68).

Ahmed and Weisberg350

Hemolysis. Massive hemolysis may occur in patientswith ESRD as a result of thermal, chemical, ormechanical damage to the red blood cells in the courseof hemodialysis. Such hemolysis, by liberating intra-cellular potassium into the extracellular ¯uid, may causesevere hyperkalemia (69,70).

Clinical Manifestations of Hyperkalemia

Because theKi:Ke ratio is themajor determinant of theresting membrane potential of cells, small changes in Ke

(i.e., SK) have profound e�ects on the function ofelectrically active, or excitable, tissues (muscle and nerve)(71). The e�ects of hyperkalemia on cardiac electrophy-siology are of greatest concern in the clinical setting.Hyperkalemia is associated with reduced myocar-dial conduction velocity and accelerated repolarization.These changes produce the classic electrocardiographic(EKG) manifestations of hyperkalemia, including(in order of their usual appearance) peaking of theT wave, prolongation of the PR interval, loss of theP-wave amplitude, widening of the QRS complex, ``sinewave'' con®guration, ventricular ®brillation, and asys-tole (72,73). These changesmaybemodi®ed by anumberof factors, such as the extracellular ¯uid pH, calciumconcentration and sodium concentration (73), and therate of increase in SK (72).Although SK in excess of 6.5 mmol/L is usually

associated with some of the EKG changes describedabove (72), patients with extreme hyperkalemia (morethan 9.0 mmol/L) have been reported to show nocorresponding EKG changes (74). There is some evi-dence to suggest that the slower the rate of increase inSK,the less pronounced the electrophysiologic consequences(75). Such protection has been inferred to apply topatients with ESRD, whose SK typically is higher thannormal (1), but data to support this hypothesis arelacking. Furthermore, the theoretical protection ofchronichyperkalemia inESRDmustbebalancedagainstthe documented impairment in extrarenal disposal ofpotassium at higher SK (10), as we discussed earlier.Besides its cardiac e�ects, hyperkalemia may result in

paresthesias and weakness, progressing in extreme casesto a ¯accid paralysis, which typically spares the dia-phragm. Deep tendon re¯exes are depressed or absent.Cranial nerves are rarely involved and sensory changesare minimal (76).

Treatment of Hyperkalemia in ESRD

In identifying when hyperkalemia requires emergencytreatment, several points should be kept in mind. First,the electrophysiologic e�ects of hyperkalemia probablyrelate to both the absolute SK and the rate of increase(72). Second, concurrent metabolic disturbances mayameliorate (e.g., hypernatremia, hypercalcemia, andalkalemia) or exacerbate (e.g., hyponatremia, hypocal-cemia, and acidemia) these electrophysiologic e�ects(73,74). Third, although the EKG manifestations of

hyperkalemia are generally progressive and proportionalto the SK, ventricular ®brillation or asystole may be the®rst EKG disturbance of hyperkalemia (77); conversely,a normal EKG may be seen with extreme hyperkalemia(74). Thus it is apparent that neither the EKGnor theSKalone is an adequate index of the urgency with whichhyperkalemia should be corrected, and that the clinicalcontext must always be carefully considered.Anypronouncement of an absoluteSKconstituting an

emergency must be seen as somewhat arbitrary. None-theless, because the treatment of hyperkalemia is safe ifproperly applied, and because hyperkalemia is unpre-dictably lethal, it is wise to maintain a low threshold forinstituting emergency therapy. Most patients manifestEKG changes at SK greater than 6.7 mmol/L (73).Consequently we propose the following general guide-lines for instituting emergency therapy: 1) SK greaterthan 6.5 mmol/L, with or without EKG changes, or2) EKG changes consistent with hyperkalemia, regard-less of the SK. In the absence of evidence to the contrary,clinicianswould be prudent to apply the same criteria forinitiation of emergency treatment for hyperkalemia topatients with ESRD as to other patients.Dialysis is the de®nitive treatment for hyperkalemia in

patients with ESRD. Because the initiation of dialysismay be delayed by hours for logistical reasons, andbecause the cardiacmanifestations of hyperkalemia maydevelop precipitously, a variety of intermediatemeasuresoften must be employed in the management of hyper-kalemia in a patient with ESRD. These intermediatemeasures fall into three mechanistic categories: 1) thosethat directly antagonize the adverse e�ects of hyperkal-emia on excitable tissue membranes, 2) those thatredistribute extracellular potassium into the intracellular¯uid space, and 3) those that enhance the elimination ofexcess potassium from the body (71).

Direct Membrane Antagonism

Calcium. Calcium directly antagonizes the myo-cardial e�ects of hyperkalemia without lowering SK(73). Calcium is bene®cial even in patients who arenormocalcemic. Calcium for injection is available as achloride or gluconate salt, both 10% by weight. Thepreferred agent is the gluconate salt, since calciumchloride may cause tissue necrosis if it extravasates.The recommended dose is 10 ml intravenously over 10minutes. The onset of action is less than 3 minutes.The EKG should be monitored continuously. The dosemay be repeated in 5 minutes if there is no improve-ment in the EKG, or if the EKG deteriorates after aninitial improvement (71). The duration of action is30±60 minutes, during which time further measuresmay be undertaken to lower SK.There are several case reports of sudden death in

patients given intravenous calcium while also receivingdigitalis glycosides (78,79). Furthermore, dogs developedventricular asystole when given a large but otherwisesublethal intravenous dose of calcium immediately afteran intravenous dose of digitalis (78). Although therelevance of these observations to hyperkalemic patients

HYPERKALEMIA IN DIALYSIS PATIENTS 351

is hardly established, it may be wise to administerintravenous calcium with great caution to patientsknown or strongly suspected to have toxic levels ofdigitalis glycosides.

Hypertonic Saline. Intravenous hypertonic sodiumchloride has been shown to reverse the EKG changes ofhyperkalemia in patients with concurrent hyponatremia(80). This e�ect appears tobemediatedbya change in theelectrical properties of cardiomyocytes rather than by areduction in SK (81). Whether hypertonic saline ise�ective in the treatment of eunatremic patients has notbeen established. Moreover, the extracellular volumeload imposed by hypertonic saline militates against itsuse.

Redistribution of Potassium into Cells

Insulin. Insulin reliably lowers SK in patients withESRD (27). The e�ect is dose dependent (20). Anintravenous dose of 10 units of regular insulin as abolus along with an intravenous bolus of dextrose(25±40 g as a 50% solution) given to adult patientslowers the SK by about 1 mmol/L. The onset of actionis less than 20 minutes and the e�ect is maximalbetween 30 and 60 minutes after a single bolus (82,83).After the initial bolus, a dextrose infusion should bestarted, since a single bolus of 25 g of dextrose hasbeen shown to be inadequate to prevent hypoglycemiaat 60 minutes (82). It is interesting to note that wheninsulin was given by continuous intravenous infusionfor 4 hours to normal volunteers, SK fell over the ®rst90 minutes and rose thereafter (21). Based on that,there seems to be no advantage to continuous infusionover a bolus injection, although relevant data inpatients with ESRD are lacking.Insulin should be used without dextrose in hypergly-

cemic patients; indeed, the cause of the hyperkalemia inthese patients may be the hyperglycemia itself (64) (seeHypertonicity above). The administration of hypertonicdextrose alone for hyperkalemia is not recommended fortwo reasons: ®rst, endogenous insulin levels are unlikelyto rise to the level necessary for a therapeutic e�ect; andsecond, there is a risk of exacerbating the hyperkalemiaby inducing hypertonicity (64).

Albuterol. The new appreciation for the e�ect ofcatecholamines on internal potassium balance has beenapplied to the clinic in thepast decade.Patientswith renalfailure given the selective b2-adrenoceptor agonist albu-terol by intravenous infusion (0.5 mg over 15 minutes)show a signi®cant decline in SK (about 1 mmol/L) whichis maximal between 30 and 60 minutes (83,84). Becauseinjectable albuterol is unavailable in the United States, itis encouraging to note that nebulized albuterol in a highdose administered to patients with ESRD has a similare�ect: SK declines by 0.6 mmol/L after inhalation of10mgof albuterol, andbyabout 1.0mmol/Lafter 20mg.The e�ect is apparent at 30 minutes and persists for atleast 2 hours (85). Even when administered by metered-dose inhalerwith a spacer, albuterol results in a small butsigni®cant reduction in SK (86). The e�ect of insulin is

additive with that of albuterol, with the combinationreported to result in a decline in SK of about 1.2 mmol/Lat 60 minutes (82).Mild tachycardia is the most commonly reported side

e�ect of high-dose nebulized albuterol. The meanincrease in heart rate in one study was reported to be6 beats/min with the 10 mg dose and 10 beats/min withthe 20 mg dose (85). Mild hyperglycemia (2±3 mmol/Lincrease) also has been seen (82,84). Patients takingnonselective b-adrenoceptor blockers are unlikely tomanifest the hypokalemic e�ect of albuterol. Evenamong ESRD patients not taking b-blockers, as manyas 40%appear tobe resistant to thehypokalemic e�ectofalbuterol (82,85). The mechanism for this resistance isunknown, and there is currently no basis for predictingwhich patients will respond. For that reason, albuterolshouldnever beusedas a single agent for the treatment ofurgent hyperkalemia in patients with renal failure.

Bicarbonate. The putative bene®ts of a bolusinjection of sodium bicarbonate in the emergencytreatment of hyperkalemia pervaded the literature untilthe past decade. Ironically, this dogma was based onstudies using a prolonged (4±6 hours) infusion ofbicarbonate (59). It has now been clearly demonstratedthat short-term bicarbonate infusion does not reduce SKin patients with ESRD. Infusion of neither a hypertonicnor an isotonic bicarbonate solution for 60 minutes hasbeen shown to have any e�ect on SK, despite asubstantial increase in serum bicarbonate concentration(44). Even when the infusions were carried out for 3hours, no changewas seen inSK (87).Only after a 4-hourinfusion was a small (0.6 mmol/L) but signi®cantdecrease in SK detectable, and even then, half thedecrement was attributable to extracellular volumeexpansion (60). Furthermore, the e�ect was heteroge-neous, such that a quarter of the patients studied had adecrement inSKof less than 0.35mmol/Lafter 6hours ofcontinuous infusion (60). Thus bicarbonate alone is notuseful for the urgent treatment of hyperkalemia inpatientswithESRDbecauseof its delayedonsetof actionand its variable e�cacy from one patient to the next.There is evidence to suggest that metabolic acidosis

may impair some of the physiologic responses to insulinand b-adrenoceptor agonists (88). On that basis onemight expect bicarbonate to augment the hypokalemice�ect of insulin or albuterol. The two studies ofbicarbonate in combination with insulin have showncon¯icting results (88,89), andbicarbonatewithalbuterolshowed no advantage over albuterol alone (89). Insummary, there appears to be noplace for bicarbonate inthemanagement of urgent hyperkalemia in patients withESRD.

Elimination of Potassium from the Body

Exchange Resin. Sodium polystyrene sulfonate(SPS; Kayexalate, Kionex) is a cation exchange resinthat is prepared in the sodium phase. In the lumen ofthe intestine it exchanges sodium for secreted potas-sium. Most of this exchange takes place in the colon,the site of most potassium secretion in the gut. Each

Ahmed and Weisberg352

gram of resin binds approximately 0.65 mmol ofpotassium in vivo (91), although the e�ect is highlyvariable and unpredictable. The sodium liberated fromthe resin may amount to 4 mmol/g, the disproportionwith bound potassium being caused by the fact that theresin binds cations other than just potassium (e.g.,hydrogen ion, calcium, and magnesium). This liberatedsodium can cause detectable volume expansion, ane�ect that is mitigated by the use of a cathartic (91).The resin causes constipation and hence almost alwaysis given with a cathartic. It may be given orally or byretention enema, although the oral route is consideredto be more e�ective because of the longer transit timethrough the gut lumen.There are two concerns with the use of SPS for the

treatment of urgent hyperkalemia. The ®rst is itsquestionable e�cacy. When given orally, the onset ofaction is at least 2 hours and themaximume�ectmaynotbe seen for 6 hours or more. The e�ect of SPS as aretention enema is more rapid but of lesser magnitude.One recent study in normokalemic hemodialysis patientsfailed to showany e�ect onSKover 12hours after anoraldose of SPS with cathartic (91). Whether an e�ect mighthave been seen with SPS in patients with hyperkalemiacannot be known, since withholding more rapid ande�cacious measures such as insulin and albuterol wouldbe unethical.The second concern with SPS is its possible toxicity.

There are numerous case reports of patients who havedeveloped intestinal necrosis after exposure to SPS insorbitol as an enema (92±94) and as an oral agent (95). Aretrospective study estimated the incidence of colonicnecrosis to be 1.8% among postoperative patientsreceiving SPS (95). Thus the slow onset of action,questionable e�cacy, and infrequent but serious toxicitymake SPS a poor choice for the treatment of urgenthyperkalemia in patients with ESRD.

Dialysis. Hemodialysis is the method of choice forremoval of potassium from the body. The change in SKwith hemodialysis is a function of the rate of potassiumremoval from plasma to bath across the dialyzermembrane (almost exclusively by di�usion in proportionto the transmembrane potassium gradient) and the rateof potassium ¯ux from the intracellular to the extra-cellular ¯uid compartment. The former rate is consider-ably greater than the latter. This leads to a steep initialdecline in SK followed by a more gradual decline as thehemodialysis treatment progresses.A typical study of 14 hyperkalemic patients on

maintenance hemodialysis demonstrated that the SKwas reduced by more than 1 mmol/L in the ®rst60 minutes of hemodialysis against a bath potassiumconcentration of 1mmol/L using a 2.0m2 dialyzer with ablood ¯ow rate of 300 ml/min (95). SK fell by another1 mmol/L over the next 2 hours, after which it wasunchanged for the remainder of the treatment, such thatby the end of the 4-hour treatment, SK had fallen byabout 2 mmol/L. The observation of a plateau in the SKafter 3 hours of hemodialysis is reproducible and appearsto be independent of the bath potassium concentrationover the range of 0±2 mmol/L (97).

The inequality in the rates of potassium ¯ux acrossthe dialyzer membrane and the cell membrane alsoexplains the rebound in SK that is universally seen inthe hours after dialysis. An average of 35% of the SKreduction is abolished in the ®rst hour after a typicalhemodialysis treatment, and nearly 70% is abolished bythe sixth hour. The postrebound SK correlates with thepredialysis SK (96). Thus hemodialysis for serioushyperkalemia may need to be repeated sooner than onemight have anticipated because of recurrent hyperkal-emia. Dialysis against a high sodium bath (143 mmol/Lversus 138 mmol/L) results in an exaggerated rebound,presumably because of the e�ect of extracellularhypertonicity to impair cellular potassium uptake(98). Temporizing treatment with insulin and albuterolbefore hemodialysis results in reduced potassiumremoval by dialysis and may also cause an exaggeratedrebound (99).The amount of potassium removed during a dialysis

treatment depends on many factors, including theinitial SK, the surface area of the dialyzer, the blood¯ow rate, the length of the treatment and the bathpotassium concentration. About 40% of the dialyzedpotassium comes from the extracellular ¯uid space, theremainder deriving from the intracellular ¯uid com-partment (96). Two studies using nearly identicaldialysis prescriptions (4-hour treatment, blood ¯owrate 300 ml/min, dialysate ¯ow rate 500 ml/min, high-¯ux dialyzer, bath potassium concentration 1 mmol/L)in similar adult populations showed that potassiumremoval ranged between about 80 mmol and 140mmol (96,97).The wide range in inter- and intraindividual potas-

sium dialysance probably relates to variations in thehormonal milieu at the time of the treatment (100). Forexample, compared with the standard 200 mg/dlglucose bath, glucose-free dialysate has been associatedwith an equivalent decline in SK, but a somewhathigher rate of potassium removal (97,100,101); this hasbeen attributed to reduced insulin levels, leading toenhanced cellular potassium e�ux during dialysis (101).Conversely, cellular potassium uptake during hemod-ialysis (due to a combination of very high dialysateglucose and abrupt correction of profound metabolicacidosis) can lead to severe hypokalemia, with apostdialysis SK substantially lower than the bathpotassium concentration (102).Several groups of investigators have found the

hemodialysis treatment itself to increase the rate ofventricular ectopy (103±106), although others note nosuch increase (107±109). Among those who haveobserved increased ectopy, the majority ®nd a relation-ship with dialysis-induced reductions in SK (103,110±112), although, again, this is not universally found (105).Serious dialysis-related arrhythmias havebeen independ-ently associated with underlying coronary artery disease(105,106), left ventricular hypertrophy and digoxin use(103), systolic blood pressure (109), and advanced age(105,109). One small study showed that hemodialysisagainst a bath without potassium was not associatedwith serious ventricular ectopy except in the one patientwho had ectopy with dialysis against even a standard

HYPERKALEMIA IN DIALYSIS PATIENTS 353

potassium bath (113). Larger studies, however, haveshown the frequency of dialysis-associated ventricularectopy to be reduced by potassium modeling of thebath, such that the bath potassium concentration isdecreased in parallel with the SK during the treatment(110,112,114). We recommend continuous cardiac mon-itoring of all patients dialyzed for hyperkalemia against a0or 1mmol/Lbath.High-riskpatients (as de®nedabove)may bene®t from a graded reduction in the bathpotassium concentration during hemodialysis forhyperkalemia.The rate of potassium removal with peritoneal dialysis

is much slower than with hemodialysis. Indeed, much ofthedecrement inSKwithperitoneal dialysis appears tobedue to translocation of potassium into cells as a result ofthe glucose load rather than extracorporeal disposal(115). This modality may be used for patients onmaintenance peritoneal dialysis who have modesthyperkalemia.

Prevention of Hyperkalemia

As detailed previously (see Cellular Uptake), manyfactors modulate the relationship between SK and totalbody potassium in patients with ESRD. Indeed, theamount of potassium removed during a hemodialysissession appears to have little in¯uence on the nextpredialysis SK (114). Nonetheless, persistent hyperkal-emia in dialysis patients is likely to be causedbydisordersof external potassium balance: excessive potassiumintake, inadequate potassium elimination, or a combi-nation of the two.Excessive potassium intake most commonly is due to

dietary noncompliance. Severe abuse of the dialysis diethas been reported to occur in more than 20%of patients(116), but noncompliance is not uniform across alldietary components. There is little or no correlationbetween other measures of dietary noncompliance, suchas interdialytic weight gain or serum phosphorus con-centration, andSK (117). Important as dietarypotassiummay be, there is little basis in the literature for making aprescription. As a rough guide to dietary potassiumintake, we may use estimates of daily potassium losses(dialytic and nondialytic) in hemodialysis patients.Dialytic losses amount to about 1.5 mmol/kg bodyweight/treatment (96,97), and stool losses account forabout 0.3 mmol/kg body weight/day (118). Assuminghemodialysis treatments three times a week, totalpotassium elimination would be 6.6 mmol/kg/weekÐabout 66 mmol/day for a 70 kg patient with no residualrenal function. This crude estimate is subject to drasticadjustment by themany in¯uences on internal potassiumbalance.Inadequate dialysis, either by prescription, noncom-

pliance, or due to vascular access complications, isanother common predisposition to hyperkalemia. Con-stipation deprives dialysis patients of a quantitativelyimportant route of potassium elimination (11,12,15)and should be avoided with the judicious use of laxa-tives. Drugs that impair renal potassium elimination(e.g., potassium-sparing diuretics, COX-1 and COX-2

inhibitors, converting enzyme inhibitors, and angioten-sin receptor blockers)may contribute to thedevelopmentof hyperkalemia in patients with substantial residualrenal function.Disorders of internal potassium balance that likewise

may predispose patients with ESRD to hyperkalemiashould be anticipated and avoided. Fasting, as inpreparation for surgical procedures, may cause signi-®cant hyperkalemia (29) and can be prevented by acontinuous intravenous infusion of 1 L of 10%dextrose and 20 units of regular insulin at a rate of50 ml/hr during the fast (119). Intravenous dextrosealone appears to be less e�cacious (119), and would becontraindicated in diabetic patients because of thepossibility of exacerbating the hyperkalemia by hyper-glycemia. Prolonged use of nonselective b-adrenoceptorblockers like propranolol has been shown to increasepredialysis SK signi®cantly (40). If b-adrenoceptorblockers are indicated, cardioselective blockers shouldbe used, recognizing that the b1-adrenoceptor speci®c-ity is lost at high doses.To the extent that aldosteronemay enhance extrarenal

potassium disposal, hemodialysis circuit anticoagulationwith low molecular weight heparin (which suppressesangiotensin-mediated aldosterone biosynthesis less thanunfractionated heparin) may be of some small bene®t inreducing predialysis SK (120). At present, there is noevidence to support the use of exogenous mineralocor-ticoids to improve long-term potassium tolerance inESRD patients (15,52). Quite contrary to expectations,an uncontrolled, unblinded study showed that fosinoprilin habitually hyperkalemic hemodialysis patientswas associated with a decrease in SK over an 8-weekperiod (121).By inhibiting Na,K-ATPase, digoxin intoxication

allows potassium e�ux from cells and can causesigni®cant hyperkalemia in ESRD (122). Thus digoxinlevels must be monitored closely in dialysis patients, anddose adjustmentsmust bemade cautiously. Succinylcho-line, which has been associated with severe redistributivehyperkalemia in patients with neuromuscular disorders,appears to be of no particular risk to patients withESRD (123).In summary, ESRD predisposes patients to hyper-

kalemia for many reasons. We have tried to elucidatethe pathophysiology of potassium homeostasis inESRD in hopes of providing a rational basis for theprevention and treatment of hyperkalemia in thispopulation of patients.

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