Brenner and Rector's The Kidney, 8th ed.

CHAPTER 15. Disorders of Potassium Balance

David B. Mount Kambiz Zandi-Nejad

		Normal Potassium Balance, 547
		Potassium Transport Mechanisms, 547
		Factors Affecting Internal Distribution of Potassium, 548
		Renal Potassium Excretion, 551
		Potassium Secretion in the Distal Nephron, 551
		Potassium Reabsorption in the Distal Nephron, 552
		Control of Potassium Secretion: Aldosterone, 553
		Control of Potassium Secretion: The Effect of K+ Intake, 554
		Urinary Indices of Potassium Excretion, 555
		Regulation of Renal Renin and Adrenal Aldosterone, 555
		Consequences of Hypokalemia and Hyperkalemia, 556
		Consequences of Hypokalemia, 556
		Consequences of Hyperkalemia, 556
		Causes of Hypokalemia, 558
		Epidemiology, 558
		Spurious Hypokalemia, 558
		Redistribution and Hypokalemia, 558
		Hypokalemic Periodic Paralysis, 558
		Non-renal Potassium Loss, 559
		Renal Potassium Loss, 559
		Treatment of Hypokalemia, 565
		Causes of Hyperkalemia, 567
		Epidemiology, 567
		Pseudohyperkalemia, 568
		Excess Intake of Potassium and Tissue Necrosis, 568
		Redistribution and Hyperkalemia, 568
		Reduced Renal Potassium Excretion, 570
		Medication-related Hyperkalemia, 571
		The Clinical Approach to Hyperkalemia, 573
		Management of Hyperkalemia, 573
		Antagonism of Cardiac Effects: Calcium, 574
		Redistribution of K+ into Cells, 575
		Removal of Potassium, 576

The diagnosis and management of potassium disorders are central skills in clinical nephrology, relevant not only to consultative nephrology but also to dialysis and renal transplantation. An understanding of the underlying physiology is an obligatory component of the approach to hyperkalemic and hypokalemic patients. This chapter reviews those aspects of the physiology of potassium homeostasis judged to be relevant to the understanding of potassium disorders; a more detailed review is provided in Chapter 5 .

The physiology and pathophysiology of potassium disorders continue to evolve at a rapid rate. The ever-expanding armamentarium of drugs with a potential to affect serum potassium (K⁺) has both complicated clinical analysis and provided new insight. The evolving molecular understanding of rare disorders affecting serum K⁺ has also uncovered novel pathways of regulation; whereas none of these disorders constitute a “public health menace”,^[1] they are experiments of nature that have provided new windows on critical aspects of potassium homeostasis. Finally, the increasing availability of knockout and transgenic mice with precisely defined genetic modifications has provided the unprecedented opportunity to extend the relevant molecular physiology to whole-animal studies. These advances can be incorporated into an increasingly mechanistic, molecular understanding of potassium disorders.^[1a]

NORMAL POTASSIUM BALANCE

The dietary intake of potassium ranges from <35 to >110 mmoles/day in U.S. men and women. Despite this widespread variation in intake, homeostatic mechanisms precisely maintain serum K⁺ between 3.5 and 5.0 mmol/L. In a healthy individual at steady state, the entire daily intake of potassium is excreted, approximately 90% in the urine and 10% in the stool. More than 98% of total body potassium is intracellular, chiefly in muscle ( Fig. 15-1 ). Buffering of extracellular K⁺ by this large intracellular pool plays a crucial role in the regulation of serum K⁺.^[2] Thus within 60 minutes of an intravenous load of 0.5 mmol/kg of K⁺-Cl^- only 41% appears in the urine, yet serum K⁺ rises by no more than 0.6 mmol/L^[3]; adding the equivalent 35 millimoles exclusively to the extracellular space of a 70 kg man would be expected to raise serum K⁺ by ∼2.5 mmol/L.^[4] Changes in cellular distribution also defend serum K⁺ during K⁺ depletion. For example, military recruits have been shown to maintain a normal serum K⁺ after 11 days of basic training, despite a profound K⁺ deficit generated by renal and extra-renal loss.^[5] The rapid exchange of intracellular K⁺ with extracellular K⁺ plays a crucial role in maintaining serum K⁺ within such a narrow range; this is accomplished by overlapping and synergistic^[6] regulation of a number of renal and extra-renal transport pathways.

FIGURE 15-1 Body K+ distribution and cellular K+ flux.

Potassium Transport Mechanisms (see Chapter 5 )

The intracellular accumulation of K⁺ against its electrochemical gradient is an energy-consuming process, mediated by the ubiquitous Na⁺/K⁺-ATPase enzyme. The Na⁺/K⁺-ATPase functions as an electrogenic pump, given that the stoichiometry of transport is three intracellular Na⁺ ions to two extracellular K⁺ ions. The enzyme complex is made up of a tissue-specific combination of multiple α-, β-, and γ-subunits, which are further subject to tissue-specific patterns of regulation.^[7] The Na⁺/K⁺-ATPase proteins share significant homology with the corresponding subunits of the H⁺/K⁺-ATPase enzymes (see later discussion on potassium reabsorption in the distal nephron). Cardiac glycosides (i.e., digoxin and ouabain) bind to the a subunits of Na⁺/K⁺-ATPase at an exposed extracellular hairpin loop that also contains the major binding sites for extracellular K⁺.^[8] The binding of digoxin and K⁺ to the Na⁺/K⁺-ATPase complex is thus mutually antagonistic, explaining in part the potentiation of digoxin toxicity by hypokalemia.^[9] Although the four a subunits have equivalent affinity for ouabain, they differ significantly in intrinsic K⁺/ouabain antagonism.^[10] Ouabain binding to isozymes containing the ubiquitous α-1 subunit is relatively insensitive to K⁺ concentrations within the physiological range, such that this isozyme is protected from digoxin under conditions wherein cardiac α-2 and α-3 subunits, the probable therapeutic targets,^[11] are inhibited.^[10] Genetic reduction in cardiac α-1 content has a negative ionotropic effect,^[11] such that the relative resistance of this subunit to digoxin at physiological serum K⁺ likely has an additional cardioprotective effect. Notably, the digoxin/ouabain binding site of a subunits is highly conserved, suggesting a potential role in the physiological response to endogenous ouabain/digoxin-like compounds. Recently, “knockin” mice have been generated that express α-2 subunits with engineered resistance to ouabain. These mice are strikingly resistant to ouabain-induced hypertension^[12] and to adrenocorticotropic hormone (ACTH)-dependent hypertension,^[13] the latter known to involve an increase in circulating ouabain-like glycosides. This provocative data lends new credence to the highly controversial role of such ouabain-like molecules in hypertension and cardiovascular disease. Furthermore, modulation of the K⁺-dependent binding of circulating ouabain-like compounds to Na⁺/K⁺-ATPase may underlie at least some of cardiovascular complications of hypokalemia.^[14]

Skeletal muscle contains as much as 75% of body potassium (see Fig. 15-1 ), and exerts considerable influence on extracellular K⁺. Exercise is thus a well-described cause of transient hyperkalemia; interstitial K⁺ in human muscle can reach levels as high as 10 μM after fatiguing exercise.^[15] Not surprisingly, therefore, changes in skeletal muscle Na⁺/K⁺-ATPase activity and abundance are major determinants of the capacity for extra-renal K⁺ homeostasis. Hypokalemia induces a marked decrease in muscle K⁺ content and Na⁺/K⁺-ATPase activity,^[16] an “altruistic”^[2] mechanism to regulate serum K⁺. This is primarily due to dramatic decreases in the protein abundance of the α-2 subunit of Na⁺/K⁺-ATPase.^[17] In contrast, hyperkalemia due to potassium loading is associated with adaptive increases in muscle K⁺ content and Na⁺/K⁺-ATPase activity.^[18] These interactions are reflected in the relationship between physical activity and the ability to regulate extracellular K⁺ during exercise.^[19] For example, exercise training is associated with increases in muscle Na⁺/K⁺-ATPase concentration and activity, with reduced interstitial K⁺in trained muscles^[20] and an enhanced recovery of serum K⁺ after defined amounts of exercise.^[19]

Potassium can also accumulate in cells by coupling to the gradient for Na⁺ entry, entering via the electroneutral Na⁺-K⁺-2Cl^- cotransporters NKCC1 and NKCC2. The NKCC2 protein is found only at the apical membrane of thick ascending limb (TAL) and macula densa cells (see Figs. 15-2 and 15-9 [2] [9]), where it functions in transepithelial salt transport and tubular regulation of renin release.^[20] In contrast, NKCC1 is widely expressed in multiple tissues,^[21] including muscle. The cotransport of K⁺-Cl^- by the four K⁺-Cl^- cotransporters (KCC1-4) can also function in the transfer of K⁺ across membranes; although the KCCs typically function as efflux pathways driven by the electrochemical gradient,^[22] they can mediate influx when extracellular K⁺ increases.^[21] Whereas the collective role of NKCC1 and the four KCCs in regulating intracellular Cl^- activity is increasingly accepted,^[21] their function in potassium homeostasis is as yet unclear.

FIGURE 15-9 Bartter syndrome and the thick ascending limb. Bartter syndrome can result from loss-of-function mutations in the Na+-K+-2Cl- cotransporter NKCC2, the K+ channel subunit ROMK, or the Cl- channel subunits CLC-NKB and Barttin (Bartter syndrome types I to IV, respectively). Gain-of-function mutations in the calcium-sensing receptor CaSR can also cause a Bartter syndrome phenotype (type V); the CaSR has an inhibitory effect on salt transport by the thick ascending limb, targeting several transport pathways. ROMK encodes the low conductance 30 pS K+ channel in the apical membrane, and also appears to function as a critical subunit of the higher conductance 70 pS channel. The loss of K+ channel activity Bartter syndrome type II leads to reduced apical K+ recycling and reduced Na+-K+-2Cl- cotransport. Decreased apical K+ channels also lead to a decrease in the lumen-positive potential difference, which drives paracellular Na+, Ca2+, and Mg2+ transport.

The efflux of K⁺ out of cells is largely accomplished by K⁺ channels, which comprise the largest family of ion channels in the human genome. There are three major subclasses of mammalian K⁺ channels; the six-transmembrane domain (TMD) family,^[23] which encompasses both the voltage-sensitive and Ca²⁺-activated K⁺ channels, the two-pore, four TMD family,^[24] and the two TMD family of inward rectifying K⁺ (Kir) channels.^[25] There is tremendous genomic variety in human K⁺ channels, with 26 separate genes encoding principal subunits of the voltage-gated Kv channels and 16 genes encoding the principal Kir subunits. Further complexity is generated by the presence of multiple accessory subunits and alternative patterns of mRNA splicing. Not surprisingly, an increasing number and variety of K⁺ channels have been implicated in the control of K⁺ homeostasis and the membrane potential of excitable cells such as muscle and heart.

Factors Affecting Internal Distribution of Potassium

A number of hormones and physiological conditions have acute effects on the distribution of K⁺ between the intracellular and extracellular space ( Table 15-1 ). Some of these factors are of particular clinical relevance, and are therefore reviewed in detail.

TABLE 15-1 -- Factors Affecting K⁺ Distribution between Intracellular and Extracellular Compartments

Acute
Factor	Effect on Potassium
Insulin	Enhanced cell uptake
β-Catecholamines	Enhanced cell uptake
α-Catecholamines	Impaired cell uptake
Acidosis	Impaired cell uptake
Alkalosis	Enhanced cell uptake
External potassium balance	Loose correlation
Cell damage	Impaired cell uptake
Hyperosmolality	Enhanced cell efflux

Chronic
Factor	Effect on ATP Pump Density
Thyroid	Enhanced
Adrenal steroids	Enhanced
Exercise (training)	Enhanced
Growth	Enhanced
Diabetes	Impaired
Potassium deficiency	Impaired
Chronic renal failure	Impaired

From Giebisch G: Renal potassium transport: Mechanisms and regulation. Am J Physiol 274:F817–833, 1998.

Insulin

The effect of insulin to decrease serum K⁺ has been known since the early twentieth century.^[26] The impact of insulin on plasma K⁺ and plasma glucose is separable at multiple levels, suggesting independent mechanisms. ^{[17] [28]}Notably, the hypokalemic effect of insulin is not renal-dependent.^[28] Insulin and K⁺ appear to form a feedback loop of sorts, in that increases in serum K⁺ have a marked stimulatory effect on insulin levels. ^{[17] [30]} Inhibition of basal insulin secretion in normal subjects by somatostatin infusion increases serum K⁺ by up to 0.5 mmol/L, in the absence of a change in urinary excretion, emphasizing the crucial role of circulating insulin in the regulation of serum K⁺.^[30]

Insulin stimulates the uptake of K⁺ by several tissues, most prominently liver, skeletal muscle, cardiac muscle, and fat. ^{[17] [32]} It does so by activating several K⁺ transport pathways, with particularly well-documented effects on the Na⁺/K⁺-ATPase.^[32] Insulin activates Na⁺-H⁺ exchange and/or Na⁺-K⁺-2Cl^- cotransport in several tissues; although the ensuing increase in intracellular Na⁺ was postulated to have a secondary activating effect on Na⁺/K⁺-ATPase,^[33] it is clear that this is not the primary mechanism in most cell types.^[34] Insulin induces translocation of the Na⁺/K⁺-ATPase α-2 subunit to the plasma membrane of skeletal muscle cells, with a lesser effect on the α-1 subunit.^[35] This translocation is dependent on the activity of phosphoinositide-3 kinase (PI-3) kinase,^[35] which itself also binds to a proline-rich motif in the N-terminus of the a subunit.^[36] The activation of PI3-kinase by insulin thus induces phosphatase enzymes to dephosphorylate a specific serine residue adjacent to the PI3-kinase binding domain. Trafficking of Na⁺/K⁺-ATPase to the cell surface also appears to require the phosphorylation of an adjacent tyrosine residue, perhaps catalyzed by the tyrosine kinase activity of the insulin receptor itself.^[37] Insulin-stimulated K⁺ uptake, measured in rats using a “K⁺ clamp” technique, is rapidly reduced by 2 days of K⁺ depletion, before a modest drop in plasma K⁺,^[38] and in the absence of a change in plasma K⁺ in rats subject to a lesser K⁺ restriction for 14 days.^[6] Insulin-mediated K⁺ uptake is thus modulated by the factors that preserve plasma K⁺ in the setting of K⁺ deprivation.

In addition to mediating the direct cellular entry of K⁺, Na⁺/K⁺-ATPase and other pathways activated by insulin induce a hyperpolarization of the plasma membrane,^[39] resulting in increased passive entry of K⁺. Electroneutral transport pathways are also activated by insulin in peripheral tissue, including Na⁺-K⁺-2Cl^- cotransport in adipocytes^[40] and K⁺-Cl^- cotransport in skeletal muscle.^[41]

Sympathetic Nervous System

The sympathetic nervous system plays a prominent role in regulating the balance between extracellular and intracellular K⁺. Again, as is the case for insulin, the effect of catecholamines on plasma K⁺ has been known for some time^[42]; however, a complicating issue is the differential effect of stimulating α- and β-adrenergic receptors ( Table 15-2 ). Uptake of K⁺ by liver and muscle, with resultant hypokalemia, is stimulated via β₂ receptors. ^{[44] [45]} The hypokalemic effect of catecholamines appears to be largely independent of changes in circulating insulin,^[45] and has been reported in nephrectomized animals.^[46] The cellular mechanisms whereby catecholamines induce K⁺uptake in muscle include an activation of the Na⁺/K⁺-ATPase,^[47] likely via increases in cyclic-AMP.^[48] However, β-adrenergic receptors in skeletal muscle also activate the inwardly directed Na⁺-K⁺-2Cl^- cotransporter NKCC1, which may account for as much as one third of the uptake response to catecholamines. ^{[17] [50]}

TABLE 15-2 -- Sustained Effects of β– and α–Adrenergic Agonists and Antagonists on Serum K⁺

Catecholamine Specificity	Sustained Effect on Serum K+
β1 + β2 agonist (epinephrine, isoproterenol)	Decrease[*]
Pure β1 agonist (ITP)	None
Pure β2 agonist (salbutamol, soterenol, terbutaline)	Decrease
β1 + β2 Antagonist (propranolol, sotalol)	Increase; blocks effect of β agonists
β1 Antagonist (practolol, metoprolol, atenolol)	None; does not block effect of β agonists
β2 Antagonist (butoxamine, H 35/25)	Blocks hypokalemic effect of β agonists
α Agonist (phenylephrine)	Increase
α Antagonist (phenoxybenzamine)	None; blocks effect of α agonist

ITP, isopropylamino-3-(2thiazoloxy)-2-propanol.

*	Results refer to the late (after 5 min), sustained effect.

In contrast to β-adrenergic stimulation, α-adrenergic agonists impair the ability to buffer increases in K⁺ induced via intravenous loading or by exercise^[50]; the cellular mechanisms whereby this occurs are not known. It is thought that β-adrenergic stimulation increases K⁺ uptake during exercise to avoid hyperkalemia, whereas α-adrenergic mechanisms help blunt the ensuing post-exercise nadir.^[50] The clinical consequences of the sympathetic control of extra-renal K⁺ homeostasis are reviewed elsewhere in this chapter.

Acid-Base Status

The association between changes in pH and serum K⁺ was observed some time ago.^[51] It has long been held that acute disturbances in acid-base equilibrium results in changes in plasma K⁺, such that alkalemia shifts K⁺ into cells whereas acidemia is associated with K⁺ release from the cells. ^{[53] [54]} It is thought that this effective K⁺-H⁺ exchange helps maintain extracellular pH. Rather limited data exists for the durable concept that a change of 0.1 unit in plasma pH will result in 0.6 mmol/L change in plasma K⁺ in the opposite direction.^[54] However, despite the complexities of changes in K⁺ homeostasis associated with various acid-base disorders, a few general observations can be made. The induction of metabolic acidosis by the infusion of mineral acids (NH₄⁺-Cl^- or H⁺-Cl^-) consistently increases serum K⁺, ^{[53] [54] [55] [56] [57]} whereas organic acidosis generally fails to increase serum K⁺. ^{[54] [56] [58] [59]}Notably, a more recent report failed to detect an increase in plasma K⁺ in normal human subjects with acute acidosis secondary to duodenal NH₄⁺-Cl^- infusion, in which a modest acidosis was accompanied by an increase in circulating insulin.^[59] However, as noted by Adrogué and Madias,^[60] the concomitant infusion of 350 ml of D5W in these fasting subjects may have served to increase circulating insulin, thus blunting the potential hyperkalemic response to NH₄⁺-Cl^-. Clinically, use of the oral phosphate binder sevelamer in patients with end-stage renal disease (ESRD) is associated with acidosis, due to effective gastrointestinal absorption of H⁺-Cl^-; in hemodialysis patients this acidosis has been associated with an increase in serum K⁺,^[61] which is ameliorated by an increase in dialysis bicarbonate concentration.^[62] Metabolic alkalosis induced by sodium-bicarbonate infusion usually results in a modest reduction in plasma K⁺. ^{[53] [54] [55] [57] [64]} Respiratory alkalosis reduces serum K⁺, by a magnitude comparable to that of metabolic alkalosis. ^{[53] [54] [55] [65]} Finally, acute respiratory acidosis increases serum K⁺; the absolute increase is smaller than that induced by metabolic acidosis secondary to inorganic acids. ^{[53] [54] [55]} Again, however, some studies have failed to show a change in serum K⁺ following acute respiratory acidosis. ^{[54] [66]}

RENAL POTASSIUM EXCRETION

Potassium Secretion in the Distal Nephron

The proximal tubule and loop of Henle mediate the bulk of potassium reabsorption, such that a considerable fraction of filtered potassium is reabsorbed prior to entry into the superficial distal tubules.^[66] Renal potassium excretion is primarily determined by regulated secretion in the distal nephron, specifically within the connecting segment (CNT) and cortical collecting duct (CCD). The principal cells of the CCD and CNT play a dominant role in K⁺ excretion; the relevant transport pathways are shown in Figures 15-2 and 15-3 [2] [3]. Apical Na⁺ entry via the amiloride-sensitive epithelial Na⁺ channel (ENaC)^[67] results in the generation of a lumen-negative potential difference in the CNT and CCD, which drives passive K⁺ exit through an expanding list of apical K⁺ channels. A critical consequence of this relationship is that K⁺ secretion is dependent on delivery of adequate luminal Na⁺ to the CNT and CCD^{[69] [70]}; K⁺ secretion by the CCD essentially ceases as luminal Na⁺ drops below 8 mmol/L.^[70] Dietary Na⁺ intake also influences K⁺ excretion, such that excretion is enhanced by excess Na⁺ intake and reduced by Na⁺restriction ( Fig. 15-4 ). ^{[69] [70]} Basolateral exchange of Na⁺ and K⁺ is mediated by the Na⁺/K⁺-ATPase, providing the driving force for both Na⁺ entry and K⁺ exit at the apical membrane (see Figs. 15-2 and 15-3 [2] [3]).

FIGURE 15-2 Schematic cell models of potassium transport along the nephron. Cell types are as specified; TAL refers to thick ascending limb. Note the differences in luminal potential difference along the nephron. (From Giebisch G: Renal potassium transport: Mechanisms and regulation. Am J Physiol 274:F817–833, 1998.)

FIGURE 15-3 K+ secretory pathways in principal cells of the connecting segment (CNT) and cortical collecting duct (CCD). The absorption of Na+ via the amiloride-sensitive epithelial sodium channel (ENaC) generates a lumen-negative potential difference, which drives K+ excretion through the apical secretory K+ channel ROMK. Flow-dependent K+ secretion is mediated by an apical voltage-gated, calcium-sensitive maxi-K channel.

FIGURE 15-4 A, Relationship between steady-state serum K+ and urinary K+ excretion in the dog, as a function of dietary Na+ intake (mmol/day). Animals were adrenalectomized and replaced with aldosterone, dietary K+ and Na+ content were varied as specified. B, Relationship between steady-state serum K+ and urinary K+ excretion as a function of circulating aldosterone. Animals were adrenalectomized and variably replaced with aldosterone, dietary K+ content was varied. A (From Young DB, Jackson TE, Tipayamontri U, Scott RC: Effects of sodium intake on steady-state potassium excretion. Am J Physiol 246:F772–778, 1984.); B (From Young DB: Quantitative analysis of aldosterone's role in potassium regulation. Am J Physiol 255:F811–822, 1988.)

Electrophysiological characterization has documented the presence of several subpopulations of apical K⁺ channels in the CCD and CNT, most prominently a small-conductance (SK) 30 pS channel ^{[72] [73]} and a large-conductance, Ca²⁺-activated 150 pS (“maxi-K”) channel. ^{[73] [74]} The higher density and higher open probability of the SK channel suggests that it likely mediates K⁺ secretion under baseline conditions, hence its frequent designation as the “secretory” K⁺ channel. The characteristics of the SK channel are particularly to those of the K⁺ channel ROMK, encoded by the Kcnj1 gene,^[74] and ROMK protein has been localized at the apical membrane of principal cells.^[75]Definitive evidence that ROMK is the SK channel was obtained from mice with a targeted deletion of both alleles of the Kcnj1 gene; no 30 pS K⁺ channels were found in apical membranes from the CCD of these mice, with an intermediate channel density in heterozygous mice.^[73] The observation that ROMK knockout mice are normokalemic with an increased excretion of K⁺ serves to emphasize that there is considerable redundancy in distal K⁺secretory pathways^[73]; recent data suggest that distal K⁺ excretion in these mice is primarily mediated by maxi-K/BK channel activity (see later discussion).^[76]

Alternative apical K⁺ secretory pathways in the CNT and/or CCD include the Ca²⁺-activated maxi-K channel,^[71] voltage-sensitive channels such as Kv1.3, ^{[78] [79]} KCNQ1, and double-pore K⁺ channels such as TWIK-1.^[24]Maxi-K channels, also known as “BK” channels, have a heteromeric structure, encompassing functional α-subunits that form the ion channel pore and modulatory β-subunits that affect the biophysical and pharmacological characteristics of the channel complex.^[71] Maxi-K α-subunit transcripts are expressed in multiple nephron segments, and channel protein is detectable at the apical membrane of principal and intercalated cells in the CCD and CNT.^[71] Increased distal flow has a well-established stimulatory effect on K⁺ secretion, due in part to both en-hanced delivery and absorption of Na⁺ and to increased removal of secreted K⁺. ^{[17] [69] [70]} The pharmacology of flow-dependent K⁺ secretion in the CCD is most consistent with maxi-K channels,^[79] and flow-dependent K⁺ secretion is reduced in mice with targeted deletion of the α1 and b1 subunits.^[71]

The role of the Kv1.3 and KCNQ1 channels in K⁺ secretion is less clear. However, Kv1.3 is activated by the aldosterone-induced kinase SGK (serum and glucocorticoid-induced kinase, see discussion on control of potassium secretion: aldosterone),^[80] and may serve as a “brake” on aldosterone-stimulated K⁺ excretion by reducing the lumen-negative potential difference.^[77] KCNQ1 mediates K⁺ secretion in the inner ear and is expressed at the apical membrane of principal cells in the CCD^[81]; the role of this channel in renal K⁺ excretion is not as yet known.

In addition to K⁺ channels, a series of studies in the distal nephron have suggested a role for apical K⁺-Cl^- cotransport in K⁺ secretion. ^{[23] [69] [83]} In rat distal tubules, a mixture of distal convoluted tubule (DCT), connecting segment, and initial collecting duct, a reduction in luminal Cl^- markedly increases K⁺ secretion. ^{[17] [84]} The replacement of luminal Cl^- with SO₄^- or gluconate has the same stimulatory effect on K⁺ secretion; analogous results have been reported in humans subjected to dietary modulation of excreted anions.^[84] This electroneutral component of K⁺ secretion is not influenced by luminal Ba²⁺, ^{[17] [84]} which inhibits K⁺ secretion through apical K⁺channels. These findings have been extended to the rabbit CCD, where a decrease in luminal Cl^- from 112 mmol/L to 5 mmol/L increases K⁺ secretion by 48%.^[85] A reduction in basolateral Cl^- also decreases K⁺ secretion without an effect on transepithelial voltage or Na⁺ transport, and the direction of K⁺ flux can be reversed by a lumen-to-bath Cl^- gradient, resulting in K⁺ absorption.^[85] In perfused CCDs from rats treated with mineralocorticoid, vasopressin increases K⁺ secretion^[86]; because this increase in K⁺ secretion is resistant to luminal Ba²⁺(2 mmol/L), vasopressin may stimulate Cl^--dependent K⁺ secretion.^[85] Recent pharmacological studies are consistent with K⁺-Cl^- cotransport mediated by the KCCs ^{[23] [83]}; of the three renal KCCs only KCC1 is apically expressed along the nephron (D.B.M., unpublished observations). Other functional possibilities for Cl^--dependent K⁺ secretion include the parallel operation of apical H⁺-K⁺-exchange and Cl^--HCO₃^- exchange in type B intercalated cells.^[87]

Potassium Reabsorption in the Distal Nephron

In addition to secretion, the distal nephron is capable of considerable reabsorption, particularly during restriction of dietary K⁺. ^{[17] [67] [89] [90]} This reabsorption is accomplished primarily by intercalated cells in the outer medullary collecting duct (OMCD), via the activity of apical H⁺/K⁺-ATPase pumps (see Fig. 15-2 ). H⁺/K⁺-ATPase constitutes the third major class of apical K⁺ transport in the distal nephron, with evolving roles in distal bicarbonate and K⁺ reabsorption.^[90] The H⁺/K⁺-ATPase enzymes are of course central to gastric acid secretion, and the availability of pharmacological inhibitors such as omeprazole was critical to the initial identification of their role in K⁺homeostasis. ^{[89] [90]}

Like the Na⁺/K⁺-ATPases, H⁺/K⁺-ATPase enzymes are members of the P-type family of ion transport ATPases. Although the HKa-1 (“gastric”) and HKa-2 (“colonic”) subunits are the best known, humans also have an HKa-4 subunit.^[91] Within the kidney, the HKa-1 subunit is expressed at the apical membrane of at least a subset of type A intercalated cells in the distal nephron. ^{[17] [92]} HKa-2 distribution in the distal nephron is more diffuse, with robust expression at the apical membrane of type A and B intercalated cells and connecting segment cells, with lesser expression in principal cells. ^{[93] [94]} Finally, the human HKa-4 subunit is detectable in intercalated cells of human kidneys.^[91] The various H⁺/K⁺-ATPase holoenzymes differ in pharmacological behavior, such that those assembled with the gastric HKa-1 are classically sensitive to the H⁺/K⁺-ATPase inhibitors SCH-28080 and omeprazole and resistant to ouabain, whereas the colonic HKa-2 subunit is usually sensitive to ouabain and resistant to SCH-28080. ^{[17] [95]} This pharmacology has helped clarify the role of individual subunits in H⁺/K⁺-ATPase activity of the distal nephron, in both normal and K⁺-restricted animals.

K⁺ deprivation induces a significant absorptive flux of K⁺ in the inner stripe of the outer medulla, which is largely inhibited by omeprazole and SCH-28080. ^{[17] [89]} Although both HKa-1 and HKa-2 are constitutively expressed in the distal nephron, tubule perfusion of normal animals suggests a functional dominance of omeprazole/SCH-28080-sensitive, ouabain-resistant H⁺/K⁺-ATPase activity, consistent with holoenzymes containing HKa-1. K⁺ depletion significantly increases the overall activity of H⁺/K⁺-ATPase in the collecting duct, with the emergence of a ouabain-sensitive H⁺/K⁺-ATPase activity.^[16] The limitations of the available pharmacology notwithstanding, these data suggest a dominance of HKa-2 during K⁺ depletion. This conclusion is supported by the dramatic up-regulation of HKa-2 transcript and protein in the outer and inner medulla during K⁺ depletion, as reported by multiple laboratories. ^{[17] [96] [97]} In contrast, HKa-1 abundance is minimally affected by K⁺ depletion. ^{[96] [97]}

The preceding discussion suggests that the HKa-2 H⁺/K⁺-ATPase plays a major role in K⁺ reabsorption by the distal nephron, serving to limit kaliuresis during K⁺ depletion. Indeed, mice with a homozygous targeted deletion of HKa-2 exhibit lower plasma and muscle K⁺ than wild-type litter mates when maintained on a K⁺-deficient diet. However, this appears to be due to marked loss of K⁺ in the colon rather than kidney because renal K⁺ excretion is appropriately reduced in the K⁺-depleted mutant mice.^[97] Presumably the lack of an obvious renal phenotype in either HKa-1^[98] or HKa-2^[97] knockout mice reflects the marked redundancy in the expression of HKa subunits in the distal nephron. Indeed, collecting ducts from the HKa-1 knockout mice have significant residual ouabain-resistant and SCH-28080-sensitive H⁺/K⁺-ATPase activities, consistent with the expression of other HKa subunits that confer characteristics similar to the “gastric” H⁺/K⁺-ATPase.^[99] However, more recent data from HKa-1 and HKa-2 knockout mice suggest that compensatory mechanisms in these mice are not accounted for by ATPase-type mechanisms.^[100]

In an alternative approach, transgenic mice have been generated with generalized over-expression of a “gain-of-function” mutation in H⁺/K⁺-ATPase. These mice globally over-express a mutant form of the HKb subunit, in which a tyrosine-to-alanine mutation within the C-terminal tail abrogates regulated endocytosis from the plasma membrane. The gastric glands of these mice constitutively express H⁺/K⁺-ATPase at the plasma membrane, with significant gastric hyperacidity.^[101] They also have higher plasma K⁺'s than their wild-type litter mates, with approximately half the fractional excretion of urinary K⁺,^[102] consistent with increased distal K⁺ reabsorption. These transgenic mice thus provide indirect evidence for the role of H⁺/K⁺-ATPase in K⁺ homeostasis.

Control of Potassium Secretion: Aldosterone

Aldosterone is well established as an important regulatory factor in K⁺ excretion. However, an increasingly dominant theme is that it plays a permissive and synergistic role (see next section). ^{[78] [104] [105]} This is reflected clinically in the frequent absence of hyperkalemia or hypokalemia in disorders associated with a deficiency or an overabundance of circulat-ing aldosterone, respectively (see Hyperaldosteronism and Hypoaldosteronism). Regardless, it is clear that aldosterone and downstream effectors of this hormone have clinically relevant effects on K⁺ secretion, and that the ability to excrete K⁺ is modulated by systemic aldosterone levels (see Fig. 15-4 ).

Aldosterone has no effect on the density of apical SK channels,^[105] despite the fact that it increases transcript levels of the ROMK (KCNJ1) gene that encodes this channel. ^{[107] [108]} Aldosterone does however induce a marked increase in the density of apical Na⁺ channels in the CNT and CCD,^[105] thus increasing the driving force for apical K⁺ excretion. The apical amiloride-sensitive epithelial Na⁺ channel is composed of three subunits, α-, β-, and γ-, that assemble together to synergistically traffic to the cell membrane and mediate Na⁺ transport.^[67] Aldosterone activates this channel complex by multiple mechanisms. First, it uniquely induces transcription of the α-ENaC subunit, via a glucocorticoid-response element in the channel's promoter.^[108] This is reflected in an increased abundance of α-ENaC protein in response to either exogenous aldosterone or dietary Na⁺-Cl^- restriction^[109]; the response of α-ENaC to Na⁺-Cl^- restriction is blunted by spironolactone, indicating that the effect is dependent on the mineralocorticoid receptor.^[110] Second, aldosterone and dietary Na⁺-Cl^- restriction stimulate a significant redistribution of ENaC subunits in the CNT and early CCD, from a largely cytoplasmic location during dietary Na⁺-Cl^- excess to a purely apical distribution after aldosterone or Na⁺-Cl^- restriction. ^{[111] [112] [113]} The leading mechanism whereby aldosterone promotes the intracellular redistribution of ENaC subunits has emerged over the past 6 to 7 years, in a spectacular convergence of human genetics and physiology. An aldosterone-induced kinase has thus been shown to regulate the interaction between ENaC channels and proteins discovered through the identification of disease-associated mutations in Liddle syndrome.

In cell culture systems, aldosterone strongly and rapidly induces a serine-threonine kinase called SGK-1 (serum and glucocorticoid-induced kinase-1)^[113]; co-expression of SGK with ENaC subunits results in a dramatic activation of the channel due to increased expression at the plasma membrane.^[111] Rapid induction of SGK-1 by aldosterone has also been shown in vivo,^[114] where it appears to correlate with the redistribution of channel protein to the plasma membrane.^[111] Unlike the effect on α-ENaC induction, spironolactone does not interfere with intracellular redistribution of ENaC subunits during dietary Na⁺-Cl^- restriction^[110]; this is consistent with the observation that SGK-1 also functions in the activation of ENaC by other hormones, including vasopressin and insulin. ^{[17] [116]}

The mechanism underlying the effect of SGK-1 on surface expression of ENaC was recently uncovered via the pathobiology of Liddle syndrome (see also discussion on Liddle syndrome). With one exception,^[116] autosomal dominant mutations in the β- and γ-ENaC subunits associated with Liddle syndrome affect a so-called PPxY motif in the cytoplasmic C-terminus of the channel proteins, resulting in a gain of function. This PPxY motif was shown to bind to WW domains of the ubiquitin-ligase Nedd4^[117] and the related protein Nedd4-2; the latter turns out to be the likely physiological regulator of ENaC.^[118] Co-expression of Nedd4-2 or Nedd4 with wild-type ENaC channel results in a marked inhibition of channel activity due to retrieval from the cell membrane, whereas channels bearing Liddle syndrome mutations are resistant.^[119] Nedd4-2 is thought to ubiquitinate ENaC subunits, resulting in the removal of channel subunits from the cell membrane and degradation in the proteosome ^{[120] [121]}; direct inhibition of channel activity by WW domains may also play a role.^[121] The circle between ENaC, aldosterone, and SGK-1 was ultimately closed with the observation that Nedd4-2 is a phosphorylation substrate for the latter, such that phosphorylation of Nedd4-2 by SGK abrogates its inhibitory effect on ENaC ( Fig. 15-5 ).^[122] Aldosterone thus rapidly induces a kinase that inhibits Nedd4-2–dependent retrieval of ENaC from the apical membrane. Aldosterone evidently stimulates Nedd4-2 phosphorylation in vivo^[123] and reduces Nedd4-2 protein expression in cultured CCD cells.^[124]

FIGURE 15-5 Coordinated regulation of ENaC by the aldosterone-induced SGK kinase and the ubiquitin ligase Nedd4-2. Nedd4-2 binds via its WW domains to ENaC subunits via their “PPXY” domains (denoted PY here), ubiquitinating the channel subunits and targeting them for removal from the cell membrane and destruction in the proteosome. Aldosterone induces the SGK kinase, which phosphorylates and inactivates Nedd4-2, thus increasing surface expression of ENaC channels. Mutations that cause Liddle syndrome affect the interaction between ENaC and Nedd4-2. (From Snyder PM, Olson DR, Thomas BC: Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. J Biol Chem 277:5–8, 2002.)

The importance of SGK-1 in K⁺ and Na⁺ homeostasis is illustrated by the phenotype of SGK-1 knockout mice. ^{[126] [127]} On a normal diet, homozygous SGK-1 -/- mice exhibit normal blood pressure and a normal serum K⁺, with only a mild elevation of circulating aldosterone. However, dietary Na⁺-Cl^- restriction of these mice results in relative Na⁺-wasting and hypotension, marked weight loss, and a drop in glomerular filtration rate (GFR), despite considerable increases in circulating aldosterone.^[126] In addition, dietary K⁺ loading over 6 days leads to a 1.5 μM increase in plasma K⁺, also accompanied by a considerable increase in circulating aldosterone (∼fivefold greater than that of wild-type litter mate controls).^[125] This hyperkalemia occurs despite evident increases in apical ROMK expression, compared with the normokalemic litter mate controls. The amiloride-sensitive, lumen-negative potential difference generated by ENaC is reduced in SGK-1 knockout mice,^[125] resulting in a decreased driving force for distal K⁺ secretion and the observed susceptibility to hyperkalemia.

Another novel mechanism whereby aldosterone activates ENaC involves proteolytic cleavage of the channel by serine proteases. A “channel activating protease” that increases channel activity of ENaC was identified some time ago in Xenopus laevis A6 cells.^[127] The mammalian ortholog, denoted CAP1^[128] or prostasin,^[129] is an aldosterone-induced protein in principal cells.^[129] Urinary excretion of CAP1 is increased in hyperaldosteronism, with a reduction after adrenalectomy. CAP1 is membrane-associated, via a glycosylphosphatidylinositol (GPI) linkage^[127]; mammalian principal cells also express two transmembrane proteases, denoted CAP2 and CAP3, with homology to CAP1.^[130] All three of these proteases activate ENaC by increasing the open probability of the channel, rather than by increasing expression at the cell surface.^[130] Because SGK increases channel expression at the cell surface,^[111] one would expect synergistic activation by co-expressed CAP1-3 and SGK; this is indeed the case.^[130] Therefore, aldosterone activates ENaC by at least three separate synergistic mechanisms; induction of α-ENaC, induction of SGK/repression of Nedd4-2, and induction of the channel-activating proteases (CAP1-3).

Aldosterone also has significant effects on the basolateral membrane of principal cells, with dramatic changes in cellular morphology and length of basolateral membranes in response to the hormone. ^{[132] [133]} This is accompanied by an increase in basolateral Na⁺/K⁺-ATPase activity, although it has been difficult to determine how much of these cellular and functional changes are due to enhanced Na⁺ entry via apical ENaC. ^{[134] [135]} It is however known that aldosterone increases the expression of the Na⁺/K⁺-ATPase α-1 and β-1 subunits in the CCD^[135]; these effects are evidently independent of ENaC activity.^[134]

Control of Potassium Secretion: The Effect of K⁺ Intake

Despite the evident importance of aldosterone in regulating K⁺ excretion, it is clear that other factors play important, synergistic roles. Chief among these is peritubular K⁺, induced experimentally by increases in K⁺ intake or by variation in tubule perfusion conditions. ^{[104] [105] [137]} A high K⁺ diet in adrenalectomized animals increases apical Na⁺ reabsorption and K⁺ secretion in the CCD, a qualitatively similar response to that induced by aldosterone.^[137] When peritubular K⁺ is increased, there is a significant activation of basolateral Na⁺/K⁺-ATPase, accompanied by a secondary activation of apical Na⁺ and K⁺ channels.^[138] Increased dietary K⁺ also significantly increases the density of SK channels in the CCD of normal, along with a modest increase in Na⁺ channel (ENaC) density.^[105] Notably, this increase in ENaC and SK density in the CCD occurs within hours of assuming a high K⁺ diet, with a minimal associated increase in circulating aldosterone.^[139] In contrast, a week of low Na⁺-Cl^- intake, with almost a 1000-fold increase in aldosterone, has no effect on SK channel density; nor for that matter does 2 days of aldosterone infusion, despite the development of hypokalemia.^[139] Therefore, despite the important role of aldosterone in “setting the stage” for K⁺ secretion, other factors affect the density and activity of apical K⁺ secretory channels in response to increases in dietary K⁺.

Considerable progress has recently been made in defining the signaling pathways that regulate the activity of ROMK, the SK channel, in response to changes in dietary K⁺. It appears that dietary K⁺ intake impacts on trafficking of the ROMK channel protein to the plasma membrane of principal cells, with a marked increase in the relative proportion of intracellular channel protein in K⁺-depleted animals ^{[141] [142]} and clearly defined expression at the plasma membrane of CCD cells from animals on a high-K⁺ diet.^[141] The membrane insertion and activity of ROMK is affected considerably by the tyrosine phosphorylation status of the channel protein, such that phosphorylation of tyrosine residue 337 stimulates endocytosis and dephosphorylation induces exocytosis ^{[143] [144]}; this tyrosine phosphorylation appears to play a dominant role in the regulation of ROMK by dietary K⁺.^[144] Whereas the levels of protein tyrosine phosphatase-1D do not vary with K⁺ intake, intra-renal activity of the cytoplasmic tyrosine kinases c-src and c-yes are inversely related to dietary K⁺ intake, with a decrease under high K⁺ conditions and a marked increase after several days of K⁺ restriction. ^{[146] [147]} Localization studies indicate co-expression of c-src with ROMK in TAL and principal cells of the CCD.^[141] Moreover, inhibition of protein tyrosine phosphatase activity, leading to a dominance of tyrosine phosphorylation, dramatically increases the proportion of intracellular ROMK in the CCD of animals on a high-K⁺ diet.^[141]

As reviewed earlier, maxi-K channels in the CNT and CCD play an important role in the flow-activated component of distal K⁺ excretion. Flow-stimulated K⁺ secretion by the CCD of both mice 76 and rats^[147] is enhanced on a high-K⁺ diet, with an absence of flow-dependent K⁺ secretion in rats on a low-K⁺ diet.^[147] This is accompanied by commensurate changes in transcript levels for α- and β_2–4-subunits of the maxi-K channel proteins in micro-dissected CCDs (β₁ subunits are restricted to the CNT^[71]), with a marked induction by dietary K⁺ loading and reduction by K⁺ deprivation. Trafficking of maxi-K subunits is also affected by dietary K⁺, with largely intracellular distribution of α-subunits in K⁺-restricted rats and prominent apical expression in K⁺-loaded rats.^[147]

The upstream K⁺-dependent stimuli that affect the trafficking and expression of ROMK and maxi-K channels in the distal nephron are not as yet known. However, a landmark study recently implicated the intra-renal generation of superoxide anions in the activation of cytoplasmic tyrosine kinases and downstream phosphorylation of the ROMK channel protein by K⁺ depletion.^[148] What might the circulating factor(s) be that respond to reduced dietary K⁺, leading to increases in intra-renal superoxides and a reduced kaliuresis? Potential candidates include angiotensin II (ATII) and growth factors such as IGF-1.^[148] Regardless, reports of a marked post-prandial kaliuresis in sheep, independent of changes in plasma K⁺ or aldosterone, have led to the suggestion that an enteric or hepatoportal K⁺ “sensor” controls kaliuresis via a sympathetic reflex.^[149] These investigators have reported similar data for humans ingesting oral K⁺-citrate.^[150] More recently, Morita and colleagues^[151] suggested that a bumetanide-sensitive hepatoportal K⁺ sensor induces a significant kaliuresis in response to infusion of K⁺-Cl^- into rat portal vein, but not the inferior vena cava. Changes in dietary K⁺ absorption may thus have a direct “anticipatory” effect on K⁺ homeostasis, in the absence of changes in plasma K⁺. Such a “feedforward” control has the theoretical advantage of greater stability because it operates prior to changes in plasma K⁺, which induce the “feedback” element of control.^[152] Notably, changes in ROMK phosphorylation status and insulin-sensitive muscle uptake can be seen in K⁺-deficient animals in the absence of a change in plasma K⁺,^[6] suggesting that upstream activation of the major mechanisms that serve to reduce K⁺ excretion (reduced K⁺ secretion in the CNT/CCD, decreased peripheral uptake, and increased K⁺ reabsorption in the OMCD) does not require changes in plasma K⁺.

Finally, we should note in this context that new evidence has stimulated a reappraisal of the role of the CNT in regulated K⁺ and Na⁺ handling by the kidney (see also Chapter 5 ). It has recently been appreciated that the density of both Na⁺ and K⁺ channels is considerably greater in the CNT than in the CCD ^{[73] [154]}; the capacity of the CNT for Na⁺ reabsorption may be as much as 10 times greater than that of the CCD.^[153] Indeed, it is likely that, under basal conditions of high Na⁺-Cl^- and low K⁺ intake, the bulk of aldosterone-stimulated Na⁺ and K⁺ transport has occurred prior to the entry of tubular fluid into the CCD.^[154] The recruitment of ENaC subunits in response to dietary Na⁺ restriction begins in the CNT, with progressive recruitment of subunits in the CCD at lower levels of dietary Na⁺.^[112] With respect to K⁺ secretion, unlike the marked increase seen in the CCD, ^{[106] [140]} the density of SK channels in the CNT is not increased by high dietary K⁺ loading; again, this is consistent with progressive, axial recruitment of transport capacity for Na⁺ and K⁺ along the distal nephron.

Urinary Indices of Potassium Excretion

A bedside test to directly measure distal tubular K⁺ excretion in humans would be ideal, however for obvious reasons this not technically feasible. A widely used surrogate is the “transtubular K⁺ gradient” (TTKG), which is defined as follows:

The expected values of the TTKG are largely based on historical data, and are <3 in the presence of hypokalemia and >7 to 8 in the presence of hyperkalemia.^[155] Clearly water absorption in the CCD and medullary collecting duct is an important determinant of the absolute K⁺ concentration in the final urine, hence the use of a ratio of urine:plasma osmolality. Indeed, water absorption may in large part determine the TTKG, such that it far exceeds the limiting K⁺ gradient.^[156] The TTKG may be less useful in patients ingesting diets of changing K⁺ and mineralocorticoid intake.^[157] There is however a linear relationship between serum aldosterone and the TTKG, suggesting that it provides a rough approximation of the ability to respond to aldosterone with a kaliuresis.^[158] Moreover, the determination of urinary electrolytes provides measurement of urinary Na⁺, which will determine whether significant pre-renal stimuli are limiting distal Na⁺ delivery and thus K⁺ excretion (see also Fig. 15-4 ). Urinary electrolytes also afford the opportunity to calculate the urinary anion gap, an indirect index of urinary NH₄⁺ content and thus the ability to respond to an acidemia.^[159] Restraint is always advised, however, to avoid excessive flights of fancy in the physiological interpretation of urinary electrolytes.

Regulation of Renal Renin and Adrenal Aldosterone

Modulation of the renin-angiotensin-aldosterone (RAS) axis has profound clinical effects on K⁺ homeostasis. Although multiple tissues are capable of renin secretion, renin of renal origin has a dominant physiological impact. Renin secretion by juxtaglomerular cells within the afferent arteriole is initiated in response to a signal from the macula densa,^[160] specifically a decrease in luminal chloride^[161] transported through the Na⁺-K⁺-2Cl^- cotransporter (NKCC2) at the apical membrane of macula densa cells.^[21] In addition to this macula densa signal, decreased renal perfusion pressure and renal sympathetic tone stimulate renal renin secretion.^[16] The various inhibitors of renin release include angiotensin II, endothelin,^[162] adenosine,^[163] ANP, ^{[165] [166]} TNF-α,^[166] and vitamin D.^[167] The cGMP-dependent protein kinase type II (cGKII) tonically inhibits renin secretion, in that renin secretion in response to several stimuli is exaggerated in homozygous cGKII knockout mice.^[168] Activation of cGKII by atrial natriuretic peptide (ANP) or nitric oxide (or both) has a marked inhibitory effect on the release of renin from juxtaglomerular cells. ^{[165] [166]} Local factors that stimulate renin release from juxtaglomerular cells include prostaglandins,^[169] adrenomedullin,^[170] and catecholamines (b-1 receptors).^[171]

The relationship between renal renin release, the RAS, and cycloogenase-2 (COX-2) is particularly complex.^[172] COX-2 is heavily expressed in the macula densa,^[173] with a significant recruitment of COX-2⁽⁺⁾ cells seen with salt restriction or furosemide treatment. ^{[17] [174]} Reduced intracellular chloride in macula densa cells appears to stimulate COX-2 expression via p38 MAP kinase,^[174] whereas both aldosterone and angiotensin II (ATII) reduce its expression.^[172] Prostaglandins derived from COX-2 in the macula densa play a dominant role in the stimulation of renal renin release by salt restriction, furosemide, renal artery occlusion, or angiotensin converting enzyme (ACE) inhibition. ^{[17] [176]}

Renin released from the kidney ultimately stimulates aldosterone release from the adrenal via angiotensin II. Hyperkalemia per se is also an independent and synergistic stimulus ( Fig. 15-6 ) for aldosterone release from the adrenal gland, ^{[17] [177]} although dietary K⁺ loading is less potent than dietary Na⁺-Cl^- restriction in increasing circulating aldosterone.^[103] ATII and K⁺ both activate Ca²⁺ entry in adrenal glomerulosa cells, via voltage-sensitive T-type Ca²⁺ channels. ^{[17] [178]} Elevations in extracellular K⁺ thus depolarize glomerulosa cells and activate these Ca²⁺ channels, which are independently and synergistically activated by ATII.^[177] The physiological importance of the K⁺-dependent stimulation of adrenal aldosterone release is vividly illustrated by the phenotype of mice with a targeted deletion of the KCNE1 K⁺ channel subunit. These mice have an exaggerated adrenal release of aldosterone when placed on a high K⁺ diet.^[178] The KCNE1 gene is expressed in adrenal glomerulosa cells, where it presumably affects the electrophysiological response to increased extracellular K⁺.^[178]

FIGURE 15-6 Synergistic effect of increased extracellular K+ and angiotensin II (ANGII) in inducing aldosterone release from bovine adrenal glomerulosa cells. Dose response curves for ANGII were performed at extracellular K+ of 2 mmol/l (○) and 5 mmol/l (&z.cirf;). (From Chen XL, Bayliss DA, Fern RJ, Barrett PQ: A role for T-type Ca2+ channels in the synergistic control of aldosterone production by ANG II and K+. Am J Physiol 276:F674–683, 1999.)

The adrenal release of aldosterone due to increased K⁺ is dependent on an intact adrenal renin-angiotensin system,^[179] particularly during Na⁺ restriction. ACE inhibitors and angiotensin-receptor blockers (ARBs) thus completely abrogate the effect of high K⁺ on salt-restricted adrenals.^[180] Other clinically relevant activators of adrenal aldosterone release include prostaglandins^[181] and catecholamines,^[182] via increases in cyclic-AMP. ^{[184] [185]} Finally, ANP exerts a potent negative effect on aldosterone release induced by K⁺ and other stimuli,^[185] at least in part by inhibiting early events in aldosterone synthesis.^[186] ANP is therefore capable of inhibiting both renal renin release and adrenal aldosterone release, functions that may be central to the pathophysiology of hyporeninemic hypoaldosteronism.

CONSEQUENCES OF HYPOKALEMIA AND HYPERKALEMIA

Consequences of Hypokalemia

Excitable Tissues: Muscle and Heart

Hypokalemia is a well-described risk factor for both ventricular and atrial arrhythmias. ^{[188] [189] [190]} For example, in patients undergoing cardiac surgery, a serum K⁺ of <3.5 mmol/L is a predictor of serious intra-operative arrhythmia, peri-operative arrhythmia, and post-operative atrial fibrillation.^[190] Moderate hypokalemia does not, however, appear to increase the risk of serious arrhythmia during exercise stress testing.^[191] Electrocardiographic changes in hypokalemia include broad flat T waves, ST depression, and QT prolongation; these are most marked when serum K⁺ is <2.7 mmol/L. ^{[193] [194]} Hypokalemia, often accompanied by hypomagnesemia, is an important cause of the long QT syndrome (LQTS), either alone or in combination with drug toxicity^[194] or with LQTS-associated mutations in cardiac K⁺ and Na⁺ channels. ^{[196] [197]}

In muscle, hypokalemia causes hyperpolarization, thus impairing the capacity to depolarize and contract. Weakness and paralysis is therefore a not-infrequent consequence of hypokalemia of diverse etiologies. ^{[198] [199]} On an historical note, the realization in 1946 that K⁺ replacement reversed the hypokalemic diaphragmatic paralysis induced by management of diabetic ketoacidosis was a milestone in diabetes care.^[199] Pathologically, muscle biopsies in hypokalemic myopathy demonstrate phagocytosis of degenerating muscle fibers, fiber regeneration, and atrophy of type 2 fibers.^[200] Most patients with significant myopathy will have elevations in creatine kinase, and hypokalemia of diverse etiologies predisposes to rhabdomyolysis with acute renal failure.

Renal Consequences

Hypokalemia causes a host of structural and functional changes in the kidney, which are reviewed in detail elsewhere.^[201] In humans, the renal pathology includes a relatively specific proximal tubular vacuolization, ^{[202] [203]}interstitial nephritis,^[203] and renal cysts.^[204] Hypokalemic nephropathy can cause end-stage renal disease, mostly in patients with long-standing hypokalemia due to eating disorders and/or laxative abuse^[205]; acute renal failure with proximal tubular vasculopathy has also been described.^[206] In animal models, hypokalemia increases susceptibility to acute renal failure induced by ischemia, gentamicin, and amphotericin.^[16] Potassium restriction in rats induces cortical ATII and medullary endothelin-1 expression, with an ischemic pattern of renal injury.^[207] Morphological changes in this model are prevented by blockade of endothelin^[208] and ATII type 1 (AT₁)^[209] receptors.

The prominent functional changes in renal physiology that are induced by hypokalemia include Na⁺-Cl^- retention, polyuria,^[202] phosphaturia,^[210] hypocitraturia,^[211] and increased ammoniagenesis.^[201] K⁺ depletion in rats causes proximal tubular hyper-absorption of Na⁺-Cl^-, in association with an up-regulation of ATII,^[207] AT₁ receptor,^[212] and the α₂-adrenergic receptor^[213] in this nephron segment. NHE3, the dominant apical Na⁺ entry site in the proximal tubule, is massively (>700%) up-regulated in K⁺-deficient rats,^[214] which is consistent with the observed hyper-absorption of both Na⁺-Cl^- and bicarbonate.^[201] Polyuria in hypokalemia is due to poly-dipsia^[215] and to a vasopressin-resistant defect in urinary concentrating ability.^[201] This renal concentrating defect is multifactorial, with evidence for both a reduced hydro-osmotic response to vasopressin in the collecting duct^[201] and decreased Na⁺-Cl^- absorption by the TAL.^[216] K⁺ restriction has been shown to result in a rapid, reversible decrease in the expression of aquaporin-2 in the collecting duct,^[217] beginning in the CCD and extending to the medullary collecting duct within the first 24 hours.^[218] In the TAL, the marked reductions seen during K⁺ restriction in both the apical K⁺ channel ROMK and the apical Na⁺-K⁺-2Cl^- cotransporter NKCC2 ^{[141] [215]} reduce Na⁺-Cl^-absorption, and thus inhibit countercurrent multiplication and the driving force for water absorption by the collecting duct.

Cardiovascular Consequences

A large body of experimental and epidemiological evidence implicates hypokalemia or reduced dietary K⁺ (or both) in the genesis or worsening of hypertension, heart failure, and stroke.^[219] K⁺ depletion in young rats induces hypertension,^[220] with a salt sensitivity that persists after K⁺ levels are normalized; presumably this salt sensitivity is due to the significant tubulointerstitial injury induced by K⁺ restriction.^[207] Short-term K⁺ restriction in healthy humans and patients with essential hypertension also induces Na⁺-Cl^- retention and hypertension, ^{[222] [223] [224]} and abundant epidemiological data links dietary K⁺ deficiency or hypokalemia with hypertension or both. ^{[190] [220]}Correction of hypokalemia is particularly important in hypertensive patients treated with diuretics; blood pressure in this setting is improved with the establishment of normokalemia,^[224] and the cardiovascular benefits of diuretic agents are blunted by hypokalemia. ^{[226] [227]} Finally, K⁺ depletion may play important roles in the pathophysiology and progression of heart failure.^[219]

Consequences of Hyperkalemia

Excitable Tissues: Muscle and Heart

Hyperkalemia constitutes a medical emergency, primarily due to its effect on the heart. Mild increases in extracellular K⁺ affect the repolarization phase of the cardiac action potential, resulting in changes in T wave morphology or direction.^[227] Mild to moderate hyperkalemia depresses intracardiac conduction, with progressive prolongation of the PR and QRS intervals.^[228] Severe hyperkalemia results in loss of the P wave and a progressive widening of the QRS complex; fusion with T waves causes a “sine-wave” sinoventricular rhythm. Cardiac arrhythmias associated with hyperkalemia include sinus bradycardia, sinus arrest, slow idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, and asystole. ^{[228] [230]} The differential diagnosis and treatment of a wide-complex tachycardia in hyperkalemia can be particularly problematic; moreover, hyperkalemia potentiates the blocking effect of lidocaine on the cardiac Na⁺ channel, such that use of this agent may precipitate asystole or ventricular fibrillation in this setting.^[230] Classically, the electrocardiographic manifestations in hyperkalemia progress as shown in Table 15-3 . However, these changes are notoriously insensitive, such that only 55% of patients with serum K⁺ > 6.8 mmol/L in one case series manifested peaked T waves.^[231] Hemodialysis patients^[232] and patients with chronic renal failure^[233] in particular may not demonstrate electrocardiographic changes, perhaps due to concomitant abnormalities in serum Ca²⁺. Care should also be taken to adequately distinguish the symmetrically peaked, “church steeple”, T waves induced by hyperkalemia from T wave changes due to other causes.^[234]

TABLE 15-3 -- The Approximate Relationship between Hyperkalemic Electrocardiographic Changes and Serum K⁺

Serum K+	ECG Abnormality
Mild hyperkalemia 5.5–6.5 mmol/L	Tall peaked T waves with narrow base, best seen in precordial leads
Moderate hyperkalemia 6.5–8.0 mmol/L	Peaked T waves
	Prolonged PR interval
	Decreased amplitude of P waves
	Widening of QRS complex
Moderate hyperkalemia >8.0 mmol/L	Absence of P wave
	Intraventricular blocks, fascicular blocks, bundle branch blocks, QRS axis shift
	Progressive widening of the QRS complex
	“Sine-wave” pattern (sinoventricular rhythm), ventricular fibrillation, asystole

From Mattu A, Brady WJ, Robinson DA: Electrocardiographic changes and hyperkalemia. Am J Emerg Med 18:721–729, 2000.

Hyperkalemia can also rarely present with ascending paralysis,^[16] denoted “secondary hyperkalemic paralysis” to differentiate it from familial hyperkalemic periodic paralysis (HYPP). This presentation of hyperkalemia can mimic Guillain-Barré syndrome, and may include diaphragmatic paralysis and respiratory failure.^[235] Hyperkalemia from a diversity of causes can cause paralysis, as reviewed by Evers and colleagues.^[236] The mechanism is not entirely clear; however, nerve conduction studies in one case suggest a neurogenic mechanism, rather than a direct effect on muscle excitability.^[236]

In contrast to secondary hyperkalemic paralysis, HYPP is a primary myopathy. Patients with HYPP develop myopathic weakness during hyperkalemia induced by increased K⁺ intake or rest after heavy exercise.^[237] The hyperkalemic trigger in HYPP serves to differentiate this syndrome from hypokalemic periodic paralysis (HOKP); a further distinguishing feature is the presence of myotonia in HYPP.^[237] Depolarization of skeletal muscle by hyperkalemia unmasks an inactivation defect in a tetrodotoxin-sensitive Na⁺ channel in patients with HYPP, and autosomal dominant mutations in the SCN4A gene encoding this channel cause most forms of the disease.^[238] Mild muscle depolarization (5–10 mV) in HYPP results in a persistent inward Na⁺ current through the mutant channel; the normal, allelic SCN4 channels quickly recover from inactivation and can then be re-activated, resulting in myotonia. When muscle depolarization is more marked (i.e., 20–30 mV) all of the Na⁺ channels are inactivated, rendering the muscle inexcitable and causing weakness ( Fig. 15-7 ). Related disorders due to mutations within the large SCN4A channel protein include HOKP type II,^[239] paramyotonia congenita,^[238] and K⁺-aggravated myopathy.^[238] American thoroughbred quarter horses have a high incidence (4.4%) of HYPP, due to a mutation in equine SCN4A traced to the sire “Impressive” (see Fig. 15-7 ).^[238] Finally, loss-of-function mutations in the muscle-specific K⁺ channel subunit “MinK-related peptide 2” (MiRP2) have also been shown to cause HYPP; MiRP2 and the associated Kv3.4 K⁺ channel play a role in setting the resting membrane potential of skeletal muscle.^[240]

FIGURE 15-7 Hyperkalemic periodic paralysis (HYPP) due to mutations in the voltage-gated Na+ channel of skeletal muscle. A, This disorder is particularly common in thoroughbred quarter horses; an affected horse is shown during a paralytic attack, triggered by rest after heavy exercise (picture courtesy of Dr. Eric Hoffman). B, Mechanistic explanation for muscle paralysis in HYPP. (From Lehmann-Horn F, Jurkat-Rott K: Voltage-gated ion channels and hereditary disease. Physiol Rev 79:1317–1372, 1999.)

Renal Consequences

Hyperkalemia has a significant effect on the ability to excrete an acid urine, due to interference with the urinary excretion of ammonium (NH₄⁺). Whereas hypokalemia increases NH3 production by the proximal tubule, hyperkalemia does not affect proximal tubular ammoniagenesis; urinary excretion of NH₄⁺ is however reduced.^[241] The TAL absorbs NH₄⁺ from the tubular lumen, followed by countercurrent multiplication and ultimately excretion from the medullary interstitium.^[242] The NH₄⁺ ion has the same ionic radius as K⁺, and can be transported in lieu of K⁺ by NKCC2,^[243] the apical Na⁺-K⁺/NH₄⁺-2Cl^- cotransporter of the TAL, in addition to a number of other pathways. As is the case for other cations, countercurrent multiplication of NH₄⁺ by the TAL greatly increases the concentration of NH₄⁺/NH₃ available for secretion in the collecting duct. The NH₄⁺ produced by the proximal tubule in response to acidosis is thus reabsorbed across the TAL, concentrated by countercurrent multiplication in the medullary interstitium, and secreted in the collecting duct. The capacity of the TAL to reabsorb NH₄⁺ is increased during acidosis, due to induction of NKCC2 expression.^[243] Hyperkalemia in turn appears to inhibit renal acid excretion by competing with NH₄⁺ for reabsorption by the TAL^[244]; this may be a major factor in the acidosis associated with various defects in K⁺ excretion.^[245]

CAUSES OF HYPOKALEMIA

Epidemiology

Hypokalemia is a relatively common finding in both outpatients and inpatients, perhaps the most common electrolyte abnormality encountered in clinical practice.^[246] When defined as a serum K⁺ of less than 3.6 mmol/L, it is found in up to 20% of hospitalized patients.^[247] Hypokalemia is usually mild, with K⁺ levels in the 3.0 to 3.5 mmol/L range, but in up to 25% it can be moderate to severe (<3.0 mmol/L). ^{[248] [249]} It is a particularly prominent problem in patients receiving thiazide diuretics for hypertension, with an incidence of up to 48% (average 15%–30%). ^{[225] [250] [251]} The thiazide-type diuretic metolazone is frequently utilized in the management of heart failure refractory to loop diuretics alone, causing moderate (K⁺≤3.0 mmol/L) or severe (K⁺≤2.5 mmol/L) hypokalemia in approximately 40% and 10% of patients, respectively.^[251] Hypokalemia is also a common finding in patients receiving peritoneal dialysis, with 10% to 20% requiring potassium supplementation.^[252] Hypokalemia per se can increase in-hospital mortality rate up to 10-fold,^[248] likely due to the profound effects on arrhythmogenesis, blood pressure, and cardiovascular morbidity. ^{[220] [254]}

Spurious Hypokalemia

Delayed sample analysis is a well-recognized cause of spurious hypokalemia, due to increased cellular uptake; this may become clinically relevant if ambient temperature is increased. ^{[255] [256] [257]} Very rarely, patients with profound leukocytosis due to acute leukemia present with artifactual hypokalemia caused by time-dependent uptake of K⁺ by the large white cell mass.^[254] Such patients do not develop cli-nical or electrocardiographic complications of hypokalemia, and serum K⁺ is normal if measured immediately after venipuncture.

Redistribution and Hypokalemia

Manipulation of the factors affecting internal distribution of K⁺ (see discussion of factors affecting internal distribution of potassium) can cause hypokalemia, due to redistribution of K⁺ between the extracellular and intracellular compartments. Endogenous insulin is rarely a cause of hypokalemia; however, administered insulin is a frequent cause of iatrogenic hypokalemia,^[247] and may be a factor in the “dead in bed syndrome” associated with aggressive glycemic control.^[257] Alterations in the activity of the endogenous sympathetic nervous system can cause hypokalemia in several settings, including alcohol withdrawal,^[258] acute myocardial infarction, ^{[220] [260]} and head injury.^{[261] [262]} Redistributive hypokalemia after severe head injury can be truly profound, with reported serum K⁺ of 1.2^[260] and 1.9,^[261] and marked rebound hyperkalemia after repletion. Due to their ability to activate both Na⁺/K⁺-ATPase^[47] and the Na⁺-K⁺-2Cl^- cotransporter NKCC1, ^{[17] [50]} β₂ agonists are powerful activators of cellular K⁺ uptake. These agents are chiefly encountered in the therapy of asthma; however, tocolytics such as ritodrine can induce hypokalemia and arrhythmias during maternal labor.^[262] Occult sources of sympathomimetics, such as pseudoephedrine and ephedrine in cough syrup^[198] or dieting agents, are an overlooked cause of hypokalemia. Finally, downstream activation of cyclic-AMP by xanthines such as theophylline ^{[17] [264]} and dietary caffeine^[264] may induce hypokalemia, and may synergize in this respect with β₂ agonists.^[265]

Whereas β₂ agonists activate K⁺ uptake via the Na⁺/K⁺-ATPase, one would expect that inhibition of passive K⁺ efflux would also lead to hypokalemia; this is accomplished by barium, a potent inhibitor of K⁺ channels. This rare cause of hypokalemia is usually due to ingestion of the rodenticide barium carbonate, either unintentionally or during a suicide attempt.^[266] Suicidal ingestion of barium-containing shaving powder^[267] and hair remover^[268] has also been described. Treatment of barium poisoning with K⁺ likely serves to both increase serum K⁺ and to displace barium from affected K⁺ channels^[266]; hemodialysis is also an effective treatment.^[269] Barium salts are widely used in industry, and poisoning has been described by various mechanisms in industrial accidents. ^{[17] [271]} Hypokalemia is also common with chloroquine toxicity or overdose,^[271] although the mechanism is not entirely clear.

Hypokalemic Periodic Paralysis

The periodic paralyses have both genetic and acquired causes, and are further subdivided into hyperkalemic and hypokalemic forms. ^{[17] [238] [239] [267]} The genetic and secondary forms of hyperkalemic paralysis are discussed earlier (see discussion on consequences of hyperkalemia). Autosomal dominant mutations in the CACNA1S gene encoding the α1 subunit of L-type calcium channels are the most common genetic cause of hypokalemic periodic paralysis (HOKP type I), whereas type II HOKP is due to mutations in the SCN4A gene encoding the skeletal Na⁺ channel.^[239] In Andersen syndrome, autosomal dominant mutations in the KCNJ2 gene encoding the inwardly rectifying K⁺channel Kir2.1 cause periodic paralysis, cardiac arrhythmias, and dysmorphic features.^[272] Paralysis in Andersen syndrome can be normokalemic, hypokalemic, or hyperkalemic; however, the symptomatic trigger is consistent within individual kindreds.^[272]

The pathophysiology of HOKP is not entirely clear. Reversible attacks of paralysis with hypokalemia are typically precipitated by rest after exercise and meals rich in carbohydrate.^[266] Although the induction of endogenous insulin by carbohydrate meals is thought to reduce serum K⁺, insulin can precipitate paralysis in HOKP in the absence of significant hypokalemia.^[273] The generation of action potentials and muscle contraction are reduced in type I and II HOKP muscle fibers exposed to insulin in vitro ^{[240] [275]}; this effect is seen at an extracellular K⁺ of 4.0 mmol/L and is potentiated as K⁺ decreases.^[274] Mutations in type I HOKP have relatively modest effects on L-type calcium channel activity, and type I HOKP may in fact be an “indirect channelopathy” wherein subtle changes in intracellular Ca²⁺ signaling exert downstream effects on the expression or function of other ion channels. Consistent with this hypothesis, type I HOKP muscles have a reduced activity of ATP-sensitive, inward rectifying K⁺ channels (K_ATP),^[275] which likely contributes to hypokalemia due to the resultant unopposed activity of muscle Na⁺/K⁺-ATPase.^[276] Insulin inhibits the remaining K_ATP activity in muscle fibers of both type I HOKP patients 274 and hypokalemic rats,^[277] resulting in a depolarizing shift towards the equilibrium potential for the Cl^- ion (approximately 50 mV); at this potential, voltage-dependent Na⁺ channels are largely inactivated, resulting in paralysis.

Paralysis is associated with multiple other causes of hypokalemia, both acquired and genetic. ^{[198] [199] [267] [279]} Renal causes of hypokalemia with paralysis include Fanconi syndrome,^[279] Gitelman syndrome, ^{[198] [279]} and the various causes of hypokalemic distal renal tubular acidosis. ^{[267] [281] [282]} The activity and regulation of skeletal muscle K_ATP channels is aberrant in animal models of hypokalemia, suggesting a parallel muscle physiology to that of genetic HOKP (see earlier discussion). However, the pathophysiology of thyrotoxic periodic paralysis (TPP), a particularly important cause of hypokalemic paralysis, is distinctly different from that of HOKP; for example, despite the clinical similarities between the two syndromes, thyroxine has no effect on HOKP.

Thyrotoxic periodic paralysis is classically seen in patients of Asian origin, but also occurs at higher frequencies in Hispanic patients.^[282] Patients typically present with weakness of the extremities and limb girdles, with attacks occurring most frequently between 1 am and 6 am. As in HOKP, attacks may be precipitated by rest, and almost never occur during vigorous activity. Again, carbohydrate-rich meals may also provoke an episode of TPP. Clinical signs and symptoms of hyperthyroidism are not invariably present. ^{[283] [284]} Hypokalemia is profound, ranging between 1.1 and 3.4 mol/L, and is frequently accompanied by hypophosphatemia and hypomagnesemia^[282]; all three abnormalities presumably contribute to the associated weakness. The hypokalemia in TPP is most likely due to both direct and indirect activation of the Na⁺/K⁺-ATPase, given the evidence for increased activity in erythrocytes and platelets in TPP patients. ^{[285] [286]} Thyroid hormone clearly induces expression of multiple subunits of the Na⁺/K⁺-ATPase in skeletal muscle.^[286] Increases in β-adrenergic response due to hyperthyroidism also play an important role because high-dose propranolol (3 mg/kg) rapidly reverses the hypokalemia, hypophosphatemia, and paralysis seen in acute attacks. ^{[288] [289]} Of particular importance, no rebound hyperkalemia is associated with this treatment, whereas aggressive K⁺ replacement in TPP is associated with an incidence of ∼25%.^[289]

Non-renal Potassium Loss

The loss of K⁺ from skin is typically low, with the exception of extremes in physical exertion.^[5] Direct gastric loss of K⁺ due to vomiting or nasogastric suctioning is also typically minimal, however the ensuing hypochloremic alkalosis results in persistent kaliuresis due to secondary hyperaldosteronism and bicarbonaturia. ^{[291] [292]} Intestinal loss of K⁺ due to diarrhea is a quantitatively important cause of hypokalemia, given the worldwide prevalence of diarrheal disease, and may be associated with acute complications such as myopathy and flaccid paralysis.^[292] The presence of a non-anion gap metabolic acidosis with a negative urinary anion gap^[159] (consistent with an intact ability to increase NH₄⁺ excretion) should strongly suggest diarrhea as a cause of hypokalemia. Non-infectious gastrointestinal processes such as celiac disease,^[293] ileostomy,^[294] and chronic laxative abuse can present with acute hypokalemic syndromes or with chronic complications such as end-stage renal disease.^[16]

Renal Potassium Loss

Drugs

Diuretics are an especially important cause of hypokalemia, due to their ability to increase distal flow rate and distal delivery of Na⁺ (see discussion on potassium secretion in the distal nephron). Thiazides generally cause more hypokalemia ^{[17] [296]} than do loop diuretics, despite their lower natriuretic efficacy. One potential explanation is the differential effect of loop diuretics and thiazides on calcium excretion. Whereas thiazides and loss-of-function mutations in the Na⁺-Cl^- cotransporter decrease Ca²⁺ excretion,^[296] loop diuretics cause a significant calciuresis.^[297] Increases in luminal Ca²⁺ in the distal nephron serve to reduce the lumen-negative driving force for K⁺excretion,^[298] perhaps by direct inhibition of ENaC in principal cells. A mechanistic explanation is provided by the presence of apical calcium-sensing receptor (CaSR) in the collecting duct^[299]; analogous to the evident decrease in the apical trafficking of aquaporin-2 induced by luminal Ca²⁺, tubular Ca²⁺ may stimulate endocytosis of ENaC via the CaSR and thus limit generation of the lumen-negative potential difference that is so critical for distal K⁺excretion. Regardless of the underlying mechanism, the increase in distal delivery of Ca²⁺ induced by loop diuretics may serve to blunt kaliuresis; such a mechanism would not occur with thiazides, which reduce distal delivery of Ca²⁺, with unopposed activity of ENaC and increased kaliuresis.

Other drugs associated with hypokalemia due to kaliuresis include high doses of penicillin-related antibiotics, thought to increase obligatory K⁺ excretion by acting as non-reabsorbable anions in the distal nephron; in addition to penicillin, implicated antibiotics include nafcillin, dicloxacillin, ticarcillin, oxacillin, and carbenicillin.^[300] Increased distal delivery of other anions such as SO₄^2- and HCO₃^- also induces a kaliuresis. The usual explanation is that K⁺ excretion increases so as to balance the negative charge of these non-reabsorbable anions. However, increased delivery of such anions will also increase the electrochemical gradient for K⁺-Cl^- exit via apical K⁺-Cl^- cotransport or parallel K⁺-H⁺ and Cl^--HCO₃^- exchange ^{[23] [69] [83]} (see also discussion on potassium secretion in the distal nephron).

Several tubular toxins result in both K⁺ and magnesium wasting. These include gentamicin, which can cause tubular toxicity with hypokalemia that can masquerade as Bartter syndrome (BS).^[301] Other drugs that can caused mixed magnesium and K⁺ wasting include amphotericin, foscarnet,^[302] cisplatin, ^{[17] [304]} and ifosfamide.^[304] Aggressive replacement of magnesium is obligatory in the management of combined hypokalemia and hypomagnesemia; successful K⁺ replacement depends on management of the hypomagnesemia.

Hyperaldosteronism

Increases in circulating aldosterone (hyperaldosteronism) may be primary or secondary. Increased levels of circulating renin in secondary forms of hyperaldosteronism leads to increased ATII and thus aldosterone, and can be associated with hypokalemia; causes include renal artery stenosis,^[305] Page kidney (renal compression by a subcapsular mass or hematoma, with hyperreninemia),^[306] a paraneoplastic process,^[307] or renin-secreting renal tumors.^[308] The incidence of hypokalemia in renal artery stenosis is thought to be <20%.^[305] An unusual but under-appreciated presentation of renal artery stenosis and renal ischemia is the “hyponatremic hypertensive syndrome”, in which concurrent hypokalemia may be profound.^[309]

Primary hyperaldosteronism may be genetic or acquired. Hypertension and hypokalemia, generally attributed to increases in circulating 11-deoxycorticosterone,^[310] are seen in patients with congenital adrenal hyperplasia due to defects in either steroid 11β-hydroxylase^[310] or steroid 17α-hydroxylase^[311]; deficient 11β-hydroxylase results in virilization and other signs of androgen excess,^[310] whereas reduced sex steroids in 17α-hydroxylase deficiency result in hypogonadism.^[311] The two major forms of isolated primary hyperaldosteronism are denoted familial hyperaldosteronism type I (FHI, also known as glucocorticoid-remediable hyperaldosteronism or GRA)^[312] and familial hyperaldosteronism type II (FHII), in which aldosterone production is not repressible by exogenous glucocorticoids. Patients with FHII are clinically indistinguishable from sporadic forms of primary hyperaldosteronism due to bilateral adrenal hyperplasia; a gene has been localized to chromosome 7p22 by linkage analysis, but has yet to be characterized.^[313]

Patients with FHI/GRA are generally hypertensive, typically presenting at an early age; the severity of hypertension is however variable, such that some affected individuals are normotensive.^[312] Aldosterone levels are modestly elevated and regulated solely by ACTH. The diagnosis is confirmed by dexamethasone suppression test, with suppression of aldosterone to <4 ng/dL consistent with the diagnosis.^[314] Patients also have high levels of abnormal “hybrid” 18-hydroxylated steroids, generated by transformation of steroids typically formed in the zona fasciculata by aldosterone synthase, an enzyme that is normally expressed in the zona glomerulosa. ^{[316] [317]} FHI has been shown to be caused by a chimeric gene duplication between the homologous 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, fusing the ACTH-responsive 11β-hydroxylase promoter to the coding region of aldosterone synthase; this chimeric gene is thus under the control of ACTH and expressed in a glucorticoid-repressible fashion.^[315] Ectopic expression of the hybrid CYP11B1- CYP11B1 gene in the zona fasciculata has been reported in a single case where adrenal tissue became available for molecular analysis.^[317]

Although the initial patients reported with FHI were hypokalemic, the majority are in fact normokalemic, ^{[317] [319]} albeit perhaps with a propensity to develop hypokalemia while on thiazide diuretics.^[316] Patients with FHI are able to appropriately increase K⁺ excretion in response to K⁺ loading or fludrocortisone, but fail to increase serum aldosterone in response to hyperkalemia.^[319] This may reflect the ectopic expression of the chimeric aldosterone synthase in the adrenal fasciculata, which likely lack the appropriate constellation of ion channels to respond to increases in extracellular K⁺ with an increase in aldosterone secretion.

Acquired causes of primary hyperaldosteronism include aldosterone-producing adenomas (APA), primary or unilateral adrenal hyperplasia (PAH), idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia, and adrenal carcinoma; APA and IHA account for close to 60% and 40%, respectively, of diagnosed hyperaldosteronism. ^{[321] [322]} A rare case involving paraneoplastic over-expression of aldosterone synthase in lymphoma has also been described.^[322] Because surgery can be curative in APA, adequate differentiation of APA from IHA is critical; this may require both adrenal imaging and adrenal venous sampling ( Fig. 15-8 ). Contemporary reports have emphasized the con-tinued importance of adrenal vein sampling in subtype differentiation. ^{[324] [325]}

FIGURE 15-8 Diagnostic algorithm in patients with primary hyperaldosteronism. Adrenal adenoma (APA) must be distinguished from glucocorticoid remediable hyperaldosteronism (FHI or GRA), primary or unilateral adrenal hyperplasia (PAH), and idiopathic hyperaldosteronism (IHA). This requires computed axial tomography (CT), adrenal venous sampling (AVS), and the relevant diagnostic biochemical and hormonal assays (see text). (From Young WF, Jr: Adrenalectomy for primary aldosteronism. Ann Intern Med 138(2):157–159, 2003.)

Increasing utilization of the plasma aldosterone (PAC)/plasma renin activity (PRA) ratio in hypertension clinics has led to reports of a much higher incidence of primary hyperaldosteronism than previously appreciated, with incidence rates in hypertension ranging from zero to 72%^[325]; however, the prevalence was 3.2% in a large, multicenter study of patients with mild to moderate hypertension without hypokalemia.^[326] The true incidence of hypokalemia in patients with acquired forms of primary hyperaldosteronism remains difficult to evaluate, due to a variety of factors. First, historically, patients have only been screened for hyperaldosteronism when hypokalemia is present, hence even recent case series from clinics with such a referral pattern may suffer from a selection bias; other recent series have concentrated on hypertensive patients, also a selection bias. Second, the incidence of hypokalemia is higher in adrenal adenomas than in IHA, likely due to higher average levels of aldosterone.^[321] Third, because increased kaliuresis in hyperaldosteronism can be induced by dietary Na⁺-Cl^- loading or diuretics, dietary factors or medications (or both) may play a role in the incidence of hypokalemia at presentation. Regardless, it is clear that hypokalemia is not a universal feature of primary hyperaldosteronism; this is perhaps not unexpected because aldosterone does not appear to affect the hypokalemic response of H⁺/K⁺-ATPase,^[327] the major reabsorptive pathway for K⁺ in the distal nephron (see discussion on K⁺ reabsorption in the distal nephron). A related issue is whether primary hyperaldosteronism is under-diagnosed when hypokalemia is used as a criterion for further investigation; the utility of the PAC/PRA ratio in screening for hyperaldosteronism is an active and controversial issue in hypertension research. ^{[326] [327]}

Finally, hypokalemia may also occur with systemic increases in glucocorticoids. ^{[329] [330]} In bona fide Cushing syndrome caused by increases in pituitary ACTH the incidence of hypokalemia is only 10%,^[328] whereas it is 57%^[329] to 100%^[328] in patients with ectopic ACTH, despite a similar incidence of hypertension. Indirect evidence suggests that the activity of renal 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2) is reduced in patients with ectopic ACTH compared with Cushing syndrome,^[330] resulting in a syndrome of apparent mineralocorticoid excess (see later discussion). Whether this reflects a greater degree of saturation of the enzyme by circulating cortisol or direct inhibition of 11βHSD-2 by ACTH is not entirely clear, and there is evidence for both mechanisms^[329]; however, indirect indices of 11βHSD-2 activity in patients with ectopic ACTH expression correlate with hypokalemia and other measures of mineralocorticoid activity.^[331] Similar mechanisms likely underlie the severe hypokalemia reported in patients with familial glucocorticoid resistance, in which loss-of-function mutations in the glucocorticoid receptor result in marked hypercortisolism without Cushingoid features, accompanied by very high ACTH levels.^[332]

Syndromes of Apparent Mineralocorticoid Excess

The syndromes of “apparent mineralocorticoid excess” (AME) have a self-explanatory label. In the classic form of AME, recessive loss-of-function mutations in the 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2) gene cause a defect in the peripheral conversion of cortisol to the inactive glucocorticoid cortisone; the resulting increase in the half-life of cortisol is associated with a marked decrease in synthesis, such that plasma levels of cortisol are normal and patients are not Cushingoid.^[333] The 11βHSD-2 protein is expressed in epithelial cells that are targets for aldosterone; in the kidney, these include cells of the distal convoluted tubule (DCT), connecting segment (CNT), and CCD.^[334] Because the mineralocorticoid receptor (MR) has equivalent affinity for aldosterone and cortisol, generation of cortisone by 11βHSD-2 serves to protect mineralocorticoid-responsive cells from illicit activation by cortisol.^[335] In patients with AME, the unregulated mineralocorticoid effect of glucocorticoids results in hypertension, hypokalemia, and metabolic alkalosis, with suppressed PRA and aldosterone.^[333] Biochemical studies of mutant enzymes usually indicate a complete loss of function; lesser enzymatic defects in patients with AME are associated with altered ratios of urinary cortisone/cortisol metabolites,^[336] lesser impairment in the peripheral conversion of cortisol to cortisone,^[337] and/or older age at presentation.^[338]

Mice with a homozygous targeted deletion of 11βHSD-2 exhibit hypertension, hypokalemia, and polyuria; the polyuria is likely secondary to the hypokalemia (see discussion on renal consequences of hypokalemia), which reaches 2.4 mmol/ml in 11βHSD-2–null mice.^[339] As expected, both PRA and plasma aldosterone in the 11βHSD-2-null mice are profoundly suppressed, with a decreased urinary Na⁺/K⁺ ratio that is increased by dexamethasone (given to suppress endogenous cortisol). These knockout mice have significant nephromegaly, due to a massive hypertrophy and hyperplasia of distal convoluted tubules. The relative effect of genotype on the morphology of cells in the DCT, CNT, and CCD was not determined by the appropriate phenotypic studies^[340]; however, it is known that both the DCT and the CCD are target cells for aldosterone ^{[110] [342]} and both cell types express 11βHSD-2. The induction of ENaC activity by unregulated glucocorticoid likely causes the Na⁺ retention and the marked increase in K⁺ excretion in 11βHSD-2-null mice; distal tubular micropuncture studies in rats treated with a systemic inhibitor of 11βHSD-2 are consistent with such a mechanism.^[342] In addition, the cellular “gain of function” in the DCT would be expected to be associated with hypercalciuria, given the phenotype of pseudohypoaldosteronism type II and Gitelman syndrome (see later discussion on hereditary tubular causes of hyperkalemia and Gitelman syndrome); indeed, patients with AME are reported to exhibit nephrocalcinosis.^[333]

Pharmacological inhibition of 11βHSD-2 is also associated with hypokalemia and AME. The most infamous offender is licorice, in its multiple guises (licorice root, tea, candies, herbal remedies, etc.). The early observations that licorice required small amounts of cortisol to exert its kaliuretic effect, in the Addisonian absence of endogenous glucocorticoid,^[343] presaged the observations that its active ingredi-ents (glycyrrhetinic/glycyrrhizinic acid and carbenoxolone) inhibit 11βHSD-2 and related enzymes.^[333] Licorice intake remains considerable in European countries, particularly Iceland, Netherlands, and Scandinavia^[344]; Pontefract cakes, eaten both as sweets and as a laxative, are a continued source of licorice in the United Kingdom,^[344] whereas it is an ingredient in several popular sweeteners and preservatives in Malaysia.^[345] Glycyrrhizinic acid is used in Japan to manage hepatitis, and has been under evaluation elsewhere for the management of hepatitis C; AME has been reported with its use for this indication.^[346] Glycyrrhizinic acid is also a component of Chinese herbal remedies, prescribed for disorders such as for allergic rhinitis.^[347] Carbenoxolone is in turn utilized in some countries in the management of peptic ulcer disease.^[333]

Finally, a rare, mechanistically distinct form of AME has been reported, due to a gain-of-function mutation in the mineralocorticoid receptor (MR).^[348] A single kindred was thus described with autosomal dominant inheritance of severe hypertension and hypokalemia; the causative mutation involves a serine residue that is conserved in the MR from multiple species, yet differs in other nuclear steroid receptors. This mutation results in constitutive activation of the MR in the absence of ligand, and induces significant affinity for progesterone.^[348] The MR is thus constitutively “on” in these patients, with a marked stimulation by progesterone; of interest, pregnancies in the affected female members of the family have all been complicated by severe hypertension, due to marked increases in serum progesterone induced by the gravid state.^[348]

Liddle Syndrome

Liddle syndrome constitutes an autosomal dominant gain-in-function of ENaC, the amiloride-sensitive Na⁺ channel of the CNT and CCD.^[349] Patients manifest severe hypertension with hypokalemia, unresponsive to spironolactone yet sensitive to triamterene and amiloride. Liddle syndrome could therefore also be classified as a syndrome of apparent mineralocorticoid excess. Both hypertension and hypokalemia are variable aspects of the Liddle phenotype; consistent features include a blunted aldosterone response to ACTH and reduced urinary aldosterone excretion. ^{[351] [352]} The vast majority of mutations target the C-terminus of either the β- or γ-ENaC subunit. ENaC channels containing Liddle syndrome mutations are constitutively over-expressed at the cell membrane ^{[353] [354]}; unlike wild-type ENaC channels, they are not sensitive to inhibition by intracellular Na⁺,^[354] an important regulator of endogenous channel activity in the CCD.^[355] The mechanism whereby mutations in the C-terminus of ENaC subunits lead to this channel phenotype are discussed earlier in this chapter (see Fig. 15-5 and discussion of control of potassium secretion: aldosterone). In addition to effects on interaction with Nedd4-2–dependent retrieval from the plasma membrane, Liddle-associated mutations increase proteolytic cleavage of ENaC at the cell membrane^[356]; as discussed earlier, aldosterone-induced “channel-activating proteases” activate ENaC channels at the plasma membrane. This important result provides a mechanistic explanation for the longstanding observation that Liddle-associated mutations in ENaC appear to have a dual activating effect, on both the open probability of the channel (i.e., on channel activity) and on expression at the cell membrane.^[352]

Given the overlapping and synergistic mechanisms that regulate ENaC activity, it stands to reason that mutations in ENaC that give rise to Liddle syndrome might do so by a variety of means. Indeed, mutation of a residue within the extracellular domain of ENaC increases open probability of the channel without changing surface expression; the patient with this mutation has a typical Liddle syndrome phenotype.^[116] Extensive searches for more common mutations and polymorphisms in ENaC subunits that correlate with blood pressure in the general population have essentially been negative. However, there are a handful of genetic studies that correlate specific variants in ENaC subunits with biochemical evidence of greater in vivo activity of the channel (i.e., a suppressed PRA and aldosterone or increased ratios of urinary K⁺: aldosterone/PRA, or both). ^{[358] [359]}

Familial Hypokalemic Alkalosis: Bartter Syndrome

Bartter and Gitelman syndromes are the two major variants of familial hypokalemic alkalosis; Gitelman syndrome is a much more common cause of hypokalemia than is Bartter syndrome (BS).^[359] Whereas a clinical subdivision of these syndromes has been used in the past, a genetic classification is increasingly in use, due in part to phenotypic overlap. Patients with “classic” BS typically suffer from polyuria and polydipsia, and manifest a hypokalemic, hypochloremic alkalosis. They may have an increase in urinary calcium (Ca²⁺) excretion, and 20% are hypomagnesemic.^[360] Other features include marked elevation of serum ATII, serum aldosterone, and plasma renin. Patients with “antenatal” BS present earlier in life with a severe systemic disorder characterized by marked electrolyte wasting, polyhydramnios, and significant hypercalciuria with nephrocalcinosis. Prostaglandin synthesis and excretion is significantly increased, and may account for much of the systemic symptoms. Decreasing prostaglandin synthesis by cyclooxygenase inhibition can improve polyuria in patients with BS, by reducing the amplifying inhibition of urinary concentrating mechanisms by prostaglandins. Indomethacin also increases serum K⁺ and decreases plasma renin activity, but does not correct the basic tubular defect. Of interest, COX-2 immunoreactivity is increased in the TAL and macula densa of patients with BS,^[361] and recent reports indicate a clinical benefit of COX-2 inhibitors.^[362]

Early studies in Bartter syndrome suggested that these patients had a defect in the function of the TAL.^[363] Many of the clinical features are mimicked by the administration of loop diuretics, to which at least a subset of patients with antenatal BS do not respond.^[364] The apical Na⁺-K⁺-2Cl^- cotransporter (NKCC2, SLC12A1) of the mammalian TAL^[21] ( Fig. 15-9 ) was thus an early candidate gene. In 1996, disease-associated mutations were found in the human NKCC2 gene in four kindreds with antenatal BS^[365]; in the genetic classification of BS, these patients are considered to have BS type I. Although the functional consequences of disease-associated NKCC2 mutations have not been comprehensively studied, the first^[365] and subsequent reports ^{[367] [368]} include patients with frameshift mutations and premature stop codons that predict the absence of a functional NKCC2 protein.

Bartter syndrome is a genetically heterogeneous disease. Given the role of apical K⁺ permeability in the TAL, encoded at least in part by ROMK, ^{[74] [76]} this K⁺ channel was another early candidate gene. K⁺ recycling via the Na⁺-K⁺-2Cl^- cotransporter and apical K⁺ channels generates a lumen-positive potential difference in the TAL, which drives the paracellular transport of Na⁺ and other cations^[368] (see Fig. 15-9 ). Multiple disease-associated mutations in ROMK have been reported in patients with BS type II, most of whom exhibit the antenatal phenotype.^[369] Finally, mutations in BS type III have been reported in the chloride channel CLC-NKB,^[370] which is expressed at the basolateral membrane of at least the thick ascending limb and distal convoluted tubule.^[371] Patients with mutations in CLC-NKB typically have the classic Bartter phenotype, with a relative absence of nephrocalcinosis. In a significant fraction of patients with BS the NKCC2, ROMK, and CLC-NKB genes are not involved.^[370] For example, a subset of patients with associated sensorineural deafness exhibit linkage to chromosome 1p31^[372]; the gene for this syndrome, denoted Barttin, is an obligatory subunit for the CLC-NKB chloride channel.^[373] The occurrence of deafness in these patients suggests that Barttin functions in the regulation or function of Cl^- channels in the inner ear. Notably, the CLC-NKB gene is immediately adjacent that for another epithelial Cl^- channel, denoted CLC-NKA; digenic inactivation was recently described in two siblings with deafness and BS,^[374] suggesting that CLC-NKA plays an important role in Barttin-dependent Cl^- transport in the inner ear.

Patients with activating mutations in the calcium-sensing receptor (CaSR) were recently described with autosomal dominant hypocalcemia and hypokalemic alkalosis. ^{[376] [377]} The CaSR is heavily expressed at the basolateral membrane of the TAL,^[377] where it is thought to play an important inhibitory role in regulating the transcellular transport of both Na⁺-Cl^- and Ca²⁺. For example, activation of the basolateral CaSR in the TAL is known to reduce apical K⁺ channel activity,^[378] which would induce a Bartter-like syndrome (see Fig. 15-9 ). Genetic activation of the CaSR by these mutations was also expected to increase urinary Ca²⁺ excretion, by inhibiting generation of the lumen-positive potential difference that drives paracellular Ca²⁺ transport in the TAL. In addition, the “set-point” of the CaSR response to Ca²⁺ in the parathyroid is shifted to the left, inhibiting PTH secretion by this gland. No doubt the positional cloning of other BS genes will have a considerable impact on mechanistic understanding of the TAL.

Despite the reasonable correlation between the disease gene involved and the associated subtype of familial alkalosis, there is significant phenotypic overlap and phenotypic variability in hereditary hypokalemic alkalosis. For example, patients with mutations in CLC-NKB most frequently exhibit classic BS, but can present with a more severe antenatal phenotype, or even with a phenotype similar to Gitelman syndrome. ^{[380] [381]} With respect to BS due to mutations in NKCC2, a number of patients have been described with variant presentations, including an absence of hypo-kalemia.^[367] Two brothers were recently described with a late onset of mild BS; these patients were found to be compound heterozygotes for a mutant form of NKCC2 that exhibits partial function, with a loss-of-function mutation on the other NKCC2 allele.^[381]

Bartter syndrome type II is particularly relevant to K⁺ homeostasis, given that ROMK is the SK secretory channel of the CNT and CCD (see discussion on potassium secretion in the distal nephron). Patients with BS type II typically have slightly higher serum K⁺ than the other genetic forms of BS ^{[370] [381]}; patients with severe (9.0 mmol/l), transient, neonatal hyperkalemia have also been described.^[382] It is likely that this reflects a transient, developmental deficit in the other K⁺ channels involved in distal K⁺ secretion, including the apical maxi-K channel responsible for flow-dependent K⁺ secretion in the distal nephron. ^{[72] [80]} Distal K⁺ secretion in ROMK knockout mice is primarily mediated by maxi-K/BK channel activity,^[76] such that developmental deficits in this channel would indeed lead to hyperkalemia in BS type II. The mammalian TAL has two major apical K⁺ conductances, the 30 pS channel corresponding to ROMK, and a 70 pS channel^[383]; both are thought to play a role in transepithelial salt transport by the TAL. ROMK is evidently a subunit of the 70 pS channel, given the absence of this conductance in TAL segments of ROMK knockout mice.^[384] The identity of the other putative subunit of this 70 pS channel is not as yet known; one would assume that deficiencies in this gene would also be a cause of BS.

Finally, BS must be clinically differentiated from the various causes of “pseudo-Bartter” syndrome; these commonly include laxative abuse, furosemide abuse, and bulimia (see discussion on the clinical approach to hypokalemia). Other reported causes include gentamicin nephrotoxicity,^[301] Sjögren syndrome,^[385] and cystic fibrosis (CF). ^{[387] [388]} Fixed loss of Na⁺-Cl^- in sweat is likely the dominant predisposing factor for hypokalemic alkalosis in patients with CF; patients with this presentation generally respond promptly to intravenous fluids and electrolyte replacement. However, the CFTR protein co-associates with ROMK in the TAL, and confers sensitivity to both ATP and glibenclamide to apical K⁺ channels in this nephron segment.^[388] Lu and colleagues^[388] have proposed that this interaction serves to modulate the response of ROMK to cAMP and vasopressin, such that K⁺ excretion in CFTR deficiency would not be appropriately reduced during water diuresis, thus predisposing such patients to the development of hypokalemic alkalosis.

Familial Hypokalemic Alkalosis: Gitelman Syndrome

A major advance in the understanding of hereditary alkaloses was the realization that a subset of patients exhibit marked hypocalciuria, rather than the hypercalciuria typically seen in BS; patients in this hypocalciuric subset are universally hypomagnesemic.^[296] Such patients are now clinically classified as suffering from Gitelman syndrome. Although plasma renin activity may be increased, renal prostaglandin excretion is not elevated in these hypocalciuric patients,^[389] another distinguishing feature between Bartter and Gitelman syndromes. Gitelman syndrome (GS) is a milder disorder than BS; however, patients do report significant morbidity, mostly related to muscular symptoms and fatigue.^[390] The QT interval is frequently prolonged in GS, suggesting an increased risk of cardiac arrhythmia.^[391] A more exhaustive cardiac evaluation of a large group of patients failed to detect significant abnormalities of cardiac structure or rhythm.^[392] However, pre-syncope or ventricular tachycardia (or both) has been observed in at least two patients with GS ^{[197] [394]} one with concomitant long QT syndrome due to a mutation in the cardiac KCNQ1 K⁺ channel.^[196]

The hypocalciuria detected in GS was an expected consequence of inactivating the thiazide-sensitive Na⁺-Cl^- cotransporter NCC (SLC12A2), and loss-of-function mutations in the human gene have been reported^[394]; many of these mutations lead to a defect in cellular trafficking when introduced into the human NCC protein.^[395] GS is genetically homogeneous, except for the occasional patient with mutations in CLC-NKB and an overlapping phenotype.^{[197] [380] [381]} The NCC protein has been localized to the apical membrane of epithelial cells in the distal convoluted tubule (DCT) and connecting segment. A mouse strain with targeted deletion of the Slc12a2 gene encoding NCC exhibits hypocalciuria and hypomagnesemia, with a mild alkalosis and marked increase in circulating aldosterone.^[396] These knockout mice exhibit marked morphological defects in the early DCT,^[396] with both a reduction in absolute number of DCT cells and changes in ultrastructural appearance. That GS is a disorder of cellular development or cellular apoptosis (or both) should perhaps not be a surprise, given the observation that thiazide treatment promotes marked apoptosis of this nephron segment.^[397] This cellular deficit leads to downregulation of the DCT magnesium channel TRPM6,^[398] resulting in the magnesium wasting and hypomagnesemia seen in GS. The downstream CNT tubules are hypertrophied in NCC-deficient mice,^[396] reminiscent of the hypertrophic DCT and CNT segments seen in furosemide-treated animals.^[399] These CNT cells also exhibit an increased expression of ENaC at their apical membranes, versus litter mate controls^[396]; this is likely due to activation of SGK1 -dependent trafficking of ENaC by the increase in circulating aldosterone (see discussion on control of potassium secretion: aldosterone).

Hypokalemia does not occur in NCC -/- mice on standard rodent diet, but emerges on a K⁺ restricted diet; plasma K⁺ of these mice is ∼1 μM lower than K⁺-restricted litter mate controls.^[400] Several mechanisms account for the hypokalemia seen in GS and NCC -/- mice. The distal delivery of both Na⁺ and fluid is decreased in NCC -/- mice, at least on a normal diet; however, the increased circulating aldosterone and CNT hypertrophy likely compensate, leading to increased kaliuresis. As discussed earlier for thiazides, decreased luminal Ca²⁺ in NCC-deficiency may augment baseline ENaC activity,^[298] further exacerbating the kaliuresis. Of particular interest, NCC-deficient mice develop considerable polydipsia and polyuria on a K⁺-restricted diet^[400]; this is reminiscent perhaps of the polydipsia that has been implicated in thiazide-associated hyponatremia.^[401]

Hypocalciuria in GS is not accompanied by changes in serum calcium, phosphate, vitamin D, or PTH,^[402] suggesting a direct effect on renal calcium transport. The late DCT is morphologically intact in NCC-deficient mice, with preserved expression of the epithelial calcium channel (ECAC1 or TRPV5) and the basolateral Na⁺-Ca²⁺ exchanger.^[396] Furthermore, the hypocalciuric effect of thiazides persists in mice deficient in TRPV5,^[398] arguing against the putative effects of this drug on distal Ca²⁺ absorption. Rather, several lines of evidence argue that the hypocalciuria of GS and thiazide treatment is due to increased absorption of Na⁺ by the proximal tubule, ^{[397] [399]} with secondary increases in proximal Ca²⁺ absorption. Regardless, reminiscent of the clinical effect of thiazides on bone,^[403] there are clear differences in bone density between affected and unaffected members of specific Gitelman kindreds. Thus homozygous patients have much higher bone densities than unaffected wild-type family members, whereas heterozygotes have intermediate values for both bone density and calcium excretion.^[402] An interesting association has repeatedly been described between chondrocalcinosis, the abnormal deposition of calcium pyrophosphate dihydrate (CPPD) in joint cartilage, and Gitelman syndrome.^[404] Patients have also been reported with ocular choroidal calcification.^[405]

Finally, as in Bartter syndrome, there are reports of acquired tubular defects that mimic GS. These include patients with hypokalemic alkalosis, hypomagnesemia, and hypocalciuria after chemotherapy with cisplatin.^[406] Patients have also been described with acquired GS due to Sjögren syndrome and tubulointerstitial nephritis ^{[408] [409]} with a documented absence of coding sequence mutations in NCC.^[408]

Magnesium Deficiency

Magnesium deficiency results in refractory hypokalemia, particularly if the serum Mg²⁺ is less than 0.5 mg/dl^[247]; hypomagnesemic patients are thus refractory to K⁺ replacement in the absence of Mg²⁺ repletion. ^{[410] [411]}Magnesium deficiency is also a common concomitant of hypokalemia, in part because associated tubular disorders (e.g., aminoglycoside nephrotoxicity) may cause both a kaliuresis and magnesium wasting. Serum Mg²⁺ must thus be checked on a routine basis, along with other electrolytes. ^{[247] [412]} Magnesium depletion has inhibitory effects on muscle Na⁺/K⁺-ATPase activity,^[412] resulting in significant efflux from muscle and a secondary kaliuresis. Furthermore, it has been suggested that the repletion of intracellular K⁺ is impaired in hypomagnesemia, even in normokalemic patients.^[411] Decreased intracellular Mg²⁺ enhances K⁺ efflux from the cytoplasm of cardiac and perhaps skeletal myocytes, likely due to both intracellular blockade of K⁺ channels and inhibition of the Na⁺/K⁺-ATPase; serum K⁺ levels thus remain normal at the expense of intracellular K⁺. ^{[17] [412]} This phenomenon is particularly important in patients with cardiac disease taking both diuretics and digoxin. In such patients hypokalemia and arrhythmias will respond to correction of magnesium deficiency and potassium supplementation. ^{[17] [412]}

The Clinical Approach to Hypokalemia

The initial priority in the evaluation of hypokalemia is an assessment for signs and/or symptoms (muscle weakness, ECG changes, etc.) suggestive of an impending emergency that requires immediate treatment. The cause of hypokalemia is usually obvious from history, physical examination, basic laboratory tests, or all three. However, persistent hypokalemia despite appropriate initial intervention requires a more rigorous workup; in most cases, a systematic approach reveals the underlying cause ( Fig. 15-10 ).

FIGURE 15-10 The diagnostic approach to hypokalemia. See text for details. FHPP: familial hypokalemic periodic paralysis; GI: gastrointestinal; TTKG: transtubular potassium gradient; CCD: cortical collecting duct; BP: blood pressure; RTA: renal tubular acidosis; DKA: diabetic ketoacidosis; RAS: renal artery stenosis; RST: renin secreting tumor; HTN: hypertension; PA: primary aldosteronism; GRA: glucocorticoid remediable aldosteronism; AME: apparent mineralocorticoid excess.

The history should focus on medications (e.g., diuretics, laxatives, antibiotics, herbal medications), diet and dietary supplements (e.g., licorice), and associated symptoms (e.g., diarrhea). During the physical examination, particular attention should be paid to blood pressure, volume status, and signs suggestive of specific disorders associated with hypokalemia (hyperthyroidism, Cushing syndrome, etc.). Initial laboratory tests should include electrolytes, BUN, creatinine, serum osmolality, Mg²⁺, and Ca²⁺, a complete blood count, and urinary pH, osmolality, creatinine, and electrolytes. Serum and urine osmolality are required for calculation of the transtubular K⁺ gradient^[155] (see discussion of urinary indices of potassium excretion). Further tests such as urinary Mg²⁺ and Ca²⁺ and plasma renin and aldosterone levels may be necessary in specific cases (see Fig. 15-10 ). The timing and evolution of hypokalemia is also helpful in differentiating the cause, particularly in hospitalized patients; for example, hypokalemia due to transcellular shift usually occurs in a matter of hours.^[413]

The most common causes of chronic, diagnosis-resistant hypokalemia are Gitelman syndrome (GS), surreptitious vomiting, and diuretic abuse.^[414] Alternatively, an associated acidosis would suggest the diagnosis of hypokalemic distal or proximal renal tubular acidosis. Hypokalemia occurred in 5.5% of patients with eating disorders in an American study from the mid 1990s,^[415] mostly in those with surreptitious vomiting (bulimia) or laxative abuse (the purging^[291] subtype of anorexia nervosa). These patients may have a constellation of associated symptoms and signs, including dental erosion and depression.^[416] Hypokalemic patients with bulimia will have an associated metabolic alkalosis, with an obligatory natriuresis accompanying the loss of bicarbonate; urinary Cl^- is typically <10 mmol/L, and this clue can often yield the diagnosis. ^{[415] [418]} Urinary electrolytes are however generally unremarkable in unselected, mostly normokalemic patients with bulimia.^[416] Urinary excretion of Na⁺, K⁺, and Cl^- is high in patients who abuse diuretics, albeit not to the levels seen in GS. Marked variability in urinary electrolytes is an important clue for diuretic abuse, which can be verified with urinary drug screens. Clinically, nephrocalcinosis is very common in furosemide abuse, due to the increase in urinary calcium excretion.^[418]Differentiation of GS from Bartter syndrome (BS) requires a 24-hour urine to assess calcium excretion, since hypocalciuria is a distinguishing feature for the former^[296]; patients with GS are also invariably hypomagnesemic. Bartter syndrome must be differentiated from “pseudo-Bartter” syndrome due to gentamicin toxicity, ^{[302] [420]} mutations in CFTR, the cystic fibrosis gene, ^{[387] [388]} or Sjögren syndrome with tubulointerstitial nephritis.^[385] Acquired forms of GS have in turn been reported after cisplatin therapy^[406] and in patients with Sjögren syndrome. ^{[408] [409]} Finally, although laxative abuse is perhaps a less common cause of chronic hypokalemia, an accompanying metabolic acidosis with a negative urinary anion gap should raise the diagnostic suspicion of this cause.^[159]

TREATMENT OF HYPOKALEMIA^[*]

The goals of therapy in hypokalemia are to prevent life-threatening conditions (diaphragmatic weakness, rhabdomyolysis, and cardiac arrhythmias), to replace any K⁺ deficit, and to diagnose and correct the underlying cause. The urgency of therapy depends on the severity of hypokalemia, associated conditions and settings (e.g., a patient with heart failure on digoxin, or a patient with hepatic encephalopathy), and the rate of decline in serum K⁺. A rapid drop to less than 2.5 mmol/L poses a high risk of cardiac arrhythmias and calls for urgent replacement.^[420] Although replacement is usually limited to patients with a true deficit, it should be considered in patients with hypokalemia due to redistribution (e.g., hypokalemic periodic paralysis) when serious complications such as muscle weakness, rhabdomyolysis, and cardiac arrhythmias are present or imminent.^[421] The risk of arrhythmia from hypokalemia is highest in older patients, patients with evidence of organic heart disease, and patients on digoxin or antiarrhythmic drugs.^[246] In these high-risk patients, an increased incidence of arrhythmias may occur at even mild to modest degrees of hypokalemia.

It is also crucial to diagnose and eliminate the underlying cause, so as to tailor therapy to the pathophysiology involved. For example, the risk of overcorrection or rebound hyperkalemia in hypokalemia caused by redistribution is particularly high, with the potential for fatal hyperkalemic arrhythmias. ^{[248] [261] [422] [423]} When increased sympathetic tone or increased sympathetic response is thought to play a dominant role, the use of non-specific β-adrenergic blockade with propranolol generally avoids this complication and should be considered; the relevant causes of hypokalemia include thyrotoxic periodic paralysis,^[287] theophylline overdose,^[423] and acute head injury.^[260]

K⁺ replacement is the mainstay of therapy in hypokalemia. However, hypomagnesemic patients can be refractory to K⁺ replacement alone,^[410] such that concomitant Mg²⁺ deficiency should always be addressed with oral or parenteral repletion. To prevent hyperkalemia due to excessive supplementation, the deficit and the rate of correction should be estimated as accurately as possible. Renal function, medications, and co-morbid conditions such as diabetes (with a risk of both insulinopenia and autonomic neuropathy) should also be considered, so as to gauge the risk of overcorrection. The goal is to raise the serum K⁺ to a safe range rapidly and then replace the remaining deficit at a slower rate over days to weeks. ^{[247] [248] [422]} In the absence of abnormal K⁺ redistribution, the total deficit correlates with serum K^+247,421,424 such that serum K⁺ drops by approximately 0.27 mmol/L for every 100-mmol reduction in total-body stores. Loss of 400 to 800 mmol of body K⁺ results in a reduction in serum K⁺ by approximately 2.0 mmol/L^[424]; these parameters can be used to estimate replacement goals.

Although the treatment of asymptomatic patients with borderline or low normal serum K⁺ remains controversial, supplementation is recommended in patients with serum K⁺ lower than 3 mmol/L. In high-risk patients (i.e., those with heart failure, cardiac arrhythmias, myocardial infarction, ischemic heart disease, or taking digoxin), serum K⁺ should be maintained at ≥4.0 mmol/L^[246] or even ≥4.5 mmol/L.^[253] Patients with severe hepatic disease may not be able to tolerate mild-to-moderate hypokalemia due to the associated augmentation in ammoniagenesis, and thus serum K⁺ should be maintained at approximately 4.0 mmol/L. ^{[426] [427]} In asymptomatic patients with mild-to-moderate hypertension, an attempt should be made to maintain serum K⁺ above 4.0 mmol/L^[246] and potassium supplementation should be considered when serum K⁺ falls below 3.5 mmol/L.^[246] Notably, prospective studies have shown an inverse relationship between dietary potassium intake and both fatal and nonfatal stroke, independent of the associated anti-hypertensive effect. ^{[247] [428] [429]}

Potassium is available in the form of potassium chloride, potassium phosphate, potassium bicarbonate or its precursors (potassium citrate, potassium acetate), and potassium gluconate. ^{[247] [248] [422]} Potassium phosphate is indicated when phosphate deficit accompanies K⁺ depletion (e.g., in diabetic ketoacidosis).^[421] Potassium bicarbonate (or its precursors) should be considered in patients with hypokalemia and metabolic acidosis. ^{[247] [422]} Potassium chloride should otherwise be the default salt of choice in most patients, for several reasons. First, metabolic alkalosis typically accompanies chloride loss from renal (e.g., diuretics) or upper gastrointestinal routes (e.g., vomiting), and contributes significantly to renal K⁺ wasting.^[247] In this setting, replacing chloride along with K⁺ is essential in treating the alkalosis and preventing further kaliuresis; because dietary K⁺ is mainly in the form of potassium phosphate or potassium citrate, it usually does not suffice. Second, potassium bicarbonate may offset the benefits of K⁺ administration by aggravating concomitant alkalosis. Third, potassium chloride raises serum K⁺ at a faster rate than does potassium bicarbonate, a factor that is crucial in patients with marked hypokalemia and related symptoms. In all likelihood, this faster rise in serum K⁺ occurs because Cl^- is mainly an extracellular fluid anion that does not enter cells to the same extent as bicarbonate, keeping the administered K⁺ in the extracellular fluid compartment.^[429]

Parenteral (intravenous) K⁺ administration should be limited to patients unable to utilize the enteral route or when the patient is experiencing associated signs and symptoms. However, rapid correction of hypokalemia through oral supplementation is possible and may be faster than intravenous K⁺ supplementation, due to limitations in the rapidity of intravenous K⁺ infusion. For example, serum K⁺ can be increased by 1 mmol/L to 1.4 mmol/L in 60 to 90 minutes, following the oral intake of 75 mmol of K^{+ 430}; the ingestion of approximately 125 to 165 mmol of K⁺ as a single oral dose can increase serum K⁺ by approximately 2.5 to 3.5 mmol/L in 60 to 120 minutes.^[431] The oral route is thus both effective and appropriate in patients with asymptomatic severe hypokalemia. If the patient is experiencing life-threatening signs and symptoms of hypokalemia, however, the maximum possible IV infusion of K⁺should be administered acutely for symptom control, followed by rapid oral supplementation.

The usual intravenous dose is 20 to 40 mmol of K⁺-Cl^- in a liter of vehicle solution.^[421] The vehicle solution should be dextrose-free to prevent a transient reduction in serum K⁺ level of 0.2 to 1.4 mmol/L, due to an enhanced endogenous insulin secretion induced by the dextrose.^[432] Higher concentrations of K⁺-Cl^- (up to 400 mmol/L, as 40 mmol in 100 ml of normal saline) have been used in life-threatening conditions. ^{[434] [435]} In these cases, the amount of K⁺ per intravenous bag should be limited (e.g., 20 mmol in 100 ml of saline solution) to prevent inadvertent infusion of a large dose. ^{[435] [436]} These solutions are best given through a large central vein. Femoral veins are preferable because infusion through upper body central lines can acutely increase the local concentration of K⁺ with deleterious effects on cardiac conduction. ^{[435] [436]} As a general rule and to avoid venous pain, irritation, and sclerosis, concentrations of more than 60 mmol/L should not be given through a peripheral vein.^[421] Although the recommended rate of administration is 10 to 20 mmol/hour, rates of 40 to 100 mmol/hour or even higher (for a short period) have been used in patients with life-threatening conditions. ^{[434] [436] [437] [438]} However, a rapid increase in serum K⁺ associated with electrocardiographic (ECG) changes may occur with higher rates of infusion (e.g., ≥80 mmol/hour).^[438] Intravenous administration of K⁺ at a rate of more than 10 mmol/hour requires continuous ECG monitoring.^[421] In patients receiving such high infusion rates, close monitoring of the appropriate physiologic consequences of hypokalemia is essential; after these effects have abated, the rate of infusion should be decreased to the standard dose of 10 to 20 mmol/hour.^[435] It is important to remember that volume expansion in patients with moderate-to-severe hypokalemia and Cl^--responsive metabolic alkalosis should be performed cautiously and with close follow-up of serum K⁺ because bicarbonaturia associated with volume expansion may aggravate renal K⁺wasting and hypokalemia.^[420] In patients with combined severe hypokalemia and hypophosphatemia (e.g., diabetic ketoacidosis), intravenous K⁺ phosphate can be used. However, this solution should be infused at a rate of less than 50 mmol over 8 hours to prevent the risk of hypocalcemia and metastatic calcification.^[420] A combination of potassium phosphate and potassium chloride may be necessary to correct hypokalemia effectively in these patients.

The easiest and most straightforward method of oral K⁺ supplementation is to increase dietary intake of potassium-rich foods^[247] ( Table 15-4 ). A recent study compared the effectiveness of diet vs medication supplementation in cardiac surgery patients receiving diuretics in hospital and found no difference between the two groups in respect to maintenance of serum K⁺. However, limitations of this study include a small number of subjects, relatively short duration, and lack of information on acid-base status, making it less than con clusive and not generalizable.^[439] Regardless, dietary K⁺ is mainly in the form of potassium phosphate or potassium citrate and is inadequate in the majority of patients who have concomitant K⁺ and Cl^- deficiency. Most patients will therefore need to combine a high-K⁺ diet with a prescribed dose of K⁺-Cl^-.^[247] Salt substitutes are an inexpensive and potent source of K⁺-Cl^-; each gram contains 10 to 13 mmol of K⁺.^[440] However, patients, particularly those with an impaired ability to excrete potassium, must be counseled regarding the appropriate amount and the potential for hyperkalemia.^[441]Potassium chloride is also available in either liquid or tablet form ( Table 15-5 ).^[246] In general, the available preparations are well absorbed.^[247] Liquid forms are less expensive but are less well tolerated. Slow-release forms are more palatable and better tolerated; however, they have been associated with gastrointestinal ulceration and bleeding, ascribed to local accumulation of high concentrations of K⁺. ^{[248] [436]} Notably, this risk is rather low, and lower still with the microencapsulated forms.^[247] The chance of overdose and hyperkalemia is higher with slow-release formulations; unlike the immediate release forms these tablets are less irritating to the stomach and less likely to induce vomiting.^[442] The usual dose is 40 to 100 mmol of K⁺ (as K⁺-Cl^-) per day, divided in 2 to 3 doses, in patients taking diuretics^[247] (K⁺-Cl^- can be toxic in doses of more than 2 mmol/Kg^[442]). This dose is effective in maintaining serum K⁺ in up to 90%; however, in the 10% of patients who remain hypokalemic, increasing the oral dose or adding a K⁺-sparing diuretic is an appropriate choice.^[247]

TABLE 15-4 -- Foods with High Potassium Content

Highest content (>1000 mg [25 mmol]/100 g) Dried figs Molasses Seaweed

Very high content (>500 mg [12.5 mmol]/100 g) Dried fruits (dates, prunes) Nuts Avocados Bran cereals Wheat germ Lima beans

High content (>250 mg [6.2 mmol]/100 g) Vegetables Spinach Tomatoes Broccoli Winter squash Beets Carrots Cauliflower Potatoes Fruits Bananas Cantaloupe Kiwis Oranges Mangos Meats Ground beef Steak Pork Veal Lamb

From Gennari FJ: Hypokalemia. N Engl J Med 339:451–458, 1998.

TABLE 15-5 -- Oral Preparations of Potassium Chloride

Supplement	Attributes
Controlled-release microencapsulated tablets	Disintegrate better in stomach than encapsulated microparticles; less adherent and less cohesive
Encapsulated controlled-release microencapsulated particles	Fewer erosions than wax-matrix tablets
Potassium chloride elixir	Inexpensive, tastes bad, poor compliance; few erosions; immediate effect
Potassium chloride (effervescent tablets) for solution	Convenient, but more expensive than elixir; immediate effect
Wax-matrix extended-release tablets	Easier to swallow; more gastrointestinal tract erosions compared with microencapsulated formulations

From Cohn JN, Kowey PR, Whelton PK, Prisant LM: New guidelines for potassium replacement in clinical practice: A contemporary review by the National Council on Potassium in Clinical Practice. Arch Intern Med 160:2429–2436, 2000.

In addition to potassium supplementation, strategies to minimize K⁺ losses should be considered. These measures may include minimizing the dose of non-K⁺-sparing diuretics, restricting Na⁺ intake, and using a combination of non-K⁺-sparing and K⁺-sparing medications (e.g., angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, K⁺-sparing diuretics, β-blockers). ^{[225] [247]} The use of a K⁺-sparing diuretic is of particular importance in hypokalemia resulting from primary hyperaldosteronism and related disorders, such as Liddle syndrome and AME; K⁺ supplementation alone may be ineffective in these settings. ^{[444] [445] [446]} In patients with hypokalemia due to loss through upper gastrointestinal secretion (continuous nasogastric tube suction, continuous or self-induced vomiting), proton-pump inhibitors are reportedly useful in helping to correct the metabolic alkalosis and reduce hypokalemia.^[446]

* All the recommended doses are for adults.

CAUSES OF HYPERKALEMIA

Epidemiology

Hyperkalemia is usually defined as a potassium level of 5.5 mmol/L or higher, ^{[448] [449]} although in some studies 5.0 to 5.4 mmol/L qualifies for the diagnosis.^[449] Hyperkalemia has been reported in 1.1% to 10% of all hospitalized patients, ^{[232] [448] [449] [450] [451] [452]} with approximately 1.0% of patients (8% to 10% of hyperkalemic patients) having significant hyperkalemia (≥6.0 mmol/L).^[447] Hyperkalemia has been associated with a higher mortality rate (14.3% to 41%), ^{[448] [449] [451]} accounting for approximately 1 death per 1000 patients in one case series from the mid 1980s.^[452] In most hospitalized patients, the pathophysiology of hyperkalemia is multifactorial, with reduced renal function, medications, older age (≥60 years), and hyperglycemia being the most common contributing factors. ^{[232] [448] [449]} However, in one study of patients younger than 60 years, ESRD was the most common cause.^[453]

In patients with ESRD, the prevalence of hyperkalemia is 5% to 10%. ^{[455] [456] [457]} Hyperkalemia accounts for or contributes to 1.9% to 5% of deaths among patients with ESRD. ^{[232] [457]} Hyperkalemia is the reason for emergency hemodialysis in 24% of patients with ESRD on hemodialysis^[456] and renal failure is the most common cause of hyperkalemia diagnosed in the emergency room.^[454] A recent study reported the prevalence of marked hyperkalemia (K⁺≥5.8 mmol/L) to be ap-proximately 1% in a general medicine outpatient setting. Alarmingly, the management was often suboptimal, with approximately 25% of the patients lacking any follow-up, ECGs performed in only 36% of cases, and frequent delays in repeating serum K⁺.^[457]

Pseudohyperkalemia

Factitious or pseudohyperkalemia is an artifactual increase in serum K⁺ due to the release of K⁺ during or after venipuncture. There are several potential causes for pseudohyperkalemia.^[458] First, forearm contraction,^[459] fist clenching,^[16] or tourniquet use^[458] may increase K⁺ efflux from local muscle and thus raise the measured serum K⁺. Second, thrombocytosis,^[460] leukocytosis,^[461] and/or erythrocytosis^[462] may cause pseudohyperkalemia due to release from these cellular elements. Third, acute anxiety during venipuncture may provoke a respiratory alkalosis and hyperkalemia due to redistribution. ^{[53] [54] [55] [65]} Fourth, mechanical and physical factors may induce pseudohyperkalemia after blood has been drawn. For example, pneumatic tube transport has been shown to induce pseudohyperkalemia in one patient with leukemia and massive leukocytosis.^[463] Cooling of blood prior to the separation of cells from plasma or serum is also a well-recognized cause of artefactual hyperkalemia.^[464] The converse is the risk of increased uptake of K⁺ by cells at high ambient temperatures, leading to normal values for hyperkalemic patients or spurious hypokalemia (or both) in patients who are normokalemic. ^{[256] [257]} This issue is particularly important for outpatient primary practice samples that are transported off-site and analyzed at a central facility ^{[256] [257] [466]}; this phenomenon leads to “seasonal pseudohyperkalemia”,^[255] with fluctuations of outpatient samples as a function of season and ambient temperature.

Finally, patients have been described with hereditary forms of pseudohyperkalemia, caused by increase in passive K⁺ permeability of erythrocytes. Abnormal red cell morphology, varying degrees of hemolysis, and/or perinatal edema can accompany hereditary pseudohyperkalemia, whereas in many kindreds there are no overt hematological consequences. Plasma K⁺ increases in pseudohyperkalemia patient samples that have been left at room temperature, due to abnormal K⁺ permeability of erythrocytes. Several subtypes have been defined, based on differences in the temperature-dependence curve of this red cell leak pathway. ^{[467] [468]} The disorder is genetically heterogeneous, with a recently characterized gene on chromosome 17q21 and uncharacterized loci on chromosomes 16q23-ter^[468] and 2q35-36.^[466] Of particular interest, 11 pedigrees of patients with autosomal dominant hemolysis, pseudohyperkalemia, and temperature-dependent loss of red cell K⁺ were recently found to have heterozygous mutations in the SLC4A1 gene on chromosome 17q21, which encodes the band 3 anion exchanger, AE1.^[467] The mutations that were detected all cluster within exon 17 of the gene,^[467] between transmembrane domains 8 and 10 of the AE1 protein. These mutations reduce anion transport in both red cells and Xenopus oocytes injected with AE1, with the novel acquisition of a non-selective transport pathway for both Na⁺ and K⁺. Pseudohyperkalemia in these patients thus results from a genetic event that endows AE1 with the ability to transport K⁺; that single point mutations can convert an anion exchanger to a non-selective cation channel serves to underline the narrow boundaries that separate exchangers and transporters from ion channels.^[467]

Excess Intake of Potassium and Tissue Necrosis

Increased intake of even small amounts of K⁺ may provoke severe hyperkalemia in patients with predisposing factors. For example, the oral administration of 32 millimoles to a diabetic patient with hyporeninemic hypoaldosteronism resulted in an increase in serum K⁺ from 4.9 mmol/l to a peak of 7.3 mmol/l, within 3 hours.^[469] Increased intake or changes in intake of dietary sources rich in K⁺ (see Table 15-4 ) may also provoke hyperkalemia in susceptible patients. Very rarely, marked intake of K⁺, for example in sports beverages,^[470] may provoke severe hyperkalemia in individuals free of predisposing factors. Other occult sources of K⁺ must also be considered, including salt substitutes,^[440] alternative medicines,^[471] and alternative diets.^[472] Geophagia with ingestion of K⁺-rich clay,^[473] and cautopyreiophagia^[474] (ingestion of burnt matchsticks), are two forms of pica that have been reported to cause hyperkalemia in dialysis patients. Sustained-release K⁺-Cl^- tablets can cause hyperkalemia in suicidal overdoses.^[442] Such pills are radio-opaque, and may thus be seen on radiographs; whole bowel irrigation should be used for gastrointestinal decontamination.^[442] Iatrogenic causes include simple over-replacement with K⁺-Cl^- or administration of a potassium-containing medication, such as K⁺-penicillin, to a susceptible patient.

Red cell transfusion is a well-described cause of hyperkalemia, typically seen in children or in massive transfusions. Risk factors for transfusion-related hyperkalemia include the rate and volume of the transfusion, the use of a central venous infusion and/or pressure pumping, the use of irradiated blood, and the age of the blood infused^[16]; whereas 7-day-old blood has a free K⁺ concentration of ∼23 mmol/L, this rises to the 50 mmol/L range in 42-day-old blood.^[475]

Tissue necrosis is an important cause of hyperkalemia. Hyperkalemia due to rhabdomyolysis is particularly common, due the enormous store of K⁺ in muscle (see Fig. 15-1 ). In many cases, volume depletion, medications (statins in particular), and metabolic predisposition contribute to the genesis of rhabdomyolysis. Hypokalemia is an important metabolic predisposing factor in rhabdomyolysis (see discussion on consequences of hypokalemia); others include hypophosphatemia, hypernatremia and hyponatremia, and hyperglycemia. Those patients with hypokalemia-associated rhabdomyolysis in whom redistribution is the cause of hypokalemia are at particular risk of subsequent hyperkalemia, as rhabdomyolysis evolves and renal function worsens. ^{[17] [269]} Finally, massive release of K⁺ and other intracellular contents may occur as a result of acute tumor lysis.^[469]

Redistribution and Hyperkalemia

Several different mechanisms can induce an efflux of intracellular K⁺, resulting in hyperkalemia. Increases in serum K⁺ due to hypertonic mannitol or hypertonic saline^[476] are generally attributed to a “solvent drag” effect, as water moves out of cells in response to the osmotic gradient. Severe hyperkalemia and ventricular tachycardia is a well-described complication of mannitol for the management or prevention of cerebral edema.^[477] Diabetics are prone to severe hyperkalemia in response to intravenous hypertonic glucose in the absence of adequate co-administered insulin, due to a similar osmotic effect. ^{[479] [480]} Finally, a retrospective report recently documented considerable increases in serum K⁺ after IV contrast dye in five patients with chronic kidney disease, four on dialysis, and one with stage IV CKD^[480]; again, the acute osmolar load was the likely cause of the acute hyperkalemia in these patients. The implications of this provocative, preliminary study are not entirely clear. However, one would expect the development or worsening of hyperkalemia in dialysis patients exposed to large volumes of hyperosmolar contrast dye.

Two reports have appeared regarding the risk of hyperkalemia with epsilon-aminocaproic acid, ^{[482] [483]} a cationic amino acid that is structurally similar to lysine and arginine. Cationic but not anionic amino acids induce efflux of K⁺ from cells, although the transport pathways involved are unknown.^[16]

Muscle plays a dominant role in extra-renal K⁺ homeostasis, primarily via regulated uptake by the Na⁺/K⁺-ATPase. Although exercise is a well-described cause of acute hyperkalemia, this effect is usually transient and clinical relevance is difficult to judge. ESRD patients on dialysis do not have an exaggerated increase in serum K⁺ with maximal exercise, perhaps due to greater insulin, catecholamine, and aldosterone responses to exercise and/or to their pre-existing hyperkalemia.^[483] The results and design of this and other studies of exercise-associated hyperkalemia in ESRD have been criticized by a more recent report, which linked abnormal extra-renal K⁺ homeostasis to increased fatigue in ESRD.^[484] Regardless, however, exercise-associated hyperkalemia is not a major clinical cause of hyperkalemia. Dialysis patients are however susceptible to modest increases in serum K⁺ after prolonged fasting, due to the relative insulinopenia in this setting.^[485] This may be clinically relevant in pre-operative ESRD patients, for whom intravenous glucose infusions +/- insulin are appropriate preventive measures for the development of hyperkalemia.^[485]

Digoxin inhibits Na⁺/K⁺-ATPase and thus impairs the uptake of K⁺ by skeletal muscle (see discussion on factors affecting internal distribution of potassium), such that digoxin overdose can result in hyperkalemia. The skin and venom gland of the cane toad Bufo marinus contains high concentrations of bufadienolide, a structurally similar glycoside. The direct ingestion of such toads^[486] or of toad extracts can result in fatal hyperkalemia. In particular, certain herbal aphrodisiac pills contain appreciable amounts of toad venom, and have lead to several case reports in the United States. ^{[17] [488]} Patients may have detectable serum levels using standard digoxin assays, since bufadienolide is immunologically similar to digoxin. Moreover, treatment with digoxin-specific Fab fragment, indicated for management of digoxin overdoses, may be effective and life-saving in bufadienolide toxicity. ^{[17] [488]}Finally, fluoride ions also inhibit Na⁺/K⁺-ATPase, such that fluoride poisoning is typically associated with hyperkalemia.^[488]

Succinylcholine depolarizes muscle cells, resulting in the efflux of K⁺ through acetylcholine receptors (AChRs) and a rapid, but usually transient hyperkalemia. The use of this agent is contraindicated in patients who have sustained thermal trauma, neuromuscular injury (upper or lower motor neuron), disuse atrophy, mucositis, or prolonged immobilization in an ICU setting; the efflux of K⁺ induced by succinylcholine is enhanced in these patients and can result in significant hyperkalemia.^[489] These disorders share a 2- to 100-fold upregulation of AChRs at the plasma membrane of muscle cells, with loss of the normal clustering at the neuromuscular junction.^[489] Depolarization of these up-regulated AChRs by succinylcholine results in an exaggerated efflux of K⁺ through the receptor-associated cation channels that are spread throughout the muscle cell membrane ( Fig. 15-11 ). Concomitant upregulation of the neuronal α7 AChR subunit has also been observed in denervated muscle; the α7-containing AChR is a homomeric, pentameric channel that depolarizes in response to both succinylcholine and choline, its metabolite.^[489]Depolarization α7-AChRs in response to choline is furthermore not subject to desensitization, and may explain in part the hyperkalemic effect that persists in some patients well after the paralytic effect of succinylcholine has subsided.^[489] Consistent perhaps with this neuromuscular pathophysiology, patients with renal failure do not appear to have an increased risk of succinylcholine-associated hyperkalemia.^[490]

FIGURE 15-11 Succinylcholine-induced efflux of potassium is increased in denervated muscle. In innervated muscle, succinylcholine interacts with the entire plasma membrane, but depolarizes only the junctional (a1, b1, d, and e-multicolored) acetylcholine receptors (AChRs); this leads to a modest, transient hyperkalemia. With denervation, there is a considerable up-regulation of muscle AChRs, with increased extra-junctional AChRs (a1, b1, d, and γ-multicolored) and acquisition of homomeric, neuronal-type α7-AChRs. Depolarization of denervated muscle leads to an exaggerated K+ efflux, due to the up-regulation and redistribution of these AChRs. In addition, choline generated from metabolism of succinylcholine maintains the depolarization mediated via α7-AChRs, thus enhancing and prolonging the K+ efflux after paralysis has subsided. (From Martyn JA, Richtsfeld M: Succinylcholine-induced hyperkalemia in acquired pathologic states: Etiologic factors and molecular mechanisms. Anesthesiology 104:158–169, 2006.)

A recent report of three patients suggested the possibility that drugs that share the ability to open K_ATP channels may have an under appreciated propensity to cause hyperkalemia in critically ill patients. The implicated drugs included cyclosporin, isoflurane, and nicorandil.^[491] These patients exhibited hyperkalemia that resisted usual therapies (insulin/dextrose +/- hemofiltration), with a temporal hypokalemic response to the K_ATP inhibitor glibenclamide (glyburide). The daring, off-label use of glibenclamide was presumably instigated by the senior author's observation that cyclosporin activates K_ATP channels in vascular smooth muscle.^[492] K_ATP channels are widely distributed, including in skeletal muscle,^[493] such that activation of such channels is indeed a plausible cause of acute hyperkalemia. However, it remains to be seen whether this is a common or important mechanism for acute hyperkalemia.

Finally, β-blockers cause hyperkalemia in part by inhibiting cellular uptake, but also through hyporeninemic hypoaldosteronism induced by effect of these drugs on both renal renin release and adrenal aldosterone release (see discussion of regulation of renal renin and adrenal aldosterone release). Labetalol, a broadly reactive sympathetic blocker, is a particularly common cause of hyperkalemia in susceptible patients. ^{[17] [495]} However, both non-specific and cardio-specific β-blockers have been shown to reduce PRA, ANG-II, and aldosterone,^[495] such that β-blockade in general will increase susceptibility to hyperkalemia.

Reduced Renal Potassium Excretion

Hypoaldosteronism

Aldosterone promotes kaliuresis by activating apical amiloride-sensitive Na⁺ currents in the CNT and CCD and thus increasing the lumen-negative driving force for K⁺ excretion (see discussion of control of potassium excretion: aldosterone). Aldosterone release from the adrenal may be reduced by hyporeninemic hypoaldosteronism and its multiple causes, by medications, or due to isolated deficiency of ACTH. The isolated loss in pituitary secretion of ACTH leads to a deficit in circulating cortisol; variable defects in other pituitary hormones are likely secondary to this reduction in cortisol.^[496] Concomitant hyporeninemic hypoaldosteronism is frequent,^[497] however hyperkalemia is perhaps less common in secondary hypoaldosteronism than in Addison disease.^[496]

Primary hypoaldosteronism may be genetic or acquired.^[498] The X-linked disorder adrenal hypoplasia congenita (AHC) is caused by loss-of-function mutations in the transcriptional repressor Dax-1. Patients with AHC present with primary adrenal failure and hyperkalemia either shortly after birth or much later in childhood.^[499] This bimodal presentation pattern does not appear to be influenced by Dax-1 genotype; rather, if patients survive the early neonatal period they will then miss being diagnosed until much later in life, presenting either with delayed puberty (see later discussion) or with an adrenal crisis. The steroidogenic factor-1 (SF-1), a functional partner for Dax-1, is also required for adrenal development in both mouse and humans. Both genes are involved in gonadal development, with Dax-1 deficiency leading to hypogonadotropic hypogonadism^[499] and SF-1 deficiency causing male-to-female sex reversal, in addition to adrenal insufficiency.

Reduced steroidogenesis causes two other important forms of primary hypoaldosteronism.^[498] Congenital lipoid adrenal hyperplasia (lipoid CAH) is a severe autosomal recessive syndrome characterized by impaired synthesis of mineralocorticoids, glucocorticoids, and gonadal steroids.^[16] Patients present in early infancy with adrenal crisis, including severe hyperkalemia.^[500] Genotypically male 46,XY patients with lipoid CAH have female external genitalia, due to the developmental absence of testosterone. Lipoid CAH is caused by loss-of-function mutations in steroidogenic acute regulatory protein, a small mitochondrial protein that helps shuttle cholesterol from the outer to the inner mitochondrial membrane, thus initiating steroidogenesis^[501]; some patients may alternatively have mutations in the side-chain cleavage P450 enzyme.^[502] The classic, salt-wasting form of congenital adrenal hyperplasia due to 21-hydroxlase deficiency is associated with marked reductions in both cortisol and aldosterone, leading to adrenal insufficiency.^[503] Concomitant over-production of androgenic steroids results in virilization in female patients with this form of CAH.

Isolated deficits in aldosterone synthesis with hyperreninemia are caused by loss-of-function mutations in aldosterone synthase, although genetic heterogeneity has recently been reported.^[504] Patients typically present in childhood with volume depletion and hyperkalemia.^[505] Much like pseudohypoaldosteronism due to loss-of-function mutations in the MR (see later discussion), patients tend to become asymptomatic in adulthood. Acquired hyperreninemic hypoaldosteronism has been described in critical illness,^[16] type II diabetes,^[506] amyloidosis due to familial Mediterranean fever,^[507] and after metastasis of carcinoma to the adrenal gland.^[16] Finally, aldosterone synthesis is selectively reduced by heparin, with a 7% incidence of hyperkalemia associated with he-parin therapy.^[508] Both unfractionated^[508] and low-molecular weight ^{[17] [510]} heparin can cause hyperkalemia. Heparin reduces the adrenal aldosterone response to both ANGII and hyperkalemia, resulting in hyperreninemic hyperaldosteronism. Histological findings in experimental animals include a marked diminution in size of the zona glomerulosa and an attenuated hyperplastic response to salt depletion.^[508]

Most primary adrenal insufficiency is due to auto-immunity, either in Addison disease or in the context of a polyglandular endocrinopathy. ^{[499] [511]} The antiphospholipid syndrome may also cause bilateral adrenal hemorrhage and adrenal insufficiency.^[511] Another renal syndrome in which there should be a high index of suspicion for adrenal insufficiency is renal amyloidosis.^[512] Finally, HIV has surpassed tuberculosis as the most important infectious cause of adrenal insufficiency. The most common cause of adrenalitis in HIV disease is CMV, however a long list of infectious, degenerative, and infiltrative processes may involve the adrenal glands in these patients.^[513] Although the adrenal involvement in HIV is usually subclinical, adrenal insufficiency may be precipitated by stress, drugs such as ketoconazole that inhibit steroidogenesis, or the acute withdrawal of steroid agents such as megestrol.

Contemporary estimates of the risk of hyperkalemia with Addison disease are lacking, however the incidence is likely 50% to 60%.^[16] The absence of hyperkalemia in such a high percentage of hypoadrenal patients underscores the importance of aldosterone-independent modulation of K⁺ excretion by the distal nephron. A high K⁺ diet and high peritubular K⁺ serves to increase apical Na⁺ reabsorption and K⁺ secretion in the CNT and CCD (see discussion on Control of potassium excretion); in most patients with reductions in circulating aldosterone this homeostatic mechanism would appear to be sufficient to regulate serum K⁺ to within normal limits.

Hyporeninemic Hypoaldosteronism

Hyporeninemic hypoaldosteronism^[514] is a very common predisposing factor in several large, overlapping subsets of hyperkalemic patients; diabetics,^[515] the elderly, ^{[17] [186] [517]} and patients with renal insufficiency.^[16]Hyporeninemic hypoaldosteronism has also been described in systemic lupus erythematosus (SLE),^[517] multiple myeloma,^[518] and acute glomerulonephritis.^[519] Classically, patients should have suppressed plasma renin activity (PRA) and aldosterone, which cannot be activated by typical maneuvers such as furosemide or sodium restriction.^[514] Approximately 50% have an associated acidosis, with a reduced renal excretion of NH₄⁺, a positive urinary anion gap, and urine pH <5.5. ^{[160] [521]} Although the generation of this acidosis is clearly multi-factorial,^[521] strong clinical ^{[521] [523] [524]} and experimental^[244] evidence suggests that hyperkalemia per se is the dominant factor, due to competitive inhibition of NH₄⁺ transport in the thick ascending limb and reduced distal excretion of NH₄^{+ 245} (see also discussion on consequences of hyperkalemia).

Several factors account for the reduced PRA in diabetic patients with hyporeninemic hypoaldosteronism.^[515] First, many patients have an associated autonomic neuropathy, with impaired release of renin during orthostatic chal-lenges.^[16] Failure to respond to isoproterenol with an in-crease in PRA, despite an adequate cardiovascular response, suggests a post-receptor defect in the ability of the juxtaglomerular apparatus to respond to β-adrenergic stimuli^[16] (see also discussion on regulation of renal renin). Second, the conversion of pro-renin to active renin is impaired in some diabetics,^[515] despite adequate release of pro-renin in response to furosemide^[16]; this suggests a defect in the normal processing of pro-renin. Third, as is the case with perhaps all patients with hyporeninemic hypoaldosteronism (see later), many diabetic patients appear to be volume expanded, with subsequent suppression of PRA.

The most attractive current hypothesis for the suppression of PRA in hyporeninemic hypoaldosteronism is that primary volume expansion increases circulating atrial natriuretic peptide (ANP), which then exerts a negative effect on both renal renin release and adrenal aldosterone release (see also discussion on regulation of renal renin and adrenal aldosterone). There is evidence that these patients are volume-expanded, and many will respond to either Na⁺-Cl^-restriction or to furosemide with an increased PRA (i.e., renin is physiologically rather than pathologically suppressed). ^{[525] [526] [527]} Patients with hyporeninemic hypoaldosteronism due to a diversity of underlying causes have elevated ANP levels, ^{[17] [186] [520] [526] [528]} which is also an indicator of their underlying volume expansion. Patients who respond to furosemide with an increase in PRA exhibit a concomitant decrease in ANP.^[525] Furthermore, the infusion of exogenous ANP can suppress the adrenal aldosterone response to both hyperkalemia^[185] and dietary Na⁺-Cl^- depletion.^[528]

Acquired Tubular Defects and Potassium Excretion

Unlike hyporeninemic hypoaldosteronism, hyperkalemic distal renal tubular acidosis is associated with a normal or increased aldosterone and/or PRA. Urine pH in these patients is greater than 5.5, and they are unable to increase acid or K⁺ excretion in response to furosemide, Na⁺-SO₄^2-, or fludrocortisone. ^{[530] [531] [532]} Classic causes include SLE,^[529] sickle cell anemia, ^{[17] [532]} and amylodosis.^[16]

Hereditary Tubular Defects and Potassium Excretion

Hereditary tubular causes of hyperkalemia have overlapping clinical features with hypoaldosteronism; hence the shared label “pseudohypoaldosteronism” (PHA). PHA-I has both an autosomal recessive and an autosomal dominant form. The autosomal dominant form is due to loss-of-function mutations in the mineralocorticoid receptor.^[532] These patients require aggressive salt supplementation during early childhood; however, similar to the hypoaldosteronism due to mutations in aldosterone synthase, they typically become asymptomatic in adulthood.^[349] Of interest, the lifelong increases in circulating aldosterone, ANGII, and renin seen in this syndrome do not appear to have untoward cardiovascular consequences.^[532]

The recessive form of PHA-I is caused by various combinations of mutations in all three subunits of ENaC, resulting in impairment in its channel activity.^[349] Patients with this syndrome present with severe neonatal salt wasting, hypotension, and hyperkalemia; in contrast to the autosomal dominant form of PHA-I, the syndrome does not improve in adulthood.^[349] One unexpected result in the physiological characterization of ENaC was that mice with a targeted deletion of the α-ENaC subunit were found to die within 40 hours of birth due to pulmonary edema.^[533] Patients with recessive PHA-I may have pulmonary symptoms, which can occasionally be very severe^[534]; however, it appears that, unlike in ENaC-deficient mice, the modest residual activity associated with heteromeric PHA-I channels is generally sufficient to mediate pulmonary Na⁺ and fluid clearance in humans with loss-of-function mutations in ENaC.^[535] PHA-I has also had a significant impact on the understanding of the biophysical properties of the ENaC channels, since the functional characterization of one specific PHA-I mutation lead to the characterization of a domain in ENaC subunits that determines channel gating.^[536]

Pseudohypoaldosteronism type II (PHA-II) (also known as Gordon syndrome and “hereditary hypertension with hyperkalemia”) is in every respect the “mirror image” of Gitelman syndrome; the clinical phenotype includes hypertension, hyperkalemia, hyperchloremic metabolic acidosis, suppressed PRA and aldosterone, hypercalciuria, and reduced bone density.^[537] PHA-II behaves like a gain-of-function in the thiazide-sensitive Na⁺-Cl^-cotransporter NCC, and treatment with thiazides typically results in resolution of the entire clinical picture.^[537] PHA-II is an extreme form of hyporeninemic hypoaldosteronism due to volume expansion; aggressive salt restriction decreases ANP levels and increases PRA, with resolution of the hypertension, hyperkalemia, and metabolic acidosis.^[527] Characterization of the diseases genes for this disorder has also revealed a direct effect of PHA-II on Na⁺, Cl^-, and K⁺ handling by the distal nephron.

PHA-II is an autosomal dominant syndrome, with as many as three genetic loci.^[16] In a landmark paper, mutations in two related serine-threonine kinases were detected in various kindreds with PHA-II.^[538] The catalytic sites of these kinases lack specific catalytic lysines conserved in other kinases, hence the designation “WNK” (with no lysine). Whereas PHA-II mutations in WNK4 affect the C-terminus of the coding sequence, large intronic deletions in the WNK1 gene result in increased expression. Both kinases are expressed within the distal nephron, in both DCT and CCD cells; whereas WNK1 localizes to the cytoplasm and basolateral membrane, WNK4 protein is found at the apical tight junctions.^[538] WNK1 is also expressed at the basolateral membrane of other epithelial tissues, suggesting a more generalized role in epithelial salt transport.^[539] Consistent with the physiological gain-of-function in NCC, WNK4 co-expression inhibits this transporter, and both kinase-dead and disease-associated mutations abolish the effect. ^{[541] [542]} WNK1 in turn has no effect on NCC, but abrogates the inhibitory effect of WNK4.^[542] These observations are consistent with the molecular genetics of PHA-II,^[538] suggesting that heterozygous loss-of-function and gain-of-function mutations in WNK4 and WNK1, respectively, cause the disorder. WNK4 reportedly interacts directly with the NCC protein.^[540] However, the WNK kinases appear to exert their effect on NCC and other cation-chloride cotransporters via the phosphorylation and activation of the SPAK and OSRI serine/threonine kinases, which in turn phosphorylate the transporter proteins. ^{[544] [545] [546]}

A unified picture has yet to emerge of the roles of WNK1/4 and associated signaling pathways in the regulation of distal Na⁺, Cl^-, and K⁺ handling. Analysis is further complicated by the transcriptional complexity of the WNK1 gene, which has at least three separate promoters and a number of alternative splice forms. In particular, the predominant intra-renal WNK1 isoform is generated by a distal nephron transcriptional site that bypasses the N-terminal exons that encode the kinase domain, yielding a kinase-deficient “short” form of the protein.^[546] It is however reported that both WNK1^[547] and WNK4^[548] inhibit ROMK, the secretory K⁺ channel; disease-associated mutations in WNK4 increase its inhibitory effect,^[548] suggesting a direct inhibition of distal K⁺ secretion in PHA-II. WNK4 also increases paracellular Cl^- permeability in transfected epithelial cells, with loss of this effect in cells expressing kinase-dead WNK4 and an augmentation of the effect in cells expressing PHA-II-associated mutations.^[549] An increase in paracellular Cl^- permeability in the CNT and CCD is expected to reduce the lumen-negative potential difference; again, this effect of disease-associated mutations in WNK4 is expected to inhibit distal K⁺ secretion.

Medication-related Hyperkalemia

Non-Steroidal Anti-Inflammatories

Hyperkalemia is a well-recognized complication of non-steroidal anti-inflammatories (NSAIDs). NSAIDs cause hyperkalemia by a variety of mechanisms, as would be predicted from the relevant physiology. By decreasing glomerular filtration rate and increasing sodium retention they decrease distal delivery of Na⁺ and reduce distal flow rate. Moreover, the flow-activated apical maxi-K channel in the CNT and CCD is activated by prostaglandins,^[550]hence NSAIDs will reduce its activity and the flow-dependent component of K⁺ excretion. ^{[72] [80]} NSAIDs are also a classic cause of hyporeninemic hypoaldosteronism. ^{[552] [553]} The administration of indomethacin to normal volunteers thus attenuates furosemide-induced increases in plasma renin activity (PRA). ^{[176] [554]} Finally, NSAIDs would not cause hyperkalemia with such regularity if they did not also blunt the adrenal response to hyperkalemia, which is at least partially dependent on prostaglandins acting though prostaglandin EP2 receptors and cyclic-AMP.^[184]

The physiology reviewed earlier in this chapter (discussion of regulation of renal renin and adrenal aldosterone) would suggest that COX-2 inhibitors are equally likely to cause hyperkalemia. Indeed, COX-2 inhibitors can clearly cause sodium retention and a decrease in glomerular filtration rate, ^{[555] [556]} suggesting NSAID-like effects on renal pathophysiology. COX-2-derived prostaglandins stimulate renal renin release^[16] and COX-2 inhibitors reduce PRA in both dogs^[556] and humans.^[175] Salt restriction potentiates the hyperkalemia seen in dogs treated with COX-2 inhibitors,^[556] such that hypovolemic patients may be particularly prone to hyperkalemia in this setting. Not surprisingly, clinical reports have begun to emerge of hyperkalemia and acute renal failure associated with COX-2 inhibitors. ^{[17] [558] [559]} Where the data have been reported, circulating PRA or aldosterone (or both) have been reduced in hyperkalemia associated with COX-2 inhibitors. ^{[558] [559]}

Cyclosporin and Tacrolimus

Both cyclosporin (CsA)^[559] and tacrolimus^[560] cause hyperkalemia; the risk of sustained hyperkalemia may be higher in renal transplant patients treated with tacrolimus than in those treated with CsA.^[561] CsA is perhaps the most versatile of all drugs in the variety of mechanisms whereby it causes hyperkalemia. It causes hyporeninemic hypoaldosteronism^[562] due in part to its inhibitory effect on COX-2 expression in the macula densa.^[563] CsA inhibits apical SK secretory K⁺ channels in the distal nephron,^[564] in addition to basolateral Na⁺-K⁺-APTase.^[16] Finally, CsA causes redistribution of K⁺ and hyperkalemia, particularly when used in combination with β-blockers.^[565] A provocative but preliminary report has linked acute hyperkalemia secondary to CsA to indirect activation of K_ATP channels (see also earlier discussion)^[491]; this is particularly intriguing given the reported response to K_ATP inhibition with glibenclamide infusion.

ENaC Inhibition

Inhibition of apical ENaC activity in the distal nephron by amiloride and other K⁺-sparing diuretics predictably results in hyperkalemia. Amiloride is structurally similar to the antibiotics trimethoprim (TMP) and pentamidine, which can also inhibit ENaC. ^{[567] [568] [569]} Trimethoprim thus inhibits Na⁺ reabsorption and K⁺ secretion in perfused CCDs.^[569] Both TMP/SMX (Bactrim) and pentamidine were reported to cause hyperkalemia during high-dose treatment of Pneumocystis pneumonia in HIV patients, ^{[17] [569]} who are otherwise predisposed to hyperkalemia. However, this side effect is not restricted to high-dose intravenous therapy; in a study of hospitalized patients treated with standard doses of trimethoprim, significant hyperkalemia occurred in greater than 50%, with severe hyperkalemia (>5.5 mmol/l) in 21%.^[570] Risk factors for hyperkalemia due to normal-dose TMP include renal insufficiency^[570] and hyporeninemic hypoaldosteronism.^[571]

Whereas TMP and pentamidine directly inhibit ENaC, a novel, indirect mechanism causing hyperkalemia has recently emerged. ^{[17] [573]} Aldosterone induces expression of the membrane associated proteases CAP1-3 (see discussion on control of potassium excretion: aldosterone). Nafamostat, a protease inhibitor this widely used in Japan for pancreatitis and other indications, is known to cause hyperkalemia^[572]; indirect evidence suggests that the mechanism involves inhibition of amiloride-sensitive Na⁺ channels in the CCD.^[16] Treatment of rats with nafamostat was also shown to reduce the urinary excretion of CAP1/prostasin, in contrast to the reported effect of aldosterone.^[129] Thus inhibition of the protease activity of CAP1, and/or other proteases, by nafamostat appears to abrogate its activating effect on ENaC ( Fig. 15-12 ), and may reduce expression of the protein in the CCD.^[573]

FIGURE 15-12 Pharmacological inhibition of the epithelial Na+ channel ENaC. Whereas amiloride and related compounds directly inhibit the channel, the protease inhibitor nafamostat inhibits membrane-associated proteases such as CAP1, thus indirectly inhibiting the channel. Spironolactone and related drugs inhibit the mineralocorticoid receptor, thus reducing transcription of the α-subunit of ENaC, the ENaC-activating kinase SGK, and several other target genes (see text for details).

ACE Inhibitors, Mineralocorticoid, and Angiotensin Antagonists

Hyperkalemia is a predictable and common effect of both ACE inhibition and antagonism of the mineralo-corticoid receptor^[16] ( Fig. 15-13 ). ARBs appear to have a lesser effect on plasma K⁺ in patients with renal insufficiency.^[574] Of note, renin-inhibitors constitute a forthcoming class of agents that also target the renin-angiotensin-aldosterone axis^[575]; these drugs are also likely to affect serum K⁺. As with many other causes of hyperkalemia, that induced by pharmacological targeting of the rennin-angiotensin-aldosterone axis depends on concomitant inhibition of the adrenal aldosterone release by hyperkalemia; the adrenal release of aldosterone due to increased K⁺ is clearly dependent on an intact adrenal renal-angiotensin system, such that this response is abrogated by systemic ACE inhibitors and ARBs^[179] (see discussion on regulation of renal renin and adrenal aldosterone release).

FIGURE 15-13 Medications that target the renin-angiotensin-aldosterone axis are common causes of hyperkalemia, as are drugs that inhibit epithelial Na+ channels (ENaC) in the renal tubule (CNT or CCD).

The increasing rationale to combine spironolactone with ACE-inhibitors or ARBs, ^{[577] [578]} along with the emergence of mineralocorticoid receptor antagonists with perhaps a greater potential for hyperkalemia,^[578] may magnify the potential for serious hyperkalemia. This is particularly true when higher than recommended doses are utilized.^[16] The prevalence of hyperkalemia associated with the combined use of mineralocorticoid receptor antagonists and ACE-inhibitors/ARBs appears to be much higher in clinical practice (∼10%)^[579] than what has been reported in large clinical trials (≤2%). ^{[575] [578] [581]} Notably, Juurlink and colleagues studied the correlation between the rate of spironolactone prescription for patients with heart failure on ACE-inhibitors, following the publication of The Randomized Aldactone Evaluation Study (RALES),^[577] with hyperkalemia and associated morbidity.^[581] This provocative study found an abrupt increase in the rate of prescription for spironolactone after release of RALES, with a temporal correlation to increases in the rate of admissions with hyperkalemia^[581]; the association remained statistically significant for admissions where hyperkalemia was the primary diagnosis.^[582]

Given the mounting evidence supporting the combined use of ACE-inhibitors, ARBs, and/or mineralocorticoid receptor antagonists, it is prudent to systematically adhere to measures that will minimize the chance of associated hyperkalemia, therefore allowing patients to benefit from the cardiovascular effects of these agents. The patients at risk for the development of hyperkalemia in response to drugs that target the renin-angiotensin-aldosterone axis, singly or in combination therapy, are those in whom the ability of kidneys to excrete the potassium load is markedly diminished due to one or a combination of the following: (1) decreased delivery of sodium to the cortical collecting duct (as in congestive heart failure, volume depletion, etc.), (2) decreased circulating aldosterone (hyporeninemic hypoaldosteronism, drugs such as heparin or ketoconazole, etc.), (3) inhibition of amiloride-sensitive Na⁺ channels in the CNT and CCD, by co-administration of TMP/SMX, pentamidine, or amiloride, (4) chronic tubulointerstitial disease, with associated dysfunction of the distal nephron, and (5) increased potassium intake (salt substitutes, diet, etc.). In these susceptible patients, the following approach is recommended to prevent or minimize the occurrence of hyperkalemia in response to medications that interfere with the renin-angiotensin-aldosterone system ^{[584] [585]}:

	A.	Estimate glomerular filtration rate using MDRD equation, Cockroft-Gault equation, and/or 24-hour creatinine clearance.
	B.	Inquire about diet and dietary supplements (e.g., salt substitutes, licorice) and prescribe a low potassium diet.
	C.	Inquire about medications, particularly those that can interfere with renal K+ excretion (e.g., NSAIDS, COX-2 inhibitors, K+-sparing diuretics) and, if appropriate, discontinue these agents.
	D.	Continue or initiate loop or thiazide-like diuretics.
	E.	Correct acidosis with sodium bicarbonate.
	F.	Initiate treatment with a low dose of only one of the agents (i.e., of ACE-inhibitors, ARB, or mineralocorticoid receptor antagonists).
	G.	Check serum K+ 3 to 5 days after initiation of the therapy and each dose increment, followed by another measurement one week later.
	H.	If the serum K+ is >5.6, ACE-inhibitors, ARBs, and/or mineralocorticoid receptor blockers should be stopped and patient be treated for hyperkalemia.
	I.	If serum K+ is increased but <5.6 mmol/L, reduce the dose and reassess the possible contributing factors. If the patient is on a combination of ACE-inhibitors, ARBs, and/or mineralocorticoid receptor blockers, all but one should be stopped and potassium rechecked.
	J.	A combination of a mineralocorticoid receptor blocker and either an ACE-inhibitor or an ARB should not be prescribed to patients with stage IV or V of chronic kidney disease.
	K.	The dose of spironolactone in combination with ACE-inhibitors or ARBs should be no more than 25 mg/day.

The Clinical Approach to Hyperkalemia

The first priority in the management of hyperkalemia is to assess the need for emergency treatment (ECG changes, K⁺≤6.0 mmol/L). This should be followed by a comprehensive workup to determine the cause ( Fig. 15-14 ). History and physical examination should focus on medications (e.g., angiotensin converting enzyme inhibitors, NSAIDs, trimethoprim/sulfamethoxazole), diet and dietary supplements (e.g., salt substitute), risk factors for kidney failure, reduction in urine output, blood pressure, and volume status. Initial laboratory tests should include electrolytes, BUN, creatinine, serum osmolality, Mg²⁺, and Ca²⁺, a complete blood count, and urinary pH, osmolality, creatinine, and electrolytes. Serum and urine osmolality are required for calculation of the transtubular K⁺ gradient (see discussion on urinary indices of potassium excretion).

FIGURE 15-14 The diagnostic approach to hyperkalemia. See text for details. ECG: electrocardiogram; TTKG: transtubular potassium gradient; CCD: cortical collecting duct; GFR: glomerular filtration rate; ECV: effective circulatory volume; acute GN: acute glomerulonephritis; HIV: human immunodeficiency virus; NSAIDs: non-steroidal anti-inflammatory drugs; LMW heparin: low molecular weight heparin; ACE-I: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; PHA: pseudohypoaldosteronism; SLE: systemic lupus erythematosus.

MANAGEMENT OF HYPERKALEMIA^[*]

Indications for the hospitalization of patients with hyperkalemia are poorly defined, in part because there is no universally accepted definition for mild, moderate, or severe hyperkalemia. The clinical sequelae of hyperkalemia, which are primarily cardiac and neuromuscular, depend on many other variables (e.g., plasma calcium level, acid-base status, chronicity), in addition to the absolute value of serum K^{+ 451,585}; these issues are likely to influence management decisions. Severe hyperkalemia (serum K⁺≤8.0 mmol/L), ECG changes other than peaked T waves, acute deterioration of renal function, and the existence of additional medical problems have been suggested as appropriate criteria for hospitalization.^[451] However, hyperkalemia in patients with any ECG manifestation should be considered a true medical emergency and treated urgently. ^{[230] [450] [587]} Given the limitations of ECG changes as a predictor of cardiac toxicity (see discussion on consequences of hyperkalemia), patients with severe hyperkalemia (K⁺ ≥ 6 to 6.5 mmol/L) in the absence of ECG changes should also be aggressively treated. ^{[229] [230] [450] [588] [589]}

Urgent management of hyperkalemia constitutes a 12-lead electrocardiogram, admission to the hospital, continuous ECG monitoring, and immediate treatment. The management of hyperkalemia is generally divided into three categories: (1) antagonism of the cardiac effects of hyperkalemia, (2) rapid reduction in K⁺ by redistribution into cells, and (3) removal of K⁺ from the body. The necessary measures to treat the underlying conditions causing hyperkalemia should be undertaken to minimize the factors that are contributing to hyperkalemia and to prevent future episodes.^[229] Dietary restriction (usually 60 meq/day) with emphasis on K⁺ content of total parenteral nutrition (TPN) solutions and enteral feeding products (typically 25 to 50 mmol/L) and adjustment of medications and intravenous fluids are necessary; hidden sources of K⁺, such as intravenous antibiotics, should not be overlooked. ^{[230] [590]}

* All the recommended doses are for adults.

Antagonism of Cardiac Effects: Calcium

Intravenous calcium is the first-line drug in the emergency management of hyperkalemia, even for patients with normal calcium levels. The mutually antagonistic effects of calcium and K⁺ on the myocardium and the protective role of Ca²⁺ in hyperkalemia have long been known.^[590] Calcium raises the action potential threshold and reduces excitability, without changing the resting membrane potential.^[591] By restoring the difference between resting and threshold potentials, Ca²⁺ reverses the depolarization blockade due to hyperkalemia.^[591]

Calcium is available as calcium chloride or calcium gluconate (10 ml ampules of 10% solutions) for intravenous infusion. Each milliliter of 10% calcium gluconate or calcium chloride has 8.9 mg (0.22 mmol) and 27.2 mg (0.68 mmol) of elemental calcium, respectively.^[592] Calcium gluconate^[593] is less irritating to the veins and can be used through a peripheral intravenous (IV) line; calcium chloride can cause tissue necrosis if it extravasates, and requires a central line. A study of patients undergoing cardiac surgery with extracorporeal perfusion (with concomitant high gluconate infusion) suggested that the increase in the ionized calcium level is significantly lower with calcium gluconate.^[594] This finding was attributed to a requirement for hepatic metabolism in the release of ionized calcium from calcium gluconate, such that less ionized calcium would be bioavailable in cases of liver failure or diminished hepatic perfusion.^[594] However, further studies in vitro,^[595] in animals,^[596] in humans with normal hepatic function,^[596] and during the anhepatic stage of liver transplantation^[597] have shown equal and rapid dissociation of ionized calcium from equal doses of calcium chloride and calcium gluconate, indicating that release of ionized cal-cium from calcium gluconate is independent of hepatic metabolism.

The recommended dose is 10 mL of 10% calcium gluconate (3 mL to 4 mL of calcium chloride), infused intravenously over 2 to 3 minutes and under continuous ECG monitoring. The effect of the infusion starts in 1 to 3 minutes and lasts 30 to 60 minutes. ^{[457] [589]} The dose should be repeated if there is no change in ECG findings or if they recur after initial improvement. ^{[457] [589]} However, calcium should be used with extreme caution in patients taking digoxin, because hypercalcemia potentiates the toxic effects of this drug on the myocardium.^[593] In this case, 10 mL of 10% calcium gluconate should be added to 100 mL of 5% dextrose in water and infused over 20 to 30 minutes to avoid hypercalcemia and to allow for an even distribution of calcium in the extracellular compartment. ^{[455] [588] [592]} To prevent the precipitation of calcium carbonate, calcium should not be administered in solutions containing bicarbonate.

Redistribution of K⁺ into Cells

Sodium bicarbonate, β₂ agonists, and insulin with glucose are all used in the management of hyperkalemia to induce redistribution of K⁺. Of these treatments, insulin with glucose is the most constant and reliable, whereas bicarbonate is the most controversial. However, these are all temporary measures and should not be substituted for the definitive therapy of hyperkalemia, which is removal of K⁺ from the body.

Insulin and Glucose

Insulin has the ability to lower serum K⁺ by shifting K⁺ into cells, particularly into skeletal myocytes and hepatocytes (see discussion on factors affecting internal distribution). This effect is reliable, reproducible, dose dependent,^[456] and effective, even for patients with chronic kidney disease and ESRD ^{[599] [600] [601]} and in the anhepatic stage of liver transplantation.^[601] The effect of insulin on serum K⁺ is independent of age, of adrenergic activity,^[602]and of its hypoglycemic effect, which in fact may be impaired in patients with chronic kidney disease or ESRD. ^{[28] [599] [604]}

Insulin can be administered with glucose as a constant infusion or as a bolus injection. ^{[600] [601]} The recommended dose for insulin with glucose infusion is 10 units of regular insulin in 500 mL of 10% dextrose, given over 60 minutes (there is no further drop in serum K⁺ after 90 minutes of insulin infusion ^{[592] [603]}). However, a bolus injection is easier to administer, particularly under emergency conditions.^[229] The recommended dose is 10 units of regular insulin administered intravenously followed immediately by 50 ml of 50% dextrose (25 g of glucose). ^{[587] [600] [605] [606]} The effect of insulin on serum K⁺ begins in 10 to 20 minutes, peaks at 30 to 60 minutes, and lasts for 4 to 6 hours. ^{[457] [588] [600] [607]} In almost all patients, the serum K⁺ drops by 0.5 to 1.2 mmol/L after this treatment. ^{[601] [602] [606] [607]} The dose can be repeated as necessary.

Despite glucose administration, hypoglycemia may occur in up to 75% of patients treated with the bolus regimen described above, typically 1 hour after the infusion.^[599] The likelihood of hypoglycemia is greater when the dose of glucose given is less than 30 g.^[454] To prevent this, infusion of 10% dextrose at 50 ml/hr to 75 ml/hr and close monitoring of the blood glucose is recommended. ^{[587] [605]} Administration of glucose without insulin is not recommended because the endogenous insulin release may be variable.^[485] Glucose in the absence of insulin may in fact increase serum K⁺ by increasing plasma osmolality. ^{[479] [480] [605]} In hyperglycemic patients with glucose levels of ≥200 to 250 mg/dl, insulin should be administered without glucose and with close monitoring of serum glucose.^[591] Combined treatment with β₂-agonists, in addition to their synergism with insulin in lowering serum K⁺, may reduce the level of hypoglycemia.^[599] Of note, the combined regimen may increase the heart rate by 15.1±6.0 beats per minute.^[599]

β₂ Adrenergic Agonists

β₂-agonists are an important but under-utilized group of agents for the acute management of hyperkalemia. They exert their effect by activating Na⁺/K⁺-ATPase and the NKCC1 Na⁺-K⁺-2Cl^- cotransporter, shifting K⁺ into hepatocytes and skeletal myocytes (see also discussion on factors affecting internal distribution). Albuterol (Salbutamol), a selective β₂-agonist, is the most widely studied and used. It is available in oral, inhaled, and intravenous forms; both the intravenous and inhaled or nebulized forms are effective.^[607]

The recommended dose for intravenous administration, which is not available in the United States, is 0.5 mg of albuterol in 100 ml of 5% dextrose, given over 10 to 15 minutes. ^{[592] [608] [609]} Its K⁺-lowering effect starts in few minutes and is maximal at about 30 to 40 minutes, ^{[608] [609]} lasting for 2 to 6 hours.^[454] It reduces serum K⁺ levels by approximately 0.9 to 1.4 mmol/L.^[454]

The recommended dose for inhaled albuterol is 10 to 20 mg of nebulized albuterol in 4 ml of normal saline, inhaled over 10 minutes.^[599] (Nebulized levalbuterol is as effective as albuterol.^[609]) Its kaliopenic effect starts at about 30 minutes, reaches its peak at about 90 minutes, ^{[600] [608]} and lasts for 2 to 6 hours. ^{[455] [608]} Inhaled albuterol reduces serum K⁺ levels by approximately 0.5 mmol/L to 1.0 mmol/L^[454]; albuterol administered by metered-dose inhaler with spacer reduced serum K⁺ level by approximately 0.4 mmol/L.^[610] Albuterol (in inhaled or parenteral form) and insulin with glucose have an additive effect on reducing serum K⁺ levels, by approximately 1.2 mmol/L to 1.5 mmol/L in total. ^{[455] [600] [607]} However, a subset of patients with ESRD (∼20% to 40%) are not responsive to the K⁺-lowering effect of albuterol (ΔK≤0.4 mmol/L); albuterol (or other β₂-agonists) should not be used as a single agent in the management of hyperkalemia. ^{[457] [486]} In an attempt to reduce pharmacokinetic variability, a recent study tested the effects of “weight-based dosing” on serum K⁺ levels, using 7 μg/kg of subcutaneous terbutaline (a β₂-agonist) in a group of ESRD patients.^[611] The results showed a significant decline in serum K⁺ levels in almost all patients (mean 1.31 mmol/L±0.5 mmol/L, range 0.5 mmol/L to 2.3 mmol/L) in 30 to 90 minutes; of note, heart rate increased by an average of 25.8±10.5 beats per minute (range 6.5 to 48).^[611]

Treatment with albuterol may result in an increase in serum glucose (∼2 mmol/L to 3 mmol/L) and heart rate. The increase in heart rate is more pronounced with the intravenous form (∼20 beats per minute) than with the inhaled form (∼6 to 10 beats per minute). ^{[486] [608]} There is no significant increase in systolic or diastolic blood pressure with nebulized or intravenous administration of albuterol.^[607] However, it is prudent to use these agents with extreme caution in patients with ischemic heart disease.^[454]

Sodium Bicarbonate

Bicarbonate prevailed as a preferred treatment modality of hyperkalemia for decades. For example, in a survey of nephrology-training program directors in 1989, it was ranked as the second-line treatment, after Ca²⁺.^[612] Its use to manage acute hyperkalemia was mainly based on small older un-controlled clinical studies with a very limited number of patients, ^{[55] [64] [614]} in which bicarbonate was typically administered as a long infusion over many hours (contrary to IV push, which later became the routine).^[614] One of these studies, which is frequently quoted, concluded that the K⁺-lowering effect of bicarbonate is independent of changes in pH.^[63] However, confounding variables included the duration of infusion, the use of glucose-containing solutions, and infrequent monitoring of serum K⁺. ^{[64] [616]}

The role of bicarbonate in the acute management of hyperkalemia has been challenged. ^{[601] [615] [617]} Blumberg and colleagues compared different K⁺-lowering modalities ( Fig. 15-15 ) and showed that bicarbonate infusion (isotonic or hypertonic) for up to 60 minutes had no effect on serum K⁺ in their cohort of ESRD patients on hemodialysis.^[600] These observations were later confirmed by others, who failed to show any acute (60 to 120 minutes) K⁺-lowering effects for bicarbonate. ^{[615] [616] [617]}

FIGURE 15-15 Changes in serum K+ during intravenous infusion of bicarbonate, epinephrine, or insulin in glucose, and during hemodialysis. (From Blumberg A, Weidmann P, Shaw S, Gnadinger M: Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure. Am J Med 85:507–512, 1988.)

A few studies have shown that metabolic acidosis may attenuate the physiologic responses to insulin and β₂ agonists. ^{[457] [617]} The combined effect of bicarbonate and insulin with glucose has been studied, with conflicting results.^[616] In addition, bicarbonate and albuterol co-administration failed to show any additional benefit over albuterol alone.^[616]

In summary, it appears that bicarbonate administration, especially as a single agent, has no role in the acute management of hyperkalemia. It also may reduce serum ionized calcium levels and cause volume overload, issues of relevance in patients with renal failure. ^{[457] [588]} The acute effect of bicarbonate infusion on serum K⁺ levels in severely acidemic patients is not clear; however, it may be of some benefit in this setting, particularly if acidemia is judged to require bicarbonate. ^{[230] [587]}

Removal of Potassium

Diuretics

Diuretics have a relatively modest effect on urinary K⁺ excretion in patients with chronic kidney disease,^[617] particularly in an acute setting.^[588] However, these medications are useful in correcting hyperkalemia in patients with the syndrome of hyporeninemic hypoaldosteronism,^[618] and selective renal K⁺ secretory problems (e.g., after transplantation or administration of trimethoprim). ^{[620] [621]} In patients with impaired renal function, use of the following agents is recommended: (1) oral diuretics with the highest bioavailability (e.g., torsemide) and the least renal metabolism (e.g., torsemide, bumetanide) in order to minimize the chance of accumulation and toxicity, (2) intravenous agents (short-term treatment) with the least hepatic metabolism (e.g., furosemide rather than bumetanide), (3) combinations of loop and thiazide-like diuretics for better efficacy, although this may decrease glomerular filtration rate due to activation of tubuloglomerular feedback,^[621] (4) the maximal effective “ceiling” dose. ^{[618] [622]}

Mineralocorticoids

Limited data are available on the role of mineralocortoids in the management of acute hyperkalemia. ^{[520] [623]} However, these agents may be useful in managing chronic hyperkalemia in patients with hypoaldosteronism with or without hyporeninism, those with systemic lupus erythematosus,^[623] kidney transplant patients on cyclosporine,^[624] and ESRD patients on hemodialysis with interdialytic hyperkalemia. ^{[626] [627]} A recent study, powered to detect a 0.7 mmol/L reduction in serum K⁺, examined the effect of 0.1 mg/day of fludrocortisone in patients on chronic hemodialysis; this showed a non-significant reduction in serum K⁺ in the treated group (4.8±0.5 mmol/L) vs the control group (5.2±0.7 mmol/L).^[627] The recommended dose is 0.1 mg/day to 0.3 mg/day of fludrocortisone, a synthetic glucocorticoid with potent mineralocorticoid activity and moderate glucocorticoid activity (0.3 mg of fludrocortisone is equal to 1 mg of prednisone with regard to glucocorticoid activity). ^{[520] [625] [626] [627]} In patients with ESRD on hemodialysis, this regimen reduces serum K⁺ by 0.5 mmol/L to 0.7 mmol/L and has not been associated with significant changes in blood pressure or weight (i.e., surrogate for fluid retention).^[625] Overall, the available data are limited for the use of fludrocortisone in hyperkalemia, and close monitoring of blood pressure and weight after initiation of these medications is prudent, especially in non-ESRD patients.

Cation-Exchange Resins

Ion-exchange resins are cross-linked polymers containing acidic or basic structural units that can exchange either anions or cations on contact with a solution. They are capable of binding to a variety of mono- and divalent cations. Cation-exchange resins are classified based on the cation (i.e., hy-drogen, ammonium, sodium, potassium, or calcium) that is cycled during the synthesis of the resin to saturate sulfonic or carboxylic groups. Elkinton and colleagues in 1950 successfully used a carboxylic resin in ammonium cycle in three patients with hyperkalemia.^[628] However, hydrogen- or ammonium-cycled resins were associated with metabolic acidosis^[629] and mouth ulcers,^[630] making the sodium-cycled resins preferable. Sodium-cycled resins were associated with volume overload in some cases.^[629] Calcium-cycled resins may have other potential benefits, including a phosphate-lowering effect; however, this requires large, potentially toxic, doses of resin.^[631] Moreover, these resins have been associated with hypercalcemia.^[632]

Sodium polystyrene sulfonate (SPS, Kayexalate) exchanges Na⁺ for K⁺ in the gastrointestinal tract, mainly in the colon ^{[587] [631] [634]} and has been shown to increase the fecal excretion of K⁺.^[630] To prevent constipation and to facilitate the passage of the resin through the gastrointestinal tract, Flinn and co-workers added sorbitol to the resin.^[634]

The current recommended dose is 15 to 30 grams of powder in water or preferably 70% sorbitol one to four times a day. A ready-made suspension is also available as 15 g of SPS per 60 ml of suspension. Its effect on K⁺ is slow, and the full effect may take up to 4 to 24 hours. ^{[588] [589]} Thus it should be used only in conjunction with other measures in the management of acute hyperkalemia. Each gram of resin binds 0.5 to 1.2 mEq of K⁺ in exchange for 2 to 3 mEq of Na⁺. ^{[589] [631] [636] [637]} The discrepancy is caused in part by the binding of small amounts of other cations.^[630]

The role of resins and their effect on potassium has recently been re-examined. One study of healthy subjects compared the rate of fecal excretion of K⁺ by different laxatives with or without resin (SPS) and found that the combination of phenolphthalein/docusate with resin produced greater fecal excretion of K⁺ (49 mmol in 12 hours) than did phenolphthalein/docusate alone (37 mmol in 12 hours) or other laxative-resin combinations.^[635] Earlier studies, mostly before the era of chronic hemodialysis, used multiple doses of the exchange resin orally or rectally as an enema and were associated with declines in serum K⁺ of 1 mEq per liter and 0.8 mEq per liter in 24 hours, respectively.^[630] However, with the advent of chronic hemodialysis, it has become common to order only a single dose of resin-cathartic in the management of acute hyperkalemia. A recent study has questioned the efficacy of this practice, evaluating the effect of four single-dose resin-cathartic regimens on serum K⁺ levels of six patients with chronic kidney disease on maintenance hemodialysis; none of the regimens used reduced the serum K⁺ below the initial baseline.^[636] Notably, the subjects in this study were normokalemic. However, when dialysis is not immediately feasible or appropriate, repeated doses of Kayexalate may be required for an adequate effect.

Kayexalate can be administered rectally as a retention enema in patients unable to take or tolerate the oral form. The recommended dose is 30 to 50 grams of resin as an emulsion in 100 mL of an aqueous vehicle every 6 hours. It should be administered warm (body temperature), after a cleansing enema with body-temperature tap water, through a rubber tube placed at about 20 cm from the rectum with the tip well into the sigmoid colon. The emulsion should be introduced by gravity, flushed with an additional 50 ml to 100 ml of non-sodium-containing fluid, retained for at least 30 to 60 minutes, and followed by a cleansing enema (250 ml to 1000 ml of body-temperature tap water).^[637]We do not recommend using emulsion in sorbitol because multiple cases of colonic necrosis secondary to SPS-sorbitol have been attributed to the sorbitol. ^{[589] [639]}

Ischemic colitis and colonic necrosis are the most serious complications of SPS ^{[639] [640]}; they are more common with the enema form, and have been attributed to the sorbitol content.^[638] However, in at least some of these cases, the enemas, including the pre-administration and post administration cleansing enemas, were not administered as recommended by the manufacturer, which might have been protective.^[637] The actual incidence of colonic necrosis following Kayexalate enemas is unknown. In a retrospective study by Gerstman and colleagues, the overall incidence was 0.27%, whereas postoperative incidence was higher (1.8%).^[640] The incidence in transplant patients has been estimated at about 1%.^[641] Postoperative ileus and the direct toxic effect of sorbitol have been suggested as potential cofactors for necrosis. This complication can also occur with oral administration of SPS in sorbitol, although the incidence tends to be much lower, and can affect both the upper and the lower gastrointestinal tract. ^{[641] [642] [643]} A case of colonic necrosis following oral SPS (without sorbitol) was reported.^[643] Other potential complications, although rare, include reduction of serum calcium,^[644] volume overload,^[629] interference with lithium absorption,^[645] and iatrogenic hypokalemia.^[637]

Dialysis

All modes of acute renal replacement therapies are effective in removing K⁺. Continuous hemodiafiltration is increasingly used in the management of critically ill and hemodynamically unstable patients.^[646] Peritoneal dialysis, although not very effective in an acute setting, has been utilized effectively in cardiac arrest complicating acute hyperkalemia.^[647] Peritoneal dialysis is capable of removing significant amounts of K⁺ (5 mmol/hour or 240 mmol in 48 hours) using 2-liter exchanges, with each exchange taking almost an hour.^[591] However, hemodialysis is the preferred mode when rapid correction of a hyperkalemic episode is desired.^[648]

An average 3- to 5-hour hemodialysis session removes approximately 40 mmol to 120 mmol of K⁺. ^{[649] [650] [651] [652] [653] [654] [655] [656] [657]} Approximately 15% of the total K⁺ removal results from ultrafiltration, with the remaining clearance from dialysis. ^{[653] [658]} Of the total K⁺ removed, about 40% is from extracellular space, and the remainder is from intracellular compartments. ^{[651] [653] [654]} In most patients, the greatest decline in serum K⁺(1.2 mmol/l to 1.5 mmol/l) and the largest amount of K⁺ removed occur during the first hour; the serum K⁺ usually reaches its nadir at about 3 hours. Despite a relatively constant serum K⁺, K⁺ removal continues until the end of the hemodialysis session, although at significantly lower rate. ^{[652] [653] [657]}

The amount of K⁺ removed depends primarily on the type and surface area of the dialyzer used, blood flow rate, dialysate flow rate, dialysis duration, and serum to dialysate K⁺ gradient. However, about 40% of the difference in removal cannot be explained by the previously mentioned factors, and may instead be related to the relative distribution of K⁺ between intracellular and extracellular spaces.^[650] Glucose-free dialysates are more efficient in removing K⁺. ^{[651] [654]} This effect may be caused by alterations in endogenous insulin levels, with concomitant intracellular shift of K⁺; the insulin level is 50% lower when glucose-free dialysates are utilized.^[650] Furthermore, these findings imply that K⁺ removal may be greater if hemodialysis is performed in a fasting state.^[657] Treatment with β₂-agonists also reduces the total K⁺ removal, by approximately 40%.^[648] The change in pH during dialysis has been thought to have no significant effect on K⁺ removal. ^{[649] [658]} A recent study evaluated this issue in detail, examining the effect of dialysate bicarbonate concentration on both serum K⁺ and K⁺ removal. Dialysates with bicarbonate concentration of 39 mmol/L (high), 35 mmol/L (standard), and 27 mmol/L (low) were utilized. The use of high concentration of bicarbonate was associated with a more rapid decline in serum K⁺; this was statistically significant for high vs both standard and low bicarbonate dialysates, at 60 and 240 minutes. However, the total amount of K⁺ removed was higher with the low bicarbonate dialysate (116.4±21.6 mmol/dialysis) in comparison to standard (73.2±12.8 mmol/dialysis) and high (80.9±15.4 mmol/dialysis) bicarbonate dialysates; all statistically not significant.^[658] Therefore, whereas high-bicarbonate dialysis may acutely have a more rapid effect on serum K⁺, this advantage is potentially mitigated by a lesser total removal of the ion over the course of a typical treatment session.

One of the major determinants of total K⁺ removal is the K⁺ gradient between the serum and dialysate. Dialysates with a lower K⁺ concentration are more effective at reducing serum K⁺. ^{[652] [656]} However, a rapid decline in the level of serum K⁺ can be of concern. An acute decrease in serum K⁺ can be associated with rebound hypertension (i.e., a significant increase in blood pressure 1 hour after dialysis),^[649] which is attributed in part to the peripheral vasoconstriction that is a direct result of the change in serum K⁺.^[649] On the other hand, a low serum K⁺ can alter the rate of tissue metabolism—the so-called Solandt effect^[659]—and decrease tissue oxygen consumption, promoting arteriolar constriction.^[649] This vasoconstriction, in turn, may reduce the efficiency of dialysis^[660]; a randomized, prospective study did not, however, confirm this finding.^[651] The difference may have been due to the glucose content of the dialysate (i.e., 200 mg/dL in the former and zero in the latter study); the glucose can increase the insulin level and thereby muscle blood flow.^[661] This effect can later be attenuated by a rapid decline in serum K⁺.^[651]

Several studies have found an increased incidence of significant arrhythmia with hemodialysis, occurring during or immediately after treatment ^{[663] [664] [665]}; an incidence of up to 76% has been reported.^[665] However, many investigators do not consider the hemodialysis procedure to be significantly arrhythmogenic. ^{[667] [668] [669]} Some have suggested that a relationship exists between decreases in K⁺, dialysate K⁺, and the incidence of significant arrhythmias.^[662] Despite the controversy, it seems prudent to recommend that dialysates with a very low K⁺ (0 mmol/L or 1 mmol/L) be used cautiously, particularly in high-risk patients. This definition includes those patients receiving digoxin; those with a history of arrhythmia, coronary artery disease, left ventricular hypertrophy, or high systolic blood pressure; and those of an advanced age. Continuous cardiac monitoring for all patients dialyzed against a 0 mmol/L or 1 mmol/L K⁺ bath is recommended.^[456] To minimize the risk of the previously mentioned complications without significantly affecting dialytic efficacy, we recommend the use of a graded reduction in the dialysate K⁺ concentration, particularly in high-risk patients. ^{[457] [670]} For example in a patient with a serum K⁺ of 8.5 mmol/L we initiate dialysis with a 4 mmol/L K⁺ dialysate and reduce the K⁺ concentration of the dialysate over the course of the dialysis treatment, by 1 mmol/L every hour to a final K⁺ concentration of 1 mmol/L. However, for those hyperkalemic patients with life-threatening arrhythmias (sinus bradycardia, sinus arrest, slow idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, and asystole ^{[228] [230]}), initiation with a low-K⁺ dialysate may be appropriate, followed by a graded approach once the acute arrhythmia has resolved.

A rebound increase in serum K⁺ can occur after hemodialysis. This phenomenon can be especially marked in cases of massive release from devitalized tissues (e.g., tumor lysis, rhabdomyolysis), requiring frequent monitoring of serum K⁺ and further hemodialysis. However, a rebound increase may also occur in ESRD patients during regular maintenance hemodialysis, despite technically adequate treatment,^[652] particularly in those patients with a high pre-dialysis K⁺. Factors attenuating K⁺ removal and thus increasing the risk and magnitude of postdialysis rebound include; pretreatment with β₂-agonists^[648]; pretreatment with insulin and glucose, eating early during the dialysis treatment^[657]; a high pre-dialysis serum K^{+ 652}; and higher dialysate Na⁺ concentrations.^[654]

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