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Disorders of Potassium Balance
David B. Mount and Kambiz Zandi-Nejad
Normal Potassium Balance, 640 Potassium Transport Mechanisms, 641 Factors Affecting Internal Distribution of Potassium, 642 Renal Potassium Excretion, 644 Potassium Transport in the Distal Nephron, 644 Control of Potassium Secretion, 645 Integrated Regulation of Distal Sodium Absorption and Potassium Secretion, 647 Regulation of Renal Renin and Adrenal Aldosterone, 648 Urinary Indices of Potassium Excretion, 649
Consequences of Hyperkalemia and Hypokalemia, 649 Consequences of Hypokalemia, 649 Consequences of Hyperkalemia, 650 Hypokalemia, 652 Epidemiology, 652 Spurious Hypokalemia, 652 Redistribution and Hypokalemia, 652 Hypokalemic Periodic Paralysis, 653 Nonrenal Potassium Loss, 654 Renal Potassium Loss, 654 Clinical Approach to Hypokalemia, 661 Treatment of Hypokalemia, 661 Hyperkalemia, 664 Epidemiology, 664
Pseudohyperkalemia, 665 Excess Intake of Potassium and Tissue Necrosis, 665 Redistribution and Hyperkalemia, 666 Reduced Renal Excretion of Potassium, 667 Medication-Related Hyperkalemia, 669 Clinical Approach to Hyperkalemia, 671 Treatment of Hyperkalemia, 672
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 critical to the diagnostic and management approach to hyperkalemia and hypokalemia. 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 of renal potassium transport is provided in Chapter 5. Knowledge of the pathophysiology of potassium disorders continue to evolve. The expanding list of drugs with a potential to affect plasma potassium concentration (K+) has both complicated clinical management and provided new insight. The evolving molecular understanding of rare disorders affecting plasma K+ has also uncovered novel pathways of regulation.1-4 Although none of these disorders constitutes a “public health menace”5 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. 640
Normal Potassium Balance
The dietary intake of potassium ranges from less than 35 to more than 110 mmol/day in U.S. men and women. Despite this widespread variation in intake, homeostatic mechanisms serve to precisely maintain plasma 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 (Figure 17-1). Buffering of extracellular K+ by this large intracellular pool plays a crucial role in the regulation of plasma K+.6 Thus within 60 minutes of an intravenous load of 0.5 mmol/kg of K+-Cl– only 41% appears in the urine, yet plasma K+ rises by no more than 0.6 mmol/L7; adding the equivalent 35 mmol exclusively to the extracellular space of a 70-kg human would be expected to raise plasma K+ by approximately 2.5 mmol/L.8 Changes in cellular distribution also serve to defend plasma K+ during K+ depletion. For example, military recruits have been shown to maintain a normal plasma K+ after 11 days of basic training, despite a profound K+ deficit generated by renal and extrarenal loss.9 The rapid exchange of intracellular K+ with extracellular K+ plays a crucial role in maintaining plasma K+ within such a
Chapter 17 Disorders of Potassium Balance
Cellular stores ~3300 mEq K+
ADP + Pi
GI intake (~100 mEq/day)
Muscle (~2500 mEq K+)
K+ Extracellular fluid (~65 mEq)
RBC (~250 mEq) Liver (~250 mEq) Bone (~300 mEq)
Renal excretion (90-95 mEq/day)
GI excretion (5-10 mEq/day)
FIGURE 17-1 Body K+ distribution and cellular K+ flux. (From Wingo CS, Weiner ID: Disorders of potassium balance, in Brenner BM [editor]: Brenner and Rector’s the kidney, ed 6, Philadelphia, 2000, Saunders, pp 998-1035.)
narrow range; this is accomplished by overlapping and synergistic10 regulation of a number of renal and extrarenal transport pathways.
Potassium Transport Mechanisms
The intracellular accumulation of K+ against its electrochemical gradient is an energy-consuming process, mediated by the ubiquitous Na+–K+–adenosine triphosphatase (Na+-K+-ATPase) enzyme. Na+-K+-ATPase functions as an electrogenic pump, since 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.11 The Na+-K+-ATPase proteins share significant homology with the corresponding subunits of the H+-K+-ATPase enzymes (see “Potassium Transport in the Distal Nephron” section). Cardiac glycosides—that is, digoxin and ouabain—bind to the α-subunits of Na+-K+-ATPase at an exposed extracellular hairpin loop that also contains the major binding sites for extracellular K+.12 The binding of digoxin and K+ to the Na+-K+-ATPase complex is thus mutually antagonistic. This explains, in part, the potentiation of digoxin toxicity by hypokalemia.13 Although the four α-subunits have equivalent affinity for ouabain, they differ significantly in intrinsic K+ouabain antagonism.14 Ouabain binding to isozymes containing the ubiquitous α1-subunit is relatively insensitive to K+ concentrations within the physiologic range, so that this isozyme is protected from digoxin under conditions in which cardiac α2- and α3-subunits, the probable therapeutic targets,15 are inhibited.14 Genetic reduction in cardiac α1 content has a negative ionotropic effect,15 so that the relative resistance of this subunit to digoxin at physiologic plasma K+ concentrations has an additional cardioprotective effect. Notably, the digoxin-ouabain binding site of α-subunits is highly conserved, which suggests a potential role in the physiologic response to endogenous ouabain- and digoxinlike compounds. Novel knock-in mice have been generated that express α2-subunits with engineered resistance to ouabain. These mice are strikingly resistant to ouabaininduced hypertension and to adrenocorticotropic hormone
(ACTH)–dependent hypertension,16 the latter of which is known to involve an increase in circulating ouabain-like glycosides. These provocative data lend new credence to the 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 hypokalemia17 (see “Consequences of Hypokalemia” section). Skeletal muscle contains as much as 75% of body potassium (see Figure 17-1) and exerts considerable influence on extracellular K+ concentration. Exercise is thus a welldescribed cause of transient hyperkalemia. Interstitial K+ in human muscle can reach levels as high as 10 mmol/L after fatiguing exercise.18 Not surprisingly, therefore, changes in skeletal muscle Na+-K+-ATPase activity and abundance are major determinants of the capacity for extrarenal K+ homeostasis. Hypokalemia induces a marked decrease in muscle K+ content and Na+-K+-ATPase activity,19 an “altruistic”6 mechanism to regulate plasma K+ concentration. This is primarily due to dramatic decreases in the protein abundance of the α2-subunit of Na+-K+-ATPase.20 In contrast, hyperkalemia due to potassium loading is associated with adaptive increases in muscle K+ content and Na+-K+-ATPase activity.21 These interactions are reflected in the relationship between physical activity and the ability to regulate extracellular K+ during exercise.22 For example, exercise training is associated with increases in muscle Na+-K+-ATPase concentration and activity, with reduced interstitial K+ in trained muscles23 and an enhanced recovery of plasma K+ after defined amounts of exercise.22 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 (Figure 17-2 and Figure 17-10), where it functions in transepithelial salt transport and tubular regulation of renin release,24 respectively. In contrast, NKCC1 is widely expressed in multiple tissues,24 including muscle.25 The cotransport of K+-Cl– by the four K+-Cl– cotransporters (KCC1 to KCC4) can also function in the transfer of K+ across membranes. Although the KCCs typically function as efflux pathways, they can mediate influx when extracellular K+ increases.24 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, which encompasses both the voltage-sensitive and Ca2+-activated K+ channels; the two-pore, four-TMD family; and the two-TMD family of inwardly rectifying K+ (Kir) channels.26 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 messenger RNA 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 cells, and understanding of their important roles in the pathophysiology of potassium disorders continues to evolve.27,28
ive ss Pa
642 Section II Disorders of Body Fluid Volume and Composition
2 CI TAL
Na K K
FIGURE 17-2 Schematic cell models of potassium transport along the nephron. Cell types are as specified. Note the differences in luminal potential difference along the nephron. TAL, Thick ascending limb. (From Giebisch G: Renal potassium transport: mechanisms and regulation, Am J Physiol 274:F817-F833, 1998.) Na
Principal K K
Factors Affecting Internal Distribution of Potassium
A number of hormones and physiologic conditions have acute effects on the distribution of K+ between the intracellular and extracellular space (Table 17-1). Some of these factors are of particular clinical relevance and are therefore reviewed in detail.
The hypokalemic effect of insulin has been known since the early twentieth century.29 The impact of insulin on plasma K+ and plasma glucose concentrations is separable at multiple levels, which suggests independent mechanisms.19,30 Notably, the hypokalemic effect of insulin is not kidney dependent.31 Insulin and K+ appear to form a feedback loop of sorts, in that
Chapter 17 Disorders of Potassium Balance
TABLE 17-1 Factors Affecting Distribution of Potassium TABLE 17-2 Sustained Effects of β- and α-Adrenergic
between Intracellular and Extracellular Compartments
Acute EFFECT ON POTASSIUM Enhanced cell uptake Enhanced cell uptake Impaired cell uptake Impaired cell uptake Enhanced cell uptake Loose correlation Impaired cell uptake Enhanced cell efflux chronic
Agonists and Antagonists on Serum Potassium Concentration
FACTOR Insulin β-Catecholamines α-Catecholamines Acidosis Alkalosis External potassium balance Cell damage Hyperosmolality
CATECHOLAMINE SPECIFICITY β1- + β2-Agonist (epinephrine, isoproterenol) Pure β1-agonist (ITP) Pure β2-agonist (salbutamol, soterenol, terbutaline β1- + β2-Antagonist (propranolol, sotalol) β1-Antagonist (practolol, metoprolol, atenolol) β2-Antagonist (butoxamine, H 35/25) α-Agonist (phenylephrine) α-Antagonist (phenoxybenzamine)
SUSTAINED EFFECT ON SERUM K+ Decreased None Decreased Increased; blocks the effect of β-agonists None; does not block effect of β-agonists Blocks hypokalemic effect of β-agonists Increased None; blocks effect of α-agonists
FACTOR Thyroid Adrenal steroids Exercise(training) Growth Diabetes Potassium deficiency Chrome renal failure
EFFECT ON ATP PUMP DENSITY Enhanced Enhanced Enhanced Enhanced Impaired Impaired Impaired
Results refer to the late (after 5 min) sustained effect. ITP, Isopropylamino-3-(2-thiazoloxy)-2-propanol. From Giebisch G: Renal potassium transport: mechanisms and regulation, Am J Physiol 274:F817-F833, 1998.
ATP, Adenosine triphosphate. From Giebisch G: Renal potassium transport: mechanisms and regulation, Am J Physiol 274:F817-F833, 1998.
increases in plasma K+ have a marked stimulatory effect on insulin levels.19,32 Insulin-stimulated K+ uptake, measured in rats using a K+ clamp technique, is rapidly reduced by 2 days of K+ depletion, prior to a modest drop in plasma K+ concentration33; however, no change in plasma K+ concentration was seen in rats subjected to a lesser K+ restriction for 14 days.10 Insulin-mediated K+ uptake is thus modulated by the factors that serve to preserve plasma K+ in the setting of K+ deprivation (see also “Potassium Intake” section). Inhibition of basal insulin secretion in normal subjects by somatostatin infusion increases plasma K+ concentration by up to 0.5 mmol/L in the absence of a change in urinary excretion, which emphasizes the crucial role of circulating insulin in the regulation of plasma K+.34 Clinically, inhibition of insulin secretion by the somatostatin agonist octreotide can cause significant hyperkalemia in both anephric patients35 and patients with normal renal function.36 Insulin stimulates the uptake of K+ by several tissues, most prominently liver, skeletal muscle, cardiac muscle, and fat.19,37 It does so by activating several K+ transport pathways, with particularly well-documented effects on Na+-K+-ATPase.38 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,26 it is clear that this is not the primary mechanism in most cell types.39 Insulin induces translocation of the Na+-K+-ATPase α2-subunit to the plasma membrane of skeletal muscle cells, with a lesser effect on the α1-subunit.40 This translocation is dependent on the activity of phosphoinositide-3-kinase (PI3K),40 which itself also binds
to a proline-rich motif in the N terminus of the α-subunit.41 The activation of PI3K by insulin thus induces phosphatase enzymes to dephosphorylate a specific serine residue adjacent to the PI3K 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.42 Finally, serum- and glucocorticoid-regulated kinase 1 (SGK1) plays a critical role in insulin-stimulated K+ uptake, presumably via the known stimulatory effects of this kinase on Na+-K+ATPase activity and/or Na+-K+-2Cl– cotransport.43 The hypokalemic effect of insulin plus glucose is blunted in SGK1 knockout mice, with a marked reduction in hepatic insulinstimulated K+ uptake.43
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 time44; however, a complicating issue is the differential effect of stimulating α- and β-adrenergic receptors (Table 17-2). Uptake of K+ by liver and muscle, with resultant hypokalemia, is stimulated via β2-receptors.26 The hypokalemic effect of catecholamines appears to be largely independent of changes in circulating insulin26 and has been reported in nephrectomized animals.45 The cellular mechanisms whereby catecholamines induce K+ uptake in muscle include an activation of Na+-K+ATPase,46 likely via increases in cyclic adenosine monophosphate (cAMP).47 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.19,25 In contrast to β-adrenergic stimulation, α-adrenergic agonists impair the ability to buffer increases in K+ induced by
55.59 Of note. A critical. due to effective gastrointestinal absorption of H+-Cl–. which has recently supplanted sevelamer hydrochloride as a phosphate binder. the relevant transport pathways are shown in Figures 17-2 and 17-3.48 The clinical consequences of the sympathetic control of extrarenal K+ homeostasis are reviewed elsewhere in this chapter. in which a modest acidosis was accompanied by an increase in circulating insulin. Clinically.1 unit in plasma pH results in 0. The absorption of Na+ via the amiloride-sensitive epithelial sodium channel (ENaC) generates a lumen-negative potential difference. so that alkalemia shifts K+ into cells whereas acidemia is associated with K+ release.56 Notably. excretion is enhanced by excess Na+ intake and reduced by Na+ restriction (Figure 17-4). as noted by Adrogué and Madias.5052. Renal Potassium Excretion Potassium Transport in the Distal Nephron The proximal tubule and loop of Henle mediate the bulk of potassium reabsorption. see “Hereditary Tubular Defects and Potassium Excretion” section). as seen in familial hyperkalemia with hypertension (FHHt. Under basal conditions of high Na+-Cl– and low K+ intake.51.50.6 mmol/L change in plasma K+ in the opposite direction. Rather limited data exist for the durable concept that a change of 0.58 the concomitant infusion of 350 mL of 5% dextrose in water in these fasting subjects may have served to increase circulating insulin. which provides the driving force for both Na+ K entry and K+ exit at the apical membrane (see Figures 17-2 and 17-3).70. use of the oral phosphate binder sevelamer hydrochloride in patients with end-stage renal disease (ESRD) is associated with acidosis. It is thought that β-adrenergic stimulation increases K+ uptake during exercise to avoid hyperkalemia. the absolute increase is smaller than that induced by metabolic acidosis secondary to inorganic acids. however. whereas α-adrenergic mechanisms help blunt the ensuing postexercise nadir.67 Selective increases in thiazide-sensitive Na+-Cl– cotransport in the distal convoluted tubule (DCT).57 However. acute respiratory acidosis increases plasma K+. some studies have failed to show a change in plasma K+ following acute respiratory acidosis.66 Basolateral exchange of Na+ and K+ is mediated by Na++-ATPase.644 Section II Disorders of Body Fluid Volume and Composition intravenous loading or by exercise48. Flow-dependent K+ secretion is mediated by an apical voltage-gated. Metabolic alkalosis induced by sodium bicarbonate infusion usually results in a modest reduction in plasma K+.65. The principal cells of the CNT and CCD play a dominant role in K+ secretion. which is ameliorated by an increase in dialysis bicarbonate concentration. hyperkalemia is not an expected complication of administration of sevelamer carbonate.68 Dietary Na+ intake also influences K+ excretion.51. 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. calcium-sensitive Maxi-K/BK channel.71 and the capacity of the CNT for Na+ reabsorption may be as much as 10 times greater than that of the CCD.60 Respiratory alkalosis reduces plasma K+ by a magnitude comparable to that of metabolic alkalosis.52 Despite the complexities of changes in K+ homeostasis associated with various acid-base disorders. which leads to hyperkalemia.63 Renal potassium excretion is primarily determined by regulated secretion in the distal nephron. a few general observations can be made. which thus blunted the potential hyperkalemic response to NH4+-Cl–.61 Finally. which drives passive K+ exit through apical K+ channels.71 .69 The density of both Na+ and K+ channels is thus considerably greater in the CNT than in the CCD. H2O Na+ Lumen (–) (+) Aquaporin-2 ENaC Aqp-4 3Na+ ATP H2O Acid-Base Status The association between changes in pH and plasma K+ was observed some time ago. prior to the entry of tubular fluid into the CCD.50-54 whereas organic acidosis generally fails to increase plasma K+.66 K+ secretion by the CCD essentially ceases as luminal Na+ drops below 8 mmol/L.65.50-52 Again.54.51 It is thought that this effective K+/H+ exchange serves to help maintain extracellular pH. specifically within the connecting segment (CNT) and cortical collecting duct (CCD). which drives K+ excretion through the apical secretory K+ channel ROMK.49 It has long been held that acute disturbances in acid-base equilibrium result in changes in plasma K+. reduce Na+ delivery to principal cells in the downstream CNT and CCD. In hemodialysis patients this acidosis has been associated with an increase in plasma K+.53.50-52. the bulk of aldosterone-stimulated Na+ and K+ transport occurs in the CNT. Apical Na+ entry via the amiloride-sensitive epithelial Na+ channel (ENaC)64 results in the generation of a lumen-negative potential difference in the CNT and CCD. Chloride-dependent electroneutral K+ secretion is likely mediated by a K+Cl– cotransporter.62 K+ 2K+ K+ K+ Cl– K+ Maxi-K/BK ROMK/SK Cl– FIGURE 17-3 K+-secretory pathways in principal cells of the connecting segment (CNT) and cortical collecting duct (CCD). the cellular mechanisms through which this occurs are not known. The induction of metabolic acidosis by the infusion of mineral acids (NH4+-Cl– or H+-Cl–) consistently increases plasma K+. so that a considerable fraction of filtered potassium is reabsorbed prior to entry into the superficial distal tubules. clinically relevant consequence of this relationship is that K+ secretion is dependent on delivery of adequate luminal Na+ to the CNT and CCD.
both to enhanced delivery and absorption of Na+ and to increased removal of secreted K+. First.91. In addition to apical K+ channels.79 A recent provocative study underlines the importance of ENaC-independent K+ excretion.65. Electrophysiologic characterization has documented the presence of several subpopulations of apical K+ channels in the CCD and CNT.84-86 This is reflected clinically in the frequent absence of hyperkalemia or hypokalemia in disorders associated with a deficiency or an overabundance of circulating aldosterone. the distal nephron is capable of considerable reabsorption of K+. 1984. targeted deletion of this gene in mice results in complete loss of SK activity within the CCD. Am J Physiol 255:F811-F822. (A from Young DB.4 Aldo 2 3 4 5 6 Plasma [K]. Whereas amiloride almost abolished K+ excretion in rats with a normal K+ intake.92 Third.88. However. Regardless.93 Coexpression of SGK1 with ENaC subunits results in increased expression at the plasma membrane. Control of Potassium Secretion Aldosterone Aldosterone is well established as an important regulatory factor in K+ excretion. and intercalated cells.89 which increases its availability for coassembly with the more abundant β. mmol/day•kg 8 6 4 2 0 200 100 10 6 4 2 0 0.90 Second. dietary K+ content was varied. and γ.80 Pharmacologic studies of perfused tubules are consistent with K+-Cl– cotransport mediated by the KCC proteins. aldosterone and dietary Na+-Cl– restriction stimulate a significant redistribution of ENaC subunits in the CNT and early CCD.65. it induces transcription of the ENaC α-subunit. which generated urinary concentrations considered sufficient to inhibit more than 98% of ENaC activity. the hormone induces a marked increase in the density of apical Na+ channels.83 This reabsorption is accomplished primarily by intercalated cells in the outer medullary collecting duct (OMCD).76 Flow-dependent K+ secretion is reduced in mice with targeted deletion of the α1. The molecular physiology of H+-K+ATPase–mediated K+ reabsorption is reviewed in Chapter 5. an increasingly dominant theme is that aldosterone plays a permissive and synergistic role in K+ homeostasis.64 Aldosterone activates ENaC channel complexes by multiple mechanisms. that assemble together to synergistically traffic to the cell membrane and mediate Na+ transport. with progressive recruitment of subunits to the apical membrane of the CCD at lower levels of dietary Na+.66 The apical Ca2+-activated BK channel plays a critical role in flow-dependent K+ secretion by the CNT and CCD. be it mediated by apical K+-Cl– cotransport and/or by other mechanisms. Animals were adrenalectomized and given replacement aldosterone. shortand long-term high-K+ diets led to an increasing fraction of K+ excretion that was independent of ENaC activity (approximately 50% after 7 to 9 days on a high-K+ diet). and increases in plasma K+ concentration are an important stimulus for aldosterone secretion (see also “Regulation of Renal Renin and Adrenal Aldosterone” section). B. The SK channel is thought to mediate K+ secretion under baseline conditions.74. particularly during restriction of dietary K+. aldosterone induces the expression of serine-threonine kinase SGK1. B from Young DB: Quantitative analysis of aldosterone’s role in potassium regulation. respectively (see “Hyperaldosteronism” and “Hypoaldosteronism” sections).82. Jackson TE.and γ-subunits. DCT.74. this is consistent with progressive axial recruitment of transport capacity for the absorption of Na+ and secretion of K+ along the distal nephron. hence its designation as the “secretory” K+ channel.) B The recruitment of ENaC subunits in response to dietary Na+ restriction begins in the CNT. Aldosterone has no effect on the density of apical SK channels in the CCD or CNT.81 Rats were infused with amiloride via osmotic minipumps. as a function of dietary Na+ intake (millimoles per day). Relationship between steady-state serum K+ concentration and urinary K+ excretion as a function of circulating aldosterone level. mM 7 Normal Aldo 10 8 645 Na intake 5 Aldo A 2 3 4 5 6 Plasma [K].78 consistent with a dominant role for BK channels.72. it is clear that aldosterone and downstream effectors of this hormone have clinically relevant effects on plasma K+ levels and that the ability to excrete K+ is modulated by systemic aldosterone levels (see Figure 17-4). dietary K+ and Na+ content were varied as specified. Tipayamontri U.81 In addition to secretion.and β1-subunits.75 (see Figure 17-3). mM 7 FIGURE 17-4 A. α. with α-subunits that form the ion channel pore and modulatory β-subunits. rather. most prominently a small-conductance (SK) 30-picosiemens channel70. in part.73 Again. et al: Effects of sodium intake on steadystate potassium excretion.63. 1988. encoded by the Kcnj1 gene.74 and a large-conductance Ca2+-activated 150-picosiemens (BK) channel70.79. from a largely cytoplasmic location during dietary Na+-Cl– excess to a purely apical distribution after aldosterone or Na+-Cl– restriction.74 The β1-subunits of BK channels are restricted to principal cells within the CNT. SK channel activity is mediated by the ROMK (renal outer medullary K+ channel) protein.72 The activity of secretory K+ channels in the CNT is also influenced by changes in dietary K+. considerable evidence implicates apical K+-Cl– cotransport in distal K+ secretion.19.87 thus increasing the driving force for apical K+ excretion.75 Increased distal flow has a significant stimulatory effect on K+ secretion.91 . Relationship between steady-state serum K+ concentration and urinary K+ excretion in the dog.74 BK channels have a heteromeric structure. The apical amiloride-sensitive ENaC is comprised of three subunits.77. β. This is due. Animals were adrenalectomized and variably given replacement aldosterone. Am J Physiol 246:F772-F778. via the activity of apical H+-K+-ATPase pumps (see Figure 17-2).76 whereas β4-subunits are detectable at the apical membranes of TAL.Chapter 17 Disorders of Potassium Balance 10 K Excretion.
104. Phosphorylation of Nedd4-2 by SGK1 abrogates the inhibitory effect of this ubiquitin ligase on ENaC subunits97 (Figure 17-5). and induction of channel-activating proteases. this is associated with an increase in apical expression of the ROMK channel protein.106 along with a modest increase in Na+ channel (ENaC) activity87. homozygous SGK1–/– mice exhibit normal blood pressure and a normal plasma K+ concentration. which is a phosphorylation substrate for the kinase. a newer anticoagulant.101 Urinary excretion of CAP1 is increased in hyperaldosteronism. leading to a gain-of-function in channel activity. also accompanied by a considerable increase in circulating aldosterone (approximately fivefold greater than that in wildtype littermate controls).) Increased surface expression ENaC SGK1 modulates membrane expression of ENaC by interfering with regulated endocytosis of its channel subunits. with homology to CAP1.90 The so-called PPxY domains in the C termini of all three ENaC subunits bind to WW domains of Nedd4-2. with largely intracellular distribution of α-subunits in K+-restricted rats and prominent apical expression in K+-loaded rats.100 The mammalian ortholog.5 mmol/L increase in plasma K+. induction of SGK1.73. A “channel-activating protease” that increases channel activity of ENaC was initially identified in Xenopus laevis A6 cells. Increased dietary K+ rapidly increases the activity of SK channels in the CCD and CNT. Trafficking of BK subunits is thus affected by dietary K+.90 A PPxY domain in SGK1 also binds to Nedd4-2. denoted CAP1 (channel-activating protease 1) or prostasin. in addition to H+K+-ATPase activity in the OMCD (reabsorptive capacity).99 On a normal diet. etc. with a reduction after adrenalectomy.106 BK channels in the CNT and CCD are also activated by dietary K+ loading. causes hyperkalemia due to inhibition of ENaC activity.) activate ENaC by excising extracellular inhibitory domains from the α.98 which results in a decreased driving force for distal K+ secretion and the observed susceptibility to hyperkalemia. and a drop in glomerular filtration rate (GFR). with a minimal associated increase in circulating aldosterone.109 A complex. lumen-negative potential difference generated by ENaC is reduced in these SGK1 knockout mice. or mutated in patients with Liddle’s syndrome95 (see “Liddle’s Syndrome” section). However. Thomas BC: Serum and glucocorticoid-regulated kinase modulates Nedd4-2–mediated inhibition of the epithelial Na+ channel.105 Potassium Intake Changes in K+ intake strongly modulate K+ channel activity in the CNT and CCD (secretory capacity). thus inducing removal of channel subunits from the cell membrane followed by degradation in lysosomes and the proteosome.and glucocorticoidregulated kinase) and the ubiquitin ligase Nedd4-2 (neural developmentally downregulated isoform 4-2). repression of Nedd4-2. aldosterone activates ENaC by at least four separate synergistic mechanisms: induction of the ENaC α-subunit.102 These and other proteases (furin. with only a mild elevation of circulating aldosterone.646 Section II Disorders of Body Fluid Volume and Composition Endocytosis/degradation ENaC Aldosterone PY Aldosterone WW Nedd4-2 P P P Nedd4-2 SGK PY FIGURE 17-5 Coordinated regulation of the epithelial sodium channel (ENaC) by the aldosterone-induced kinase SGK (serum.98 This hyperkalemia occurs despite evident increases in apical ROMK expression. the WNK (with no lysine [K]) kinases play a critical role in modulating distal .102.94 These PPxY domains are deleted. J Biol Chem 277:5-8.98. 2002.103 Because SGK1 increases channel expression at the cell surface. In particular.99 In addition. despite considerable increases in circulating aldosterone.101 CAP1 is membrane associated. marked weight loss.108 Again. the kinase interferes with interactions between ENaC subunits and the ubiquitin ligase Nedd4-2 (neural developmentally downregulated isoform 4-2). dietary K+ loading over 6 days leads to a 1. Nedd4-2 binds via its WW domains to ENaC subunits via their PPXY domains (denoted PY here).107 The increase in ENaC and SK channel density in the CCD occurs within hours of assuming a high-K+ diet. is an aldosteroneinduced protein in principal cells.and γ-subunits. and thus surface expression of ENaC channels is increased. Mutations that cause Liddle’s syndrome affect the interaction between ENaC and Nedd4-2. synergistic mix of signaling pathways regulates K+ channel activity in response to changes in dietary K+ (see also Chapter 5). Olson DR. which phosphorylates and inactivates Nedd4-2. denoted CAP2 and CAP3. (From Snyder PM. Another mechanism whereby aldosterone activates ENaC involves proteolytic cleavage of the channel proteins by serine proteases. Specifically.96 Nedd4-2 ubiquitinates ENaC subunits.100 Mammalian principal cells also express two transmembrane proteases. The importance of SGK1 in K+ and Na+ homeostasis is illustrated by the phenotype of SGK1 knockout mice. truncated. plasmin. and this is indeed the case. dietary Na+-Cl– restriction in these mice results in relative Na+ wasting and hypotension. via a glycosylphosphatidylinositol linkage. aldosterone does not contribute to the regulation of BK channel activity or expression in response to high-K+ diet. the inhibition of channel-activating proteases by the protease inhibitor nafamostat. ubiquitinating the channel subunits and targeting them for removal from the cell membrane and destruction in the proteosome. The amiloride-sensitive. Clinically.91 one would expect synergistic activation by coexpressed CAP1 through CAP3 and SGK. Aldosterone induces SGK.102 Therefore. which increases the open probability of channels at the plasma membrane. compared with normokalemic littermate controls.
116.132. increases in aldosterone should lead to an obligatory kaliuresis.91.115 Intrarenal activity of the cytoplasmic tyrosine kinases c-src and c-yes is inversely related to dietary K+ intake.1 Finally.113 and increased by K+ loading (reduced endocytosis of ROMK).126 which leads to unopposed inhibition of ROMK by WNK4. Although ENaC is activated. isoform 8) Cl–/HCO3– exchanger and the SLC26A4 Cl–/HCO3– exchanger125 (see also Chapter 5). reduce Na+ delivery to principal cells in the downstream CNT and CCD.126 (see also Chapter 5). This transport mechanism is apparently responsible for as much 50% of Na+-Cl– transport in mineralocorticoid-stimulated rat CCD. with a decrease under high-K+ conditions and a marked increase after several days of K+ restriction. Angiotensin II–dependent activation of c-src kinases has direct inhibitory effects on ROMK trafficking and also abrogates the inhibitory effect of SGK1 on WNK4. kinase-deficient WNK1S isoform inhibits this effect of WNK1-L. and dietary K+ intake1.111-113 WNK1-S antagonizes the effect of WNK1-L on NCC.Chapter 17 Disorders of Potassium Balance K+ secretion.124 which allows for ENaC-independent.68 Angiotensin II also activates NCC via WNK-dependent activation of the kinase SPAK (STE20/SPS1-related proline/ alanine-rich kinase) and phosphorylation of the transporter protein. angiotensin II appears to mediate part of its inhibitory effect on ROMK through activation of c-src.” the independent regulation of Na+ and K+ handling by the aldosterone-sensitive distal nephron. the . which phosphorylates WNK4 and attenuates the effect of WNK4 on ROMK. increases in dietary K+ are suppressive. the shorter. electroneutral Na+ absorption that will not directly affect K+ secretion.112 The ratio of WNK1-S to WNK1-L transcripts is reduced by K+ restriction (greater endocytosis of ROMK)112. thiazide-sensitive.127. angiotensin II. angiotensin II and aldosterone are both strongly induced.126 Again.114. In addition. angiotensin II inhibits ROMK activity in K+-restricted rats.81 Recent reports have indicated a key role in K+ homeostasis for NCC. which increases the fraction of ENaC-independent. The membrane trafficking of ROMK is also modulated by tyrosine phosphorylation of the channel protein.122. and amiloride-resistant Na+-Cl– transport within the CCD123-125 are mediated by the combined activity of the Na+-dependent SLC4A8 (solute carrier family 4. Full-length WNK1 (WNK1-L) inhibits ROMK by inducing endocytosis of the channel protein.128 which reduce delivery of Na+ to the CNT and limit K+ secretion. and decreased secretory K+ channel activity.120-122 Whereas K+ restriction induces renin and circulating angiotensin II (see “Consequences of Hypokalemia” section).117 Several studies have implicated the intrarenal generation of superoxide anions in the activation of cytoplasmic tyrosine kinases by K+ depletion.123-125 ENaC-independent K+ excretion within the distal nephron.118-120 Potential candidates for the upstream hormonal signals include angiotensin II and growth factors such as insulin-like growth factor-1. the relative inhibition of ROMK by the increased angiotensin II prevents excessive kaliuresis.81 and the differential regulation of various signaling pathways by aldosterone. Electroneutral. The major factors that allow for integrated but independent control of Na+ and K+ transport appear to include electroneutral thiazide-sensitive Na+Cl– transport within the CCD. which causes direction inhibition of ROMK activity via tyrosine phosphorylation of the channel. the differential effects of K+ intake on angiotensin II versus aldosterone appear to be critical in resolving the aldosterone paradox. In contrast. such that tyrosine phosphorylation stimulates endocytosis and tyrosine dephosphorylation induces exocytosis. How is this physiologic consequence avoided? The mechanisms that underlie this “aldosterone paradox.122 so that c-src serves as an important component of the “switch” that regulates K+ secretion in response to changes in dietary K+. increases in aldosterone induce the SGK1 kinase. increased ENaC activity. Selective increases in DCT and NCC activity. WNK1 and WNK4 were initially identified as the causative genes for FHHt (see also “Hereditary Tubular Defects and Potassium Excretion” section). including downstream activation of c-src tyrosine kinases (see earlier). but not in rats consuming a normal-K+ diet. To summarize this important physiology. amiloride-resistant K+ excretion to approximately 50%. FHHt-associated mutations increase this effect. Yet by activating ENaC and generating a more lumen-negative potential difference. which leads to enhanced Na+-Cl– transport via NCC.93 When dietary K+ intake is reduced. such as dietary sodium restriction.111.133 The increase in c-src tyrosine kinase activity also abrogates the inhibitory effect of SGK1 on WNK4. which suggests a direction inhibition of SK channels in FHHt. angiotensin II inhibits ROMK activity via several mechanisms.114. have recently begun to emerge. within principal cells. Electroneutral Na+-Cl– transport in the CCD and ENaCindependent K+ secretion may play important roles in disconnecting Na+ and K+ transport within the distal nephron.130 due the associated decrease in angiotensin II.131 while activating EnaC. c-src tyrosine kinase activity increases under the influence of increased angiotensin II. subfamily A.90. Na+ balance can be maintained without significant effects on K+ excretion. the thiazide-sensitive Na+-Cl– cotransporter in the DCT.4 Transcription of the WNK1 gene generates several different isoforms. so too are the differential effects of K+ intake on NCC-dependent Na+Cl– transport in the DCT and on secretory K+ channels within the downstream CNT and CCD (Figure 17-6). as seen in FHHt. which leads to inhibition of NCC in conditions with a relative excess of WNK1-S.113 which suggests that this ratio between WNK1-S and WNK1-L functions as a molecular “switch” to regulate distal K+ secretion.118 In particular. yielding a kinase-deficient “short” isoform110 (WNK1-S). leading to hyperkalemia.129 A high-K+ diet also inactivates NCC. in addition to the increase in the ratio of WNK1-S to WNK1-L isoforms that occurs with increased K+ intake. however.123.111. Under conditions of low Na+ intake but moderate K+ intake. ROMK expression at the membrane of Xenopus oocytes is reduced by coexpression of WNK4. so that the induction of angiotensin II by a low-K+ diet appears to play a major role in reducing distal tubular K+ secretion.122 647 Integrated Regulation of Distal Sodium Absorption and Potassium Secretion Under certain physiologic conditions associated with marked induction of aldosterone.121 This inhibition by angiotensin II involves downstream activation of superoxide production and c-src activity. The converse effect emerges after dietary K+ loading. The predominant intrarenal WNK1 isoform is generated by a distal nephron transcriptional site that bypasses the N-terminal exons which encode the kinase domain.
The pathway in the setting of a low-Na+ diet. its type 1 receptor (AT1R) cannot activate WNK4.134 specifically a decrease in luminal chloride135 transported through the Na+-K+-2Cl– cotransporter (NKCC2) at the apical membrane of macula densa cells. Aldosterone stimulation of the epithelial sodium channel (ENaC. decreased renal perfusion pressure and renal sympathetic tone stimulate renal renin secretion. furosemide. This leads to inhibition of NCC and increased downstream delivery of Na+ to principal cells in the CNT and CCD. and the red blunt end indicates an inhibitory pathway. endothelin-1. This stimulates phosphorylation of SPAK (STE20/SPS1-related proline/alanine-rich kinase). in which aldosterone is stimulated and angiotensin II is low. Although multiple tissues are capable of renin secretion. renal artery occlusion. whereas NCC is suppressed. which allows robust potassium secretion without changes in sodium balance. which can also stimulate SPAK phosphorylation. Kidney Int 77:1063-1069. which in turn phosphorylates and activates thiazidesensitive Na+-Cl– cotransport in the DCT via NCC (Na+-Cl– cotransporter).19. Chang YP.144 and succinate (GPR91 receptor). see text for further details. and cyclooxygenase-2 (COX-2) is an interesting one.) aldosterone-dependent induction of electroneutral Na+-Cl– transport within the CCD123-125 increases Na+-Cl– reabsorption but blunts the effect on the lumen-negative potential. The net effect is that K+ secretion in the DCT and CNT/CCD is maximized. circulating aldosterone is moderately induced.145 The relationship between renal renin release.142 COX-2 is heavily expressed in the macula densa.142 Prostaglandins derived from COX-2 in the macula densa play a dominant role in the stimulation of renal renin release by salt restriction. but angiotensin II is suppressed. Stimulation of unknown receptors is hypothesized to cause phosphorylation of full-length WNK1 (L-WNK1). In the absence of sufficient angiotensin II. and (2) it inhibits secretion of K+ via ROMK (renal outer medullary potassium) channels. connecting segment (CNT). which causes ROMK to increase at the apical membrane.142 adrenomedullin.19 The various inhibitors of renin release include angiotensin II. ENaC-independent K+ secretion is also strongly induced by increased dietary K+ intake. thus activating NCC. L-WNK1 has other functions: (1) it blocks the NCC-inhibitory form of WNK4. and salt in essential hypertension.143 catecholamines (β1-receptors). The roles of WNK3.142 Reduced intracellular chloride in macula densa cells appears to stimulate COX-2 expression via p38 mitogen-activated protein kinase.140 Cyclic guanosine monophosphate–dependent protein kinase type II (cGKII) tonically inhibits renin secretion.139 and vitamin D. The green arrowheads indicate activating pathways.146 whereas both aldosterone and angiotensin II reduce its expression. kinase-deficient short isoform of WNK1 (KS-WNK1) to suppress the activity of L-WNK1.24 In addition to this macula densa signal. Delpire E: Multigene kinase network.138 tumor necrosis factor-α. This reduces SPAK activation and NCC phosphorylation. Renin secretion by juxtaglomerular cells within the afferent arteriole is initiated in response to a signal from the macula densa. SGK1.138 Local factors that stimulate renin release from juxtaglomerular cells include prostaglandins. Left. thus limiting kaliuresis. not shown) offsets the decreased Na+ reabsorption by NCC. renin of renal origin has a dominant physiologic impact. in which angiotensin II and SGK1 (serum. Dietary potassium loading also increases the level of a kidney-specific.and glucocorticoid-regulated kinase 1) signaling leads to phosphorylation of WNK4 (with no lysine [K] 4).142 with a significant recruitment of COX-2(+) cells seen with salt restriction or furosemide treatment.137 atrial natriuretic peptide (ANP). Right. (From Welling PA.141 Activation of cGKII by ANP and/or nitric oxide has a marked inhibitory effect on the release of renin from juxtaglomerular cells. 2010.136 adenosine.81 which contributes significantly to the ability to excrete K+ in the urine. When dietary K+ increases. In consequence. the RAAS. Regulation of Renal Renin and Adrenal Aldosterone Modulation of the renin-angiotensin-aldosterone system (RAAS) has profound clinical effects on K+ homeostasis. kidney transport. . in that renin secretion in response to several stimuli is exaggerated in homozygous cGKII knockout mice. KS-WNK1 also blocks the effect of L-WNK1 on ROMK endocytosis. blocking traffic of NCC to the apical membrane and thereby reducing NCC activity. the inhibitory effect of WNK4 on NCC dominates. and c-src cytoplasmic tyrosine kinases are not shown in the interest of clarity. where ENaC activity is increased and ROMK and BK channels are significantly activated.648 Section II Disorders of Body Fluid Volume and Composition Hypovolemia (low-Na diet) NCC Na+Cl– P P Na+Cl– P Normal diet ROMK Tubule P lumen Na+Cl– Hyperkalemia (high-K diet) K+ SGK1 SPAKP WNK4PP SPAK WNK4 L-WNK1 KS-WNK1 ~ AT1R ?R NaKATPase AT1R ?R WNK4 L-WNK1P SGK1 WNK4P SPAK L-WNK1 KS-WNK1 SPAKP L-WNK1P K+ SGK1 WNK4P SPAK WNK4 SPAK K+ L-WNK1P L-WNK1 KS-WNK1 ~ NaKATPase AT1R ?R ~ NaKATPase High angiotensin II High aldosterone Na+-Cl– K+ Low angiotensin II High aldosterone FIGURE 17-6 Integrated regulation of and transport in the distal convoluted tubule (DCT). and cortical collecting duct (CCD). The pathway in the setting of high dietary K+ intake.
151 Elevations in extracellular K+ thus depolarize glomerulosa cells and activate these Ca2+ channels.162 The TTKG may be less useful in patients ingesting diets of changing K+ and mineralocorticoid content. so that it far exceeds the limiting K+ gradient. Combined deletion of genes encoding these channels leads to baseline depolarization of adrenal glomerulosa cells and an increase in plasma aldosterone that is resistant to dietary sodium loading. (From Chen XL.160 ANP is therefore capable of inhibiting both renal renin release and adrenal aldosterone release. water absorption may in large part determine the TTKG.19. a linear relationship between plasma aldosterone level and the TTKG. Indeed. however.167.161 Clearly water absorption in the CCD and medullary collecting duct is an important determinant of the absolute K+ concentration in the final urine.166 Consequences of Hyperkalemia and Hypokalemia Consequences of Hypokalemia Excitable Tissues: Muscle and Heart Hypokalemia is a well-described risk factor for both ventricular and atrial arrhythmias. 1999.Chapter 17 Disorders of Potassium Balance Aldosterone secretion (pg/min/106 cells) 300 250 200 150 100 50 0 5K 2K 649 by ARBs or ACE inhibitors. which are independently and synergistically activated by angiotensin II. dietary K+ loading is less potent than dietary Na+-Cl– restriction in increasing circulating aldosterone. an indirect index of urinary NH4+ content and thus the ability to respond to acidemia. Bayliss DA.) A bedside test to directly measure distal tubular K+ secretion in humans would be ideal. Urinary Indices of Potassium Excretion 0 –11 –10 –9 –8 –7 Log [ANG II] (M) FIGURE 17-7 Synergistic effect of increased extracellular K+ and angiotensin II (ANG II) in inducing aldosterone release from bovine adrenal glomerulosa cells. this ultimately amplifies the induction of aldosterone synthase. which suggests that it provides a rough approximation of the ability to respond to aldosterone with kaliuresis. et al: A role for T-type Ca2+ channels in the synergistic control of aldosterone production by ANG II and K+. COX-2–derived prostaglandins appear to play a role in tonic expression of renin in juxtaglomerular cells via modulation of intracellular cAMP and calcium.2. ANP exerts a potent negative effect on aldosterone release induced by K+ and other stimuli.2 Ca2+ channel by abrogating repression of this gene by neuron restrictive silencing factor.152 K+ and angiotensin II also enhance transcription of the Cav 3. the value of which determines whether significant prerenal stimuli are limiting distal Na+ delivery and thus K+ excretion (see also Figure 17-4). Am J Physiol 276:F674-F683. which is defined as follows: TTKG = [K + ] urine × Osmolalityblood [K + ] blood × Osmolalityurine or angiotensin converting enzyme (ACE) inhibition. Other clinically relevant activators of adrenal aldosterone release include prostaglandins155 and catecholamines. in patients undergoing cardiac surgery.165 The determination of urinary electrolyte levels for calculation of the TTKG provides the opportunity for the measurement of urinary Na+.142 Renin released from the kidney ultimately stimulates aldosterone release from the adrenal via angiotensin II.150 Calcium-dependent activation of calciumcalmodulin (CaM)–dependent protein kinase in turn activates the synthesis and release of aldosterone via induction of aldosterone synthase. a plasma K+ concentration of . the use of a ratio of urine/plasma osmolality.164 The response of the TTKG to mineralocorticoid administration. rather than functioning in the acute regulation of renin release. A widely used surrogate is the transtubular K+ gradient (TTKG). for obvious reasons this not technically feasible.159 at least in part by inhibiting early events in aldosterone synthesis.154 Direct G protein–dependent activation of the TASK-1 and/or TASK-3 K+ channels by type 1A or 1B angiotensin II receptors (AT1A. can thus be utilized in the diagnostic approach to hyperkalemia.168 For example.157.147 Specifically.19.150 primarily Cav 3.156 via increases in cAMP. who will have TTKG values that are higher than 4. however.84 The resting membrane potential of adrenal glomerulosa cells is hyperpolarized. Hyperkalemia per se is also an independent and synergistic stimulus (Figure 17-7) for aldosterone release from the adrenal gland. Dose-response curves for ANG-II were measured at extracellular K+ concentrations of 2 mmol/L (open circles) and 5 mmol/L (filled circles).148 Importantly. The shifting opinions regarding the physiologically appropriate TTKG in hyperkalemia were recently reviewed.149 with abrogation of this effect The expected values of the TTKG are based largely on historical data and are less than 3 to 4 in the presence of hypokalemia and higher than 6 to 7 in the presence of hyperkalemia. AT1B) is thought to underlie the effect of angiotensin II on adrenal aldosterone release.19.158 Finally. Measurement of urinary electrolyte levels also affords the opportunity to calculate the urinary anion gap. a TTKG of less than 2 to 3 separates patients with redistributive hypokalemia from those with hypokalemia due to renal potassium wasting.161 In hypokalemic patients. Fern RJ.149 Angiotensin II and K+ both activate Ca2+ entry into glomerulosa cells via voltage-sensitive T-type Ca2+ channels.151 The adrenal release of aldosterone due to increased K+ is dependent on an intact adrenal renin-angiotensin system. ACE inhibitors and angiotensin-receptor blockers (ARBs) thus markedly abrogate the effect of high K+ on salt-restricted adrenals. functions that may be central to the pathophysiology of hyporeninemic hypoaldosteronism.153 particularly during Na+ restriction. hence.26. due to the activity of the “leak” K+ channels TASK-1 and TASK-3 (tandem of P domains in weak inward rectifier K+ channel [TWIK]–related acidsensitive K+ channels). typically fludrocortisone.163 There is.
7 mmol/L. the dominant apical Na+ entry site in the proximal tubule.180 interstitial nephritis.185 The prominent functional changes in renal physiology that are induced by hypokalemia include Na+-Cl– retention. flat T waves. primarily due to its effect on the heart.26 hypocitraturia. Cardiovascular Consequences A large body of experimental and epidemiologic evidence implicates hypokalemia and/or reduced dietary K+ in the genesis or worsening of hypertension. Mild and/or rapid-onset hyperkalemia will initially increase cardiac excitability. These are most marked when plasma K+ concentration is less than 2. mostly in patients with long-standing hypokalemia due to eating disorders and/or laxative abuse. Mild increases in extracellular K+ also affect the repolarization phase of the cardiac action potential via increases in IKr. hypokalemia causes hyperpolarization.26 and the α2-adrenergic receptor26 in this nephron segment.177 Pathologically. and hypokalemia of diverse causes predisposes to rhabdomyolysis with acute renal failure.191 Correction of hypokalemia is particularly important in hypertensive patients treated with diuretics. perioperative arrhythmia. Consequences of Hyperkalemia Excitable Tissues: Muscle and Heart Hyperkalemia constitutes a medical emergency. often accompanied by hypomagnesemia.19 Potassium restriction in rats induces cortical angiotensin II and medullary endothelin-1 expression. blood pressure in this setting is improved with the establishment of normokalemia. fiber regeneration.26 and abundant epidemiologic data link dietary K+ deficiency and/or hypokalemia with hypertension. either alone or in combination with drug toxicity172 or with LQTS-associated mutations in cardiac K+ and Na+ channels.26 K+ restriction has been shown to result in a rapid. with evidence for both a reduced hydroosmotic response to vasopressin in the collecting duct179 and decreased Na+Cl– absorption by the TAL. the renal pathology includes a relatively specific proximal tubular vacuolization. Weakness and paralysis are therefore a not-infrequent consequence of hypokalemia of diverse etiologies. and stroke.179 Many of these clinical features are not broadly appreciated. the realization in 1946 that K+ replacement reversed the hypokalemic diaphragmatic paralysis induced by treatment of diabetic ketoacidosis was a milestone in diabetes care.187 which is consistent with the observed hyperabsorption of both Na+-Cl– and bicarbonate. and amphotericin.650 Section II Disorders of Body Fluid Volume and Composition less than 3.184 In animal models.192 with a salt sensitivity that persists after K+ levels are normalized.175. K+ depletion may play significant roles in the pathophysiology and progression of heart failure. however.179.185 the AT1 receptor. peaked . and postoperative atrial fibrillation. presumably this salt sensitivity is due to the significant tubulointerstitial injury induced by K+ restriction.189 beginning in the CCD and extending to the medullary collecting duct within the first 24 hours. Hyperkalemia depolarizes cardiac myocytes.191 K+ depletion in young rats induces hypertension. This brings the membrane potential closer to the threshold for generation of an action potential.171 Hypokalemia. K+ depletion in rats causes proximal tubular hyperabsorption of Na+-Cl–. Guo and colleagues recently demonstrated that hypokalemia accelerates the clathrin-dependent internalization and degradation of the HERG (human etherà-go-go–related gene) K+ channel protein.5 mmol/L is a predictor of serious intraoperative arrhythmia.173 In a landmark study. polyuria. gentamicin.183 Acute renal failure with proximal tubular vacuolopathy has also been described.28 This effect on repolarization is thought to underlie the “early” signs of hyperkalemia. is an important cause of the long QT syndrome (LQTS) and torsades de pointes.195 Finally. ST depression. hypokalemia increases susceptibility to acute renal failure induced by ischemia.174 Loss-of-function mutations in HERG reduce IKr and cause type 2 LQTS. which are reviewed in detail elsewhere.170 Electrocardiographic changes in hypokalemia include broad. with an ischemic pattern of renal injury.169 Moderate hypokalemia does not appear to increase the risk of serious arrhythmia during exercise stress testing. and atrophy of type 2 fibers.185 Short-term K+ restriction in healthy humans and patients with essential hypertension also induces Na+-Cl– retention and hypertension.28 Downregulation of HERG and IKr by hypokalemia provides an elegant explanation for the association with LQTS and torsades de pointes.193 and the cardiovascular benefits of diuretic agents are blunted by hypokalemia. Na+/H+ exchanger isoform 3 (NHE3).182 Hypokalemic nephropathy can cause ESRD.180 phosphaturia.186 and increased ammoniagenesis.191 Renal Consequences Hypokalemia causes a host of structural and functional changes in the kidney. the marked reductions seen during K+ restriction in both the apical K+ channel ROMK and the apical Na+-K+-2Cl– cotransporter NKCC2187 reduce Na+-Cl– absorption and thus inhibit countercurrent multiplication and the driving force for water absorption by the collecting duct. muscle biopsy specimens in hypokalemic myopathy demonstrate phagocytosis of degenerating muscle fibers. reversible decrease in the expression of aquaporin-2 in the collecting duct. in association with an upregulation of angiotensin II.179 Polyuria in hypokalemia is due to polydipsia188 and to a vasopressin-resistant defect in urinary concentrating ability. reducing the membrane potential from –90 mV to approximately –80 mV. heart failure. and QT prolongation. IKr is largely responsible for potassium efflux during phases 2 and 3 of the cardiac action potential. since a lesser depolarizing stimulus is required to generate an action potential. as discussed earlier (see “Consequences of Hypokalemia” section).168. is massively (>700%) upregulated in K+-deficient rats.179 This renal concentrating defect is multifactorial.196 including ST-T segment depression.28 HERG encodes pore-forming subunits of the cardiac rapidly activating delayed rectifier K+ channel (IKr). IKr is highly sensitive to changes in extracellular K+. this effect may be important in thiazide-associated diabetes.194 Hypokalemia reduces insulin secretion.178 Most patients with significant myopathy have elevations in creatine kinase levels.179 In humans.26.190 In the TAL.181 and renal cysts. thus impairing the capacity to depolarize and contract. In muscle.176 On a historical note.
followed by countercurrent multiplication and ultimately excretion from the medullary interstitium. 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.217 the apical Na+-K+/NH4+-2Cl– cotransporter of the TAL. rather than a direct effect on muscle excitability.216 The NH4+ ion has the same ionic radius as K+ and can be transported in lieu of K+ by NKCC2.214 The TAL absorbs NH4+ from the tubular lumen. Relevant variables include the rapidity of the onset of hyperkalemia201. however.5 mmol/L 6. ventricular fibrillation.214 Proximal tubular ammonia generation falls. Potassium loading in humans results in modest reduction in urinary NH4+ excretion and an impaired response to acid loading. Robinson DA: Electrocardiographic manifestations of hyperkalemia. with progressive prolongation of the P wave. so that only 55% of patients with plasma K+ concentrations of more than 6. all of the Na+ channels are inactivated.5-6. The decrease in Vmax results in a reduction in myocardial conduction.196. which results in myotonia.211 paramyotonia congenita.4 play a role in setting the resting membrane potential of skeletal muscle.197 The differential diagnosis and treatment of a wide-complex tachycardia in hyperkalemia can be particularly problematic. moreover. This “hyperkalemic Brugada sign” occurs in critically ill patients with significant hyperkalemia (plasma K+ > 7 mmol/L) and can be differentiated from genetic Brugada syndrome by an absence of P waves. the normal. and QRS complex. sinus arrest.0 mmol/L Tall peaked T waves with narrow base. however.19 denoted secondary hyperkalemic paralysis to differentiate it from familial hyperkalemic periodic paralysis (HYPP).208 The mechanism is not entirely clear. and autosomal dominant mutations in the SCN4A gene encoding this channel cause most forms of the disease.8 mmol/L in one case series manifested peaked T waves. Am J Emerg Med 18:721-729. Related disorders due to mutations within the large SCN4A channel protein include HOKP type II. A further distinguishing feature is the presence of myotonia in HYPP. chronic potassium loading leads to hyperkalemia and a metabolic acidosis. MiRP2 and the associated voltage-sensitive K+ channel Kv 3.205 in particular. Cardiac arrhythmias associated with hyperkalemia include sinus bradycardia. best seen in precordial leads Peaked T waves Prolonged PR interval Decreased amplitude of P waves Widening of QRS complex Absence of P waves Intraventricular blocks.202 and the presence or absence of concomitant hypocalcemia.218 As is the case for other cations.174 Severe hyperkalemia results in loss of the P wave and a progressive widening of the QRS complex. Brady WJ. 2000. and QT interval shortening. fusion with T waves causes a “sine-wave” sinoventricular rhythm. Patients with HYPP develop myopathic weakness during hyperkalemia induced by increased K+ intake or rest after heavy exercise.198 Hyperkalemia can also cause a type 1 Brugada pattern in the electrocardiogram (ECG). QRS axis shift Progressive widening of the QRS complex “Sine-wave” pattern (sinoventricular rhythm). T waves. 20 to 30 mV).212 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+). marked QRS widening. PR interval. bundle branch blocks. fascicular blocks. with a pseudo–right bundle branch block and persistent “coved” ST segment elevation in at least two precordial leads. due to a 40% reduction in urinary NH4+ excretion.4%) of HYPP due to a mutation in equine SCN4A traced to the sire Impressive (see Figure 17-8). When muscle depolarization is more marked (i. thus reducing the rate of phase 0 of the action potential (Vmax).209 The hyperkalemic trigger in HYPP serves to differentiate this syndrome from hypokalemic periodic paralysis (HOKP). . asystole >8. nerve conduction studies in one case suggested a neurogenic mechanism.207 Hyperkalemia from a diversity of causes can cause paralysis. loss-of-function mutations in the muscle-specific K+ channel subunit MinK-related peptide 2 (MiRP2) have also been shown to cause HYPP.210 and K+-aggravated myopathy.210 Mild muscle depolarization (5 to 10 mV) in HYPP results in a persistent inward Na+ current through the mutant channel. but without a significant effect on proximal tubular secretion of NH4+.200 There is large interpatient variability in the absolute potassium level leading to ECG changes and cardiac toxicity of hyperkalemia. which renders the muscle inexcitable and causing weakness (Figure 17-8). and an abnormal QRS axis. ventricular tachycardia. and asystole. as reviewed by Evers and colleagues. This presentation of hyperkalemia can mimic Guillain-Barré syndrome and may include diaphragmatic paralysis and respiratory failure. so that use of this agent may precipitate asystole or ventricular fibrillation in this setting.213 In rats.215 Hyperkalemia appears to inhibit renal acid excretion by competition of K+ with NH4+ for reabsorption by the TAL.203.206 Hyperkalemia can also rarely present with ascending paralysis.210 American quarter horses have a high incidence (4. acidemia.209 Depolarization of skeletal muscle by hyperkalemia unmasks an inactivation defect in a tetrodotoxin-sensitive Na+ channel in patients with HYPP.204 Hemodialysis patients204 and patients with chronic renal failure.210 Finally. NH4+ exits the TAL via the basolateral Na+/H+ exchanger NHE4. HYPP is a primary myopathy. hyperkalemia potentiates the blocking effect of lidocaine on the cardiac Na+ channel. ventricular fibrillation.0 mmol/L From Mattu A. and/or hyponatremia.5-8. These changes are notoriously insensitive.208 In contrast to secondary hyperkalemic paralysis. may not demonstrate ECG changes. allelic SCN4 channels quickly recover from inactivation and can then be reactivated.e.199 The classical ECG manifestations in the progress of hyperkalemia are given in Table 17-3. slow idioventricular rhythms.174 Persistent and increasing depolarization inactivates cardiac sodium channels.Chapter 17 Disorders of Potassium Balance TABLE 17-3 Approximate Relationship between Hyperkalemic 651 Electrocardiographic (ECG) Changes and Serum Potassium Concentration ECG ABNORMALITY SERUM K+ CONCENTRATION 5.
0 to 3. due to increased cellular uptake. blood pressure.5 mmol/L) hypokalemia in approximately 40% and 10% of patients. Physiol Rev 79:1317-1372. including alcohol withdrawal. concentrated by countercurrent multiplication in the medullary interstitium.231 Insulin also may play a significant role in the hypokalemia associated with refeeding syndrome. B. Paralytic attack B FIGURE 17-8 Hyperkalemic periodic paralysis (HYPP) due to mutations in the voltage-gated Na+ channel of skeletal muscle.229.0 mmol/L).222 Hypokalemia is usually mild. . diuretic therapy. with 10% to 20% requiring potassium supplementation.230 Very rarely.236 Redistributive hypokalemia after severe head injury can be truly profound.222.191.234 and head injury. and secreted in the collecting duct. Mechanistic explanation of muscle paralysis in HYPP. perhaps the most common electrolyte abnormality encountered in clinical practice. triggered by rest after heavy exercise.5 mmol/L range. and hypomagnesemia. but in up to 25% it can be moderate to severe (<3. An affected horse is shown during a paralytic attack.229 Such patients do not develop clinical or ECG complications of hypokalemia. with reported plasma K+ concentrations of 1.226 Hypokalemia is also a common finding in patients receiving peritoneal dialysis. it is found in up to 20% of hospitalized patients. B from Lehmann-Horn F. administered insulin is a frequent cause of iatrogenic hypokalemia222 and may be a factor in the “dead in bed syndrome” associated with aggressive glycemic control.652 Section II Disorders of Body Fluid Volume and Composition Hypokalemia Epidemiology Hypokalemia is a relatively common finding in both outpatients and inpatients.228 A Explanation for paralytic attacks in Hyperkalemic Periodic Paralysis Patients [K ] intake or exercise followed by rest Small increase of extracellular [K ] Slight membrane depolarization Opening of Na channels but also switch abnormal Na channels to non-inactivating mode Persistent inward Na current Sustained depolarization of cell membrane Efflux of K Increase of [K ]e Inactivation of normal Na channels Loss of electrical excitability Spurious Hypokalemia Delayed sample analysis is a well-recognized cause of spurious hypokalemia.191.0 mmol/L) or severe (K+ ≤ 2. Redistribution and Hypokalemia Manipulation of the factors affecting internal distribution of K+ (see “Factors Affecting Internal Distribution of Potassium” section) can cause hypokalemia due to redistribution of K+ between the extracellular and intracellular compartments. A. with an incidence of up to 48% (average = 15% to 30%). with K+ levels in the 3. The capacity of the TAL to reabsorb NH4+ is increased during acidosis. this may become clinically relevant if ambient temperature is increased. 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. 1999.220 which indicates a significant role for hyperkalemia in generation of the acidosis.) countercurrent multiplication of NH4+ by the TAL greatly increases the concentration of NH4+/NH3 available for secretion in the collecting duct.235.227 Hypokalemia in itself can increase the in-hospital mortality rate up to 10-fold. due to an induction of NKCC2217 and NHE4 expression. however. and cardiovascular morbidity.221 When defined as a plasma K+ concentration of less than 3.2 mmol/L235 and 1. Jurkat-Rott K: Voltage-gated ion channels and hereditary disease. Endogenous insulin is only rarely a cause of hypokalemia.223 likely due to the profound effects on arrhythmogenesis.216 due to interference with absorption of NH4+ by the TAL.225 The thiazide-type diuretic metolazone is frequently used the management of heart failure refractory to loop diuretics alone and causes moderate (K+ ≤ 3. This disorder is particularly common in thoroughbred quarter horses.9 mmol/L.224 Hypokalemia is a particularly prominent problem in patients receiving thiazide diuretics for hypertension. patients with hyperkalemic acidosis due to hyporeninemic hypoaldosteronism demonstrate an increase in urinary NH4+ excretion in response to normalization of plasma K+ levels with cation-exchange resins.223 The most common causative factors in hospitalized patients with hypokalemia are gastrointestinal losses of potassium.26. and plasma K+ level is normal if measured immediately after venipuncture.219. respectively.6 mmol/L.26.233 acute myocardial infarction. (A courtesy of Dr.218 Hyperkalemia induces acidosis in rats by reducing the NH4+ between the vasa recta (surrogate for interstitial fluid) and collecting duct.236 and marked rebound hyperkalemia after repletion. Clinically. The NH4+ produced by the proximal tubule in response to acidosis is thus reabsorbed across the TAL. Eric Hoffman.232 Alterations in the activity of the endogenous sympathetic nervous system can cause hypokalemia in several settings.
259 The activity and regulation of skeletal muscle KATP channels is aberrant in animal models of hypokalemia.6.253 Type I HOKP muscles show reduced activity of adenosine triphosphate (ATP)–sensitive. At this potential.237 The long-acting β2-agonist clenbuterol.175. Structurally. however. Diagnostically.254 which likely contributes to hypokalemia due to the resultant unopposed activity of muscle Na+K+-ATPase. voltage-dependent Na+ channels are largely inactivated.242 Whereas β2-agonists activate K+ uptake via Na+-K+ATPase. This abnormal cation leak may directly lead to K+-dependent paradoxical depolarization and hypokalemic weakness. a TTKG of less than 2 to 3 separates patients with TPP from those with hypokalemia due to renal potassium wasting. As in HOKP. which has a significant risk of rebound hyperkalemia in patients with TPP and related disorders.Chapter 17 Disorders of Potassium Balance Due to their ability to activate both Na+-K+-ATPase46 and the Na+-K+-2Cl– cotransporter NKCC1.255 Insulin inhibits the remaining KATP activity in muscle fibers of both patients with type I HOKP253 and hypokalemic rats256. Finally.257 Renal causes of hypokalemia with paralysis include Fanconi’s syndrome.211 Although the induction of endogenous insulin by carbohydrate meals is thought to reduce plasma K+.249 In Andersen’s syndrome. despite the clinical similarities between the two syndromes. and is frequently accompanied by hypophosphatemia and hypomagnesemia. however. with attacks occurring most frequently between 1 and 6 am.260 This shared predisposition has recently been linked to genetic variation in Kir 2.253 This effect is seen at an extracellular K+ concentration of 4. However.209-211 The genetic and secondary forms of hyperkalemic paralysis were discussed earlier (see “Consequences of Hyperkalemia” section).0 mmol/L and is potentiated as K+ level decreases.243 Suicidal ingestion of barium-containing shaving powder244 and hair remover245 has also been reported. Barium salts are widely used in industry. this leads to a depolarizing shift toward the equilibrium potential for the Cl– ion (approximately 50 mV). Reversible attacks of paralysis with hypokalemia in HOKP are typically precipitated by rest after exercise and/or meals rich in carbohydrate.27 Patients typically have weakness of the extremities and limb girdles.19.248 although the mechanism is not entirely clear.25 β2-agonists are powerful activators of cellular K+ uptake.19. including a recent outbreak of toxicity due to clenbuterol-adulterated heroin in the East Coast of the United States. Autosomal dominant mutations in the CACNA1S gene encoding the α1-subunit of L-type calcium channels are the most common genetic cause of HOKP type I. who have TTKG values that are above 4. downstream activation of cAMP by xanthines such as theophylline19.26.257 and the various causes of hypokalemic distal renal tubular acidosis. given the evidence for increased activity in erythrocytes and platelets in TPP patients. hypokalemic. such as pseudoephedrine and ephedrine in cough syrup176 or weight-loss agents. cardiac arrhythmias. this is accomplished by barium.240 and dietary caffeine241 may induce hypokalemia and may be synergistic in this respect with β2-agonists.1 and 3.250 Paralysis in Andersen’s syndrome can be normokalemic. both acquired and genetic. a potent inhibitor of K+ channels. insulin can precipitate paralysis in HOKP in the absence of significant hypokalemia.239 can be an overlooked cause of hypokalemia. for example. and dysmorphic features. thus triggering weakness. inwardly rectifying K+ channels (KATP). 653 Hypokalemic Periodic Paralysis The periodic paralyses have both genetic and acquired causes. the pathophysiology of thyrotoxic periodic paralysis (TPP). has caused hypokalemia in poisonings. generated by a cation leak through an aberrant pore. since high-dose propranolol . paralytic attacks in TPP may be precipitated by rest and/or by carbohydraterich meals. or hyperkalemic.260.1 cause periodic paralysis. Clinical signs and symptoms of hyperthyroidism are not invariably present. a particularly important cause of hypokalemic paralysis. and are further subdivided into hyperkalemic and hypokalemic forms. the symptomatic trigger is consistent within individual kindreds. one would expect that inhibition of passive K+ efflux would also lead to hypokalemia.263 Thyroid hormone clearly induces expression of multiple subunits of the Na+-K+-ATPase in skeletal muscle. which suggests a muscle physiology parallel to that in genetic HOKP (see earlier). autosomal dominant mutations in the KCNJ2 gene encoding the inwardly rectifying K+ channel Kir 2. which results in paralysis.264 Increases in β-adrenergic response due to hyperthyroidism also play an important role.246 Treatment of barium poisoning with K+ serves both to increase plasma K+ and to displace barium from affected K+ channels243.211 This generates a so-called gating current. thyroid hormone– responsive K+ channel.176.258 Gitelman’s syndrome. tocolytics such as ritodrine can induce hypokalemia and arrhythmias during maternal labor. TPP is classically seen in patients of Asian origin. but also occurs at higher frequencies in Hispanic patients. ranging between 1.262 The hypokalemia in TPP is most likely due to both direct and indirect activation of Na+-K+-ATPase.19.260 All three abnormalities presumably contribute to the associated weakness.26. is distinctly different from that of HOKP.250 The pathophysiology of HOKP is not entirely clear.252 The generation of action potentials and muscle contraction are reduced in type I and II HOKP muscle fibers exposed to insulin in vitro. either unintentionally or during a suicide attempt. These agents are chiefly encountered in the treatment of asthma.247 Hypokalemia is also common with chloroquine toxicity or overdose. This rare cause of hypokalemia is usually associated with ingestion of the rodenticide barium carbonate. not approved for medical use in the United States. changes in insulin-sensitive transport events may cause the hypokalemic weakness.238 Occult sources of sympathomimetics.165 This distinction is of considerable therapeutic relevance: patients with large potassium deficits require aggressive repletion with K+-Cl–.249. more than 90% of the HOKP-associated mutations result in loss of positively charged arginine residues in the S4 voltage-sensor domains of L-type calcium channels and the skeletal Na+ channel.4 mol/L. Paralysis is associated with multiple other causes of hypokalemia.251 Alternatively.261 Hypokalemia is profound. and poisoning by various mechanisms has been described in industrial accidents. whereas type II HOKP is due to mutations in the SCN4A gene encoding the skeletal Na+ channel. thyroxine has no effect on HOKP. a muscle-specific. hemodialysis is also an effective treatment.
One potential explanation is the differential effect of loop diuretics and thiazides on calcium excretion. A mechanistic explanation is provided by the presence of the apical calcium-sensing receptor (CaSR) in the collecting duct.279 loop diuretics cause a significant calciuresis.19 Three recent reports have identified a novel association between colonic pseudo-obstruction (Ogilvie’s syndrome) and hypokalemia due to secretory diarrhea with an abnormally high K+ content. hypophosphatemia. because successful K+ replacement depends on treatment of the hypomagnesemia.225 than do loop diuretics.290 One intriguing cause of hypomagnesemia and hypokalemia is cetuximab.288 and cisplatin19.193. Polyethylene glycol– based bowel preparation regimens for colonoscopy can also lead to hypokalemia in elderly patients.295 and renin-secreting renal tumors.278 Renal Potassium Loss Drugs Diuretics are an especially important cause of hypokalemia. increasing obligatory K+ excretion by acting as nonreabsorbable anions in the distal nephron.298 are seen in patients with congenital adrenal hyperplasia due to defects in either steroid 11β-hydroxylase298 or steroid . oxacillin.280 Increases in luminal Ca2+ in the distal nephron serve to reduce the lumen-negative driving force for K+ excretion. ticarcillin. however. increased delivery of such anions also increases the electrochemical gradient for K+-Cl– exit via apical K+-Cl– cotransport or parallel K+/H+ and Cl–/HCO3– exchange65.271 Noninfectious gastrointestinal processes such as celiac disease. with magnesium wasting and hypomagnesemia seen in patients treated with cetuximab. generally attributed to increases in circulating 11-deoxycorticosterone. including active stimulation by catecholamines induced by colonic pseudoobstruction.80 (see also “Potassium Transport in the Distal Nephron” section).292 Aggressive replacement of magnesium is obligatory in the treatment of combined hypokalemia and hypomagnesemia. which can cause tubular toxicity with hypokalemia that can masquerade as Bartter’s syndrome. Regardless of the underlying mechanism.79.285 Increased distal delivery of other anions such as SO42– and HCO3– also induces kaliuresis.270 The presence of a non–anion gap metabolic acidosis with a negative urinary anion gap166 (consistent with an intact ability to increase NH4+ excretion) should strongly suggest diarrhea as a cause of hypokalemia. including ESRD.282 Analogous to the evident decrease in the apical trafficking of aquaporin-2 induced by luminal Hyperaldosteronism Increases in circulating aldosterone (hyperaldosteronism) may be primary or secondary. and paralysis seen in acute attacks. foscarnet (an antiviral drug). The usual explanation is that K+ excretion increases so as to balance the negative charge of these nonreabsorbable anions. whereas aggressive K+ replacement in TPP is associated with an incidence of approximately 25%262. Thiazides generally cause more hypokalemia19. Such a mechanism would not occur with thiazides.269 Intestinal loss of K+ due to diarrhea is a quantitatively important cause of hypokalemia.284 High doses of penicillin-related antibiotics are another important cause of hypokalemia.291 Paracrine EGF stimulates magnesium transport via the apical TRPM6 cation channel in the DCT. immunohistochemical analysis revealed massive upregulation of the apical BK channel throughout the surface-crypt axes.266 Of particular importance. the increase in distal delivery of Ca2+ induced by loop diuretics may serve to blunt kaliuresis. due to their ability to increase distal flow rate and distal delivery of Na+. Drugs are also an important cause of Fanconi’s syndrome. repletionassociated rebound hyperkalemia in TPP can be fatal. Hypertension and hypokalemia. and carbenecillin. Whereas thiazides and loss-of-function mutations in the Na+Cl– cotransporter decrease Ca2+ excretion. despite their lower natriuretic efficacy. Another drug associated with hypokalemia due to kaliuresis is acetaminophen. and may be associated with acute complications such as myopathy and flaccid paralysis. In addition to penicillin. These include gentamicin. in which the concurrent hypokalemia may be profound.276 BK channels appear to medicate adrenalineinduced colonic K+ secretion.294 a paraneoplastic process. a humanized monoclonal antibody specific for the receptor for epidermal growth factor (EGF).296 The incidence of hypokalemia in renal artery stenosis is thought to be less than 20%. Several tubular toxins result in both K+ and magnesium wasting. which at toxic levels causes dose-dependent hypokalemia.283.268.265. the ensuing hypochloremic alkalosis results in persistent kaliuresis due to secondary hyperaldosteronism and bicarbonaturia.267 Ca2+.274 Colonic BK channels may play a significant role in intestinal K+ secretion in a variety of pathologic conditions.287 Other drugs that can cause mixed magnesium and K+ wasting include amphotericin.293 Page kidney (renal compression by a subcapsular mass or hematoma with hyperreninemia). dicloxacillin. implicated antibiotics include nafcillin. which reduce distal delivery of Ca2+.274-276 In one patient with concomitant ESRD.297 Primary hyperaldosteronism (PA) may be genetic or acquired.277 Several hypotheses have been put forward to explain the association between Ogilvie’s syndrome and enhanced intestinal K+ secretion. 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. Nonrenal Potassium Loss The loss of K+ from skin is typically low.9 Direct gastric loss of K+ due to vomiting or nasogastric suctioning is also typically minimal. given the worldwide prevalence of diarrheal disease. However. with unopposed activity of ENaC and increased kaliuresis.281 perhaps by direct inhibition of ENaC in principal cells. and can be associated with hypokalemia. with the exception of extremes in physical exertion.286 which is often associated with significant hypokalemia (see “Renal Tubular Acidosis” section). Causes include renal artery stenosis. Increased levels of circulating renin in secondary forms of hyperaldosteronism lead to increased levels of angiotensin II and thus aldosterone.293 An unusual presentation of renal artery stenosis and renal ischemia is hyponatremic hypertensive syndrome.289 and ifosfamide (both chemotherapeutic agents).273 and chronic laxative abuse can present with acute hypokalemic syndromes or with chronic complications such as ESRD. no rebound hyperkalemia is associated with this treatment.272 ileostomy.654 Section II Disorders of Body Fluid Volume and Composition (3 mg/kg) rapidly reverses the hypokalemia.
35% of cases).305. also known as glucocorticoidremediable hyperaldosteronism or GRA)300 and familial hyperaldosteronism type II (FH-II). The diagnosis can be biochemically confirmed by a dexamethasone suppression test. Contemporary reports and recommendations have thus emphasized the continued importance of adrenal vein sampling in subtype differentiation.314 Third. it is clear that hypokalemia is not a universal feature of PA. primary or unilateral adrenal hyperplasia (PAH. Regardless.309 This may reflect the ectopic expression of the chimeric aldosterone synthase in the adrenal fasciculata. with incidence rates in patients with hypertension ranging from 0% to 72%312. since increased kaliuresis in hyperaldosteronism can be induced by dietary Na+-Cl– loading or diuretic use. adequate differentiation of APA from IHA is critical.310 The true incidence of hypokalemia in patients with acquired forms of PA remains difficult to evaluate. a gene has been localized to chromosome region 7p22 by linkage analysis. The 24-hour sodium excretion should exceed 200 mmol/day for adequate suppression. an enzyme that is normally expressed in the zona glomerulosa. however.315 the major reabsorptive pathway for K+ in the distal nephron (see also Chapter 5). in which aldosterone production is not repressible by exogenous glucocorticoids. patients have only been screened for hyperaldosteronism when hypokalemia is present. oral salt loading over 3 days is followed by measurement of 24-hour urine aldosterone. This chimeric gene is thus under the control of ACTH and is expressed in a glucocorticoid-repressible fashion. Patients with FH-II are clinically indistinguishable from those with sporadic forms of PA due to bilateral adrenal hyperplasia. 2% of cases).310 Because surgery can be curative in APA.300 Aldosterone levels are modestly elevated and regulated solely by ACTH. sodium. with the disease typically manifesting at an early age.310 After hypertension and hypokalemia are controlled. In patients without PA. The measured PAC in patients with PA usually does not suppress to less than 277 pmol/L.313 Finally. generated by transformation of steroids typically formed in the zona fasciculata by aldosterone synthase. other recent series have concentrated on hypertensive patients. despite a .307 Although the first patients reported with FH-I were hypokalemic.305 FH-I has been shown to be caused by a chimeric gene duplication between the homologous 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. the PAC/PRA ratio is a screening tool.313 Regardless.301 A kindred with a third form of familial hyperaldosteronism (FH-III) has also been recently described.316.317 In bona fide Cushing’s syndrome caused by increases in pituitary ACTH the incidence of hypokalemia is only 10%. and some affected individuals are normotensive.307. due to a variety of factors.307.312. which is also a selection bias.307 Laparoscopic adrenalectomy is increasingly the preferred surgical management in APA or PAH. the majority are in fact normokalemic. genetic testing for FH-I should be pursued in patients with PA and a family history of PA and/or of strokes at a young age. and adrenal carcinoma (<1% of cases). the severity of hypertension is variable. historically.304 Ectopic expression of the hybrid CYP11B1-CYP11B2 gene in the zona fasciculata has been reported in a single case in which adrenal tissue became available for molecular analysis. First. however. A related issue is whether PA is underdiagnosed when hypokalemia is used as a criterion for further investigation. and in young patients with PA (<20 years of age). likely due to higher average levels of aldosterone. in which the ACTH-responsive 11β-hydroxylase promoter is fused to the coding region of aldosterone synthase.302 Patients with FH-I/GRA are generally hypertensive. Indeterminate values between 139 and 277 pmol/L can been seen in patients with IHA. The utility of the PAC/ PRA ratio in screening for hyperaldosteronism is an active issue in hypertension research.2% in a large. the incidence of hypokalemia is higher in adrenal adenomas than in IHA.304. and a suppression of aldosterone level to less than 4 ng/ dL is consistent with the diagnosis.299 The two major forms of isolated PA are denoted familial hyperaldosteronism type I (FH-I.316 whereas it is 57%317 to 100%316 in patients with ectopic ACTH expression. but fail to increase plasma aldosterone level in response to hyperkalemia. which likely lack the appropriate constellation of ion channels to respond to increases in extracellular K+ with an increase in aldosterone secretion. this requires both adrenal imaging and adrenal venous sampling (Figure 17-9).307. because aldosterone does not appear to affect the hypokalemic response of H+-K+-ATPase. with hyporeninemia. but has yet to be characterized.310 A rare case involving paraneoplastic overexpression of aldosterone synthase in lymphoma has also been described.299 Deficient 11β-hydroxylase results in virilization and other signs of androgen excess.Chapter 17 Disorders of Potassium Balance 17α-hydroxylase.310 Mineralocorticoid receptor antagonists are indicated for medical treatment of PA. and a urinary aldosterone level of more than 33 nmol/day is consistent with PA. and PAC is then measured. Second.308 albeit perhaps with a propensity to develop hypokalemia while taking thiazide diuretics. idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia (60% of cases).305 Patients with FH-I are able to appropriately increase K+ excretion in response to K+ loading or fludrocortisone administration. This is perhaps not unexpected. and results must be confirmed by aldosterone suppression testing in which PAC or aldosterone secretion is measured after loading with salt or intravenous saline.311 655 Increasing use of the plasma aldosterone concentration (PAC)/plasma renin activity (PRA) ratio in hypertension clinics has led to reports of a much higher incidence of PA than previously appreciated.306 Direct genetic testing for the hybrid CYP11B1-CYP11B2 has largely supplanted biochemical screening for FH-I. even recent case series from clinics with such a referral pattern may suffer from a selection bias. dietary factors and/or medications may play a role in the incidence of hypokalemia at presentation. and creatinine excretion. Alternatively.298 whereas reduced sex steroids in 17α-hydroxylase deficiency result in hypogonadism. hyperaldosteronism resistant to dexamethasone. hence. the measured PAC after saline infusion should decrease to less than 139 pmol/L. hypokalemia may also occur with systemic increases in glucocorticoids. in the saline infusion test.303 Patients also have high levels of abnormal “hybrid” 18-hydroxylated steroids. Acquired causes of PA include aldosterone-producing adenomas (APAs. with carefully monitored use of glucocorticoid to suppress ACTH in some patients with FH-I/GRA. the prevalence was 3. recumbent patients are infused with 2 L of isotonic saline over 4 hours. multicenter study of patients with mild to moderate hypertension without hypokalemia. and very high levels of 18-oxocortisol and 18-hydroxycortisol.
The resulting increase in the half-life of cortisol is associated with a marked decrease in synthesis. most commonly bronchial carcinoid tumors. Ann Intern Med 138:157-159. and idiopathic hyperaldosteronism (IHA).327 Mice with a homozygous targeted deletion of the 11βHSD2 gene exhibit hypertension. Whether this reflects a greater degree of saturation of the enzyme by circulating cortisol or direct inhibition of 11β-HSD2 by ACTH is not entirely clear. generation of cortisone by 11β-HSD2 serves to protect mineralocorticoid-responsive cells from illicit activation by cortisol.324 In patients with AME. the unregulated mineralocorticoid effect of glucocorticoids results in hypertension. or familial hyperaldosteronism type I [FH-I]. recessive loss-of-function mutations in the 11β-HSD2 gene cause a defect in the peripheral conversion of cortisol to the inactive glucocorticoid cortisone. In the kidney.4 mmol/mL in 11β-HSD2–null .) Unilateral hypodense nodule > 1 cm Low probability of APA High probability of APA Age > 40 y. Biochemical studies of mutant enzymes usually indicate a complete loss of function. the polyuria is likely secondary to the hypokalemia (see “Renal Consequences” section under “Consequences of Hypokalemia”). In the classical form of AME. hypokalemia.321 Syndromes of Apparent Mineralocorticoid Excess The syndromes of apparent mineralocorticoid excess (AME) have a self-explanatory label. indirect indices of 11β-HSD2 activity in patients with ectopic ACTH expression correlate with hypokalemia and other measures of mineralocorticoid activity.656 Section II Disorders of Body Fluid Volume and Composition Biochemically confirmed primary aldosteronism Adrenal CT Normal results Micronodularity Bilateral masses FIGURE 17-9 Diagnostic algorithm for patients with primary hyperaldosteronism. accompanied by very high ACTH levels.318 Indirect evidence suggests that the activity of renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is lower in patients with ectopic ACTH expression than in those with Cushing’s syndrome. Lesser enzymatic defects in patients with AME are associated with altered ratios of urinary cortisone/cortisol metabolites.322 The 11β-HSD2 protein is expressed in epithelial cells that are targets for aldosterone. and there is evidence for both mechanisms317. This requires computed axial tomography (CT). in which loss-of-function mutations in the glucocorticoid receptor result in marked hypercortisolism without cushingoid features. with suppressed PRA and aldosterone. however. primary or unilateral adrenal hyperplasia (PAH). and metabolic alkalosis. and polyuria. (From Young WF Jr: Adrenalectomy for primary aldosteronism. hypokalemia. and other neuroendocrine tumors. adrenal venous sampling (AVS). Ectopic ACTH expression is associated primarily with neuroendocrine malignancies. small cell lung cancer. CNT.326 and/or older age at presentation. Hyperaldosteronism caused by adrenal adenoma (APA) must be distinguished from glucocorticoidremediable hyperaldosteronism (GRA.320 Similar mechanisms likely underlie the severe hypokalemia reported in patients with familial glucocorticoid resistance.319 which results in a syndrome of apparent mineralocorticoid excess (see next section). and CCD.323 Since the mineralocorticoid receptor has equivalent affinity for aldosterone and cortisol. 2003. consider Age < 40 y AVS Consider screening for GRA No lateralization with AVS Lateralization with AVS IHA: Pharmacologic therapy GRA: Pharmacologic therapy APA or PAH: Unilateral laparoscopic adrenalectomy similar incidence of hypertension. these include cells of the DCT. which reaches 2. so that plasma levels of cortisol are normal and patients do not have cushingoid features.325 lesser impairment in the peripheral conversion of cortisol to cortisone.322 Biochemical diagnosis entails measuring the urinary free cortisol/urinary free cortisone ratio in a 24-hour urine collection. and the relevant diagnostic biochemical and hormonal assays (see text).
in its multiple guises (licorice root. Liddle’s-associated mutations increase proteolytic cleavage of ENaC at the cell membrane. The most infamous offender is licorice. on channel activity) and on expression at the cell membrane.337 Pharmacologic inhibition of 11β-HSD2 has also been tested in patients with ESRD as a novel mechanism to control hyperkalemia (see “Treatment of Hyperkalemia” section).347 Familial Hypokalemic Alkalosis Bartter’s and Gitelman’s syndromes are the two major variants of familial hypokalemic alkalosis. Both hypertension and hypokalemia are variable aspects of the Liddle’s phenotype. prescribed for disorders such as allergic rhinitis. suppression of PRA and aldosterone.338 Carbenoxolone in turn is used in some countries in the management of peptic ulcer disease.339 The mineralocorticoid receptor is thus constitutively “on” in these patients. Indeed. 657 Liddle’s Syndrome Liddle’s syndrome is associated with an autosomal dominant gain-in-function mutation in ENaC.334 Pontefract cakes. 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. the patient with this mutation has a typical Liddle’s syndrome phenotype.345 Extensive searches for more common mutations and polymorphisms in ENaC subunits that correlate with blood pressure in the general population have essentially been negative. it stands to reason that mutations in ENaC that give rise to Liddle’s syndrome might do so by a variety of means. AME patients are sensitive to both drugs. The early observations that licorice required small amounts of cortisol to exert its kaliuretic effect. The induction of ENaC activity by unregulated glucocorticoid likely causes the Na+ retention and the marked increase in K+ excretion in 11β-HSD2–null mice.322 Licorice intake remains considerable in European countries.96.. are a continued source of licorice in the United Kingdom. in the addisonian absence of endogenous glucocorticoid.95. unresponsive to spironolactone yet sensitive to triamterene and amiloride. a mechanistically distinct form of AME has been reported caused by a gain-of-function mutation in the mineralocorticoid receptor. particularly Iceland.335 Glycyrrhizinic acid is used in Japan to treat hepatitis and has been under evaluation elsewhere for the management of hepatitis C. given the phenotype of pseudohypoaldosteronism type 2 and Gitelman’s syndrome (see “Hereditary Tubular Defects of Potassium Excretion” and “Gitelman’s Syndrome” sections). The relative effect of genotype on the morphology of cells in the DCT. the cellular “gain of-function” in the DCT would be expected to be associated with hypercalciuria.339 A single kindred was described with autosomal dominant inheritance of severe hypertension and hypokalemia.322 Pharmacologic inhibition of 11β-HSD2 is also associated with hypokalemia and AME.3 Aldosterone-induced channel-activating proteases activate ENaC channels at the plasma membrane.96 Given the overlapping and synergistic mechanisms that regulate ENaC activity. due to marked increases in plasma progesterone induced by the gravid state.333 presaged the observations that its active ingredients (glycyrrhetinic/glycyrrhizinic acid and carbenoxolone) inhibit 11β-HSD2 and related enzymes. that is. and so on). AME has been reported with its use for this indication. However. mutation of a residue within the extracellular domain of ENaC increases the open probability of the channel without changing surface expression. indeed. The overwhelming majority of mutations target the C terminus of either the β or γ ENaC subunit. The Netherlands. and/or increased ratios of urinary K+ level to aldosterone or to PRA.322 Finally. The causative mutation involves a serine residue that is conserved in the mineralocorticoid receptor from multiple species. These knockout mice have significant nephromegaly.342 Unlike wild-type ENaC channels. they are not sensitive to inhibition by intracellular Na+. candies.341 The differential diagnosis for Liddle’s syndrome. ENaC channels containing Liddle’s syndrome mutations are constitutively overexpressed at the cell membrane. with a marked stimulation by progesterone. with a decreased urinary Na+/K+ ratio that is increased by dexamethasone (given to suppress endogenous cortisol). Liddle’s syndrome could therefore also be classified as a syndrome of AME. This mutation results in constitutive activation of the mineralocorticoid receptor in the absence of ligand and induces significant affinity for progesterone. Consistent features include a blunted aldosterone response to ACTH and reduced urinary aldosterone excretion.336 Glycyrrhizinic acid is also a component of Chinese herbal remedies. Commercial genetic testing for both syndromes is available in the United States. includes AME due to deficient 11β-HSD2.346. however. Results of distal tubular micropuncture studies in rats treated with a systemic inhibitor of 11β-HSD2 are consistent with such a mechanism. whereas patients with a Liddle’s syndrome phenotype are resistant to blockade of the mineralocorticoid receptor with spironolactone and sensitive to amiloride. and CCD was not determined by the appropriate phenotypic studies329. tea.344 The mechanism whereby mutations in the C terminus of ENaC subunits lead to this channel phenotype were discussed earlier in this chapter (see Figure 17-5 and “Aldosterone” section). In addition to effects on interaction with Nedd4-2–dependent retrieval from the plasma membrane.328 As expected. both PRA and plasma aldosterone in the 11β-HSD2–null mice are profoundly suppressed.e. This important result provides a mechanistic explanation for the long-standing observation that Liddle’s-associated mutations in ENaC appear to have a dual activating effect: on both the open probability of the channel (i.334 and licorice is an ingredient in several popular sweeteners and preservatives in Malaysia. yet differs in other nuclear steroid receptors. due to a massive hypertrophy and hyperplasia of DCTs. Gitelman’s syndrome is a much more common cause of hypokalemia than is Bartter’s .343 an important regulator of endogenous channel activity in the CCD. eaten both as sweets and as a laxative.Chapter 17 Disorders of Potassium Balance mice. Of interest. CNT. patients with AME are reported to exhibit nephrocalcinosis. the amiloridesensitive Na+ channel of the CNT and CCD.339 Spironolactone can paradoxically activate this mutant receptor. however. it is known that both the DCT and the CCD are target cells for aldosterone330. herbal remedies. as a cause of hereditary hypertension with hypokalemia and suppressed aldosterone levels. and Scandinavia.340 Patients manifest severe hypertension with hypokalemia. pregnancies in the affected female members of the family have all been complicated by severe hypertension.332 In addition.331 and both cell types express 11β-HSD2.
polyhydramnios. They may have an increase in urinary calcium (Ca2+) excretion.358 Finally.354 The apical Na+-K+2Cl– cotransporter (NKCC2/SLC12A1) of the mammalian TAL24 (Figure 17-10) was thus an early candidate gene. a subset of patients with associated sensorineural deafness exhibit linkage to chromosome band 1p31. the set point of the CaSR Bartter’s Syndrome Patients with classical Bartter’s syndrome typically have polyuria and polydipsia. and significant hypercalciuria with nephrocalcinosis. denoted ClC-NKa.361 The occurrence of deafness in these patients suggests that barttin functions in the regulation or function of Cl– channels in the inner ear. these patients are considered to have Bartter’s syndrome type 1. due in part to phenotypic overlap. however. or the ClC-NKb and barttin subunits of the Cl– channel (causing Bartter’s syndrome types 1 to 4. Notably. but does not correct the basic tubular defect. CI Barttin CaSR Ca2 ATP 2K Ca2 FIGURE 17-10 Bartter’s syndrome and the thick ascending limb.658 Section II Disorders of Body Fluid Volume and Composition syndrome.349 Other features include marked elevation of plasma angiotensin II. K+ recycling via the Na+-K+-2Cl– cotransporter and apical K+ channels generates a lumen-positive potential difference in the TAL.350 Of interest. The CaSR has an inhibitory effect on salt transport by the thick ascending limb. Bartter’s syndrome can result from loss-of-function mutations in the Na+-K+2Cl– cotransporter NKCC2. denoted BARTTIN.365 where it is thought to play an important inhibitory role in regulating the transcellular transport of both Na+-Cl– and Ca2+. and plasma renin levels. COX-2 immunoreactivity is increased in the TAL and macula densa of patients with Bartter’s syndrome.363. disease-associated mutations were found in the human NKCC2 gene in four kindreds with antenatal Bartter’s syndrome. In 1996. Na K Na K 2CI CI NKCC2 K 3Na K K Lumen ( ) ( ) 30 pS ROMK 70 pS Inhibitory CIC-NKb. most of whom exhibit the antenatal phenotype. Digenic inactivation was described in two siblings with deafness and Bartter’s syndrome. targeting several transport pathways. a genetic classification is increasingly in use.359 For example. In a significant fraction of patients with Bartter’s syndrome the NKCC2. Ca2+. . The loss of K+ channel activity in Bartter’s syndrome type 2 leads to reduced apical K+ recycling and reduced Na+-K+-2Cl– cotransport. Bartter’s syndrome is a genetically heterogeneous disease and shows allelic heterogeneity. Multiple disease-associated mutations in ROMK have been reported in patients with Bartter’s syndrome type 2.75.26 The gene for this syndrome.355 In the genetic classification of Bartter’s syndrome.350. plasma aldosterone. respectively). and manifest a hypokalemic. For example. which drives paracellular Na+. ROMK encodes the low-conductance 30-picosiemens K+ channel in the apical membrane and also appears to function as a critical subunit of the higher-conductance 70-picosiemens channel. the CLCNKB gene is immediately adjacent to that for another epithelial Cl– channel. and 20% are hypomagnesemic. Although the functional consequences of disease-associated NKCC2 mutations have not been comprehensively studied.356 this K+ channel was another early candidate gene. Prostaglandin synthesis and excretion are significantly increased and may account for many of the systemic symptoms. It does. with a relative absence of nephrocalcinosis. Decreasing prostaglandin synthesis by cyclooxygenase inhibition can improve polyuria in patients with Bartter’s syndrome by reducing the amplifying inhibition of urinary concentrating mechanisms by prostaglandins. appear to help increase the growth of Bartter’s syndrome patients. mutations in Bartter’s syndrome type 3 have been reported in the chloride channel ClC-NKb. ROMK. Decrease in apical K+ channels also leads to a decrease in the lumen-positive potential difference.352 Early studies of Bartter’s syndrome suggested that these patients had a defect in the function of the TAL. In addition. hypochloremic alkalosis.364 The CaSR is heavily expressed at the basolateral membrane of the TAL. encoded at least in part by ROMK.362 which suggests that ClC-NKa plays an important role in barttindependent Cl– transport in the inner ear. and Mg2+ transport.351 and reports indicate a clinical benefit of COX-2 inhibitors. Gain-offunction mutations in the calcium-sensing receptor CaSR can also cause a Bartter’s syndrome phenotype (type 5).348 Although a clinical subdivision of these syndromes has been used in the past. which drives the paracellular transport of Na+ and other cations357 (see Figure 17-10). Given the role of apical K+ permeability in the TAL. Genetic activation of the CaSR by these mutations was also expected to increase urinary Ca2+ excretion by inhibiting generation of the lumenpositive potential difference that drives paracellular Ca2+ transport in the TAL.353 Many of the clinical features are mimicked by the administration of loop diuretics. activation of the basolateral CaSR in the TAL is known to reduce apical K+ channel activity.366 which would induce a Bartter’slike syndrome (see Figure 17-10). and CLCNKB genes are not involved. Indomethacin also increases plasma K+ concentration and decreases plasma renin activity. encodes a protein that is an obligatory subunit for the ClC-NKb chloride channel.360 Patients with mutations in CLCNKB typically have the classical Bartter’s phenotype. Patients with autosomal dominant activating mutations in the CaSR have been described with hypocalcemia and hypokalemic alkalosis.359 which is expressed at the basolateral membrane of at least the TAL and DCT. Patients with antenatal Bartter’s syndrome present earlier in life with a severe systemic disorder characterized by marked electrolyte wasting. to which at least a subset of patients with antenatal Bartter’s syndrome do not respond. the first355 and subsequent reports26 included patients with frameshift mutations and premature stop codons that predict the absence of a functional NKCC2 protein. the ROMK (renal outer medullary potassium) subunit of the K+ channel.
For example.0 mmol/L) transient neonatal hyperkalemia have also been described. however.26.368 Bartter’s syndrome type 2 is particularly relevant to K+ homeostasis. these patients were found to be compound heterozygotes for a mutant form of NKCC2 that exhibits partial function.384 This cellular deficit leads to downregulation of the DCT magnesium channel TRPM6. rather than the hypercalciuria typically seen in Bartter’s syndrome. or even with a phenotype similar to that of Gitelman’s syndrome. however. renal prostaglandin excretion is not elevated in these hypocalciuric patients.373 The identity of the other putative subunit of this 70-picosiemens channel is not yet known.26 Two brothers were described with a late onset of mild Bartter’s syndrome. given the significant number of exons in SLC12A2 and the absence of “hot-spot” mutations in this disorder. given that ROMK is the SK secretory channel of the CNT and CCD (see “Potassium Transport in the Distal Nephron” section).26.380 Many of these mutations lead to a defect in cellular trafficking when introduced into the human NCC protein. and bulimia (see “Clinical Approach to Hypokalemia” section).377 The QT interval is frequently prolonged in Gitelman’s syndrome. The downstream CNT tubules are hypertrophied in NCCdeficient mice.374 Fixed loss of Na+-Cl– in sweat is likely the dominant predisposing factor for hypokalemic alkalosis in patients with cystic fibrosis. The mammalian TAL has two major apical K+ channels with different conductances. Patients with Bartter’s syndrome type 2 typically have slightly higher plasma K+ concentrations than those with the other genetic forms of Bartter’s syndrome. so that in patients with CFTR deficiency K+ excretion would not be appropriately 659 reduced during water diuresis. given the observation that thiazide treatment promotes marked apoptosis of this nephron segment. patients do report significant morbidity. genetic analysis is not generally available. and loss-of-function mutations in the human gene have been reported. developmental deficit in the other K+ channels involved in distal K+ secretion.26 and cystic fibrosis. including the apical maxi-K/BK channel responsible for flow-dependent K+ secretion in the distal nephron.Chapter 17 Disorders of Potassium Balance response to Ca2+ in the parathyroid is shifted to the left.173 one with concomitant LQTS due to a mutation in the cardiac KCNQ1 K+ channel.367 With respect to Bartter’s syndrome due to mutations in NKCC2.381 Gitelman’s syndrome is genetically homogeneous.358. patients with Gitelman’s syndrome have a blunted excretion of chloride after the administration of hydrochlorothiazide. there is significant phenotypic overlap and phenotypic variability in hereditary hypokalemic alkalosis.372 Both are thought to play a role in transepithelial salt transport by the TAL. Despite the reasonable correlation between the disease gene involved and the associated subtype of familial alkalosis.385 which results in the magnesium wasting and hypomagnesemia seen in Gitelman’s syndrome. Finally. patients with mutations in CLCNKB most frequently exhibit classical Bartter’s syndrome.367 Patients with severe (9.287 Sjögren’s syndrome.369 It is likely that this reflects a transient. with a mild alkalosis and marked increase in circulating aldosterone. mostly related to muscular symptoms and fatigue.379 Nevertheless. but can present with a more severe antenatal phenotype.375 Gitelman’s Syndrome A major advance in the understanding of hereditary alkaloses was the realization that a subset of patients exhibit marked hypocalciuria. given the absence of this conductance in TAL segments of ROMK knockout mice. Bartter’s syndrome must be clinically differentiated from “pseudo–Bartter’s syndrome. ROMK is evidently a subunit of the 70-picosiemens channel. the 30-picosiemens channel corresponding to ROMK. One diagnostic alternative is to assess the physiologic response to thiazides. furosemide abuse. A mouse strain with targeted deletion of the Slc12a2 gene encoding NCC exhibits hypocalciuria and hypomagnesemia. presyncope and/or ventricular tachycardia has been observed in at least two patients with Gitelman’s syndrome.173 The hypocalciuria detected in Gitelman’s syndrome is an expected consequence of inactivation of the thiazide-sensitive Na+-Cl– cotransporter NCC (SLC12A2).370 Distal K+ secretion in ROMK knockout mice is primarily mediated by maxi-K/BK channel activity.26. However.26. That Gitelman’s syndrome is a disorder of cellular development and/or cellular apoptosis should perhaps not be a surprise. One would assume that deficiencies in the associated gene would also be a cause of Bartter’s syndrome. the cystic fibrosis transmembrane regulator (CFTR) protein coassociates with ROMK in the TAL and confers sensitivity to both ATP and glibenclamide to apical K+ channels in this nephron segment. Other reported causes include gentamicin nephrotoxicity.371 so that developmental deficits in this channel would indeed lead to hyperkalemia in Bartter’s syndrome type 2. which inhibits parathyroid hormone (PTH) secretion by this gland.26 These CNT cells also exhibit an increased expression of ENaC at their apical membranes compared with littermate controls.367 However. Gitelman’s syndrome is a milder disorder than Bartter’s syndrome.173. Patients with this presentation generally respond promptly to administration of intravenous fluids and electrolyte replacement. and a 70-picosiemens channel.” The common causes of the latter include laxative abuse. a number of patients have been described with variant presentations. including an absence of hypokalemia. a more exhaustive cardiac evaluation of a large group of patients failed to detect significant abnormalities of cardiac structure or rhythm.375 Lu and colleagues have proposed that this interaction serves to modulate the response of ROMK to cAMP and vasopressin. with a loss-of-function mutation on the other NKCC2 allele. which suggests an increased risk of cardiac arrhythmia378. No doubt the positional cloning of other Bartter’s syndrome genes will have a considerable impact on mechanistic understanding of the TAL.383 with both a reduction in absolute number of DCT cells and changes in ultrastructural appearance.383 These knockout mice exhibit marked morphologic defects in the early DCT.376 another feature distinguishing Bartter’s and Gitelman’s syndromes. Although plasma renin activity may be increased.74. Patients in this hypocalciuric subset are universally hypomagnesemic.383 reminiscent of the hypertrophic DCT and CNT segments seen in furosemide-treated animals.382 The NCC protein has been localized to the apical membrane of epithelial cells in the DCT and CNT.279 Such patients are now clinically classified as having Gitelman’s syndrome. which would predispose such patients to the development of hypokalemic alkalosis.383 This is likely due to activation of SGK1-dependent trafficking . except for the occasional patient with mutations in CLCNKB and an overlapping phenotype.
or TRPV5) and the basolateral Na+/Ca2+ exchanger. due primarily to baseline hyperaldosteronism393. The distal delivery of both Na+ and fluid is decreased in NCC–/– mice. the so-called type 1 RTA. The late DCT is morphologically intact in NCCdeficient mice. hypercalciuria. Of particular interest. with reduced H+-ATPase activity and decreased ability to acidify the urine.387 Hypocalciuria in Gitelman’s syndrome is not accompanied by changes in plasma calcium. but emerges on a K+-restricted diet.388 which suggests a direct effect on renal calcium transport. in addition to aggressive K+-Cl– supplementation. Even though outward conductance is usually less than inward conductance. hypokalemia. aminoglycoside nephrotoxicity) may cause both kaliuresis and magnesium wasting. Regardless. at least with consumption of a normal diet.400 Several mechanisms appear to contribute to the effect of magnesium depletion on plasma K+ concentration. Rather.397 Sjögren’s syndrome is perhaps the most common cause of hypokalemic distal RTA in adults. hypouricemia.383 Furthermore.402 The hypomagnesemia-associated reduction in cytoplasmic Mg2+ in principal cells reduces inward Renal Tubular Acidosis Renal tubular acidosis (RTA) and related tubular defects can be associated with hypokalemia. the hypocalciuric effect of thiazides persists in mice deficient in TRPV5.395 The pathophysiology of the associated hypokalemia is multifactorial. K+ efflux predominates in the CNT and CCD because the membrane potential is more positive than the equilibrium potential for K+. Thus homozygous patients have much higher bone densities than unaffected family members with wild-type genes.5 mmol/L222.392 The cardinal features of Fanconi’s syndrome are hyperaminoaciduria. salt wasting. particularly if the plasma Mg2+ is less than 0. in hypomagnesemic patients hypokalemia is thus resistant to K+ replacement in the absence of Mg2+ repletion. Proximal RTA is characterized by a reduction in proximal bicarbonate absorption. ifosfamide.386 Several mechanisms account for the hypokalemia seen in Gitelman’s syndrome and NCC–/– mice. Distal K+ secretion also appears to be enhanced due to a reduction in the normal physiologic inward rectification of ROMK secretory K+ channels.392 with a documented absence of coding sequence mutations in NCC. More commonly. as in Bartter’s syndrome.390 Finally.397 Magnesium Deficiency Magnesium deficiency results in refractory hypokalemia. there are reports of patients with acquired tubular defects that mimic Gitelman’s syndrome. binding and blocking the pore of the channel from the cytoplasmic side. causing a marked increase in renal potassium wasting. the abnormal deposition of calcium pyrophosphate dihydrate in joint cartilage.401 which results in significant efflux from muscle and a secondary kaliuresis.383. and Gitelman’s syndrome.385 with secondary increases in proximal Ca2+ absorption. and hypocalciuria after chemotherapy with cisplatin. treatment with oral sodium bicarbonate markedly increases distal tubular Na+ and HCO3– delivery. encompassing Fanconi’s syndrome. patients with proximal RTA typically demonstrate mild hypokalemia. For example. whereas heterozygotes have intermediate values of both bone density and calcium excretion.393 Patients often require mixed base replacement with oral citrate and bicarbonate.398. vitamin D.26. with preserved expression of epithelial calcium channel 1 (ECaC1. with a reduced plasma bicarbonate concentration. which leads to increased kaliuresis. K+ flows inward more readily than outward. or PTH levels. Magnesium depletion has inhibitory effects on muscle Na+-K+ATPase activity. The plasma K+ concentration of these mice is approximately 1 mmol/L lower than that of K+-restricted littermate controls.385 which argues against the putative effects of this drug on distal Ca2+ absorption.660 Section II Disorders of Body Fluid Volume and Composition of ENaC by the increase in circulating aldosterone (see “Aldosterone” section).. and the acyclic nucleoside phosphonates (tenofovir.281 further exacerbating the kaliuresis. Hypokalemia is also associated with distal RTA. These include patients with hypokalemic alkalosis. and increased excretion of low molecular weight proteins. Isolated proximal RTA is quite rare. there are clear differences in bone density between affected and unaffected members of specific Gitelman kindreds. Fanconi’s syndrome is most commonly drug associated. genetic causes include loss of function due to mutations in the basolateral Na+-HCO3– transporter. and increases in aldosterone. that is. patients have been described with profound hypokalemia on presentation.286 Prior to treatment with bicarbonate. Plasma Mg2+ levels thus must be checked routinely in patients with hypokalemia.396.402 ROMK and other Kir channels are inwardly rectifying.391 Patients have also been described with acquired Gitelman’s syndrome due to Sjögren’s syndrome and tubulointerstitial nephritis. before treatment. Hypokalemic distal RTA is most commonly due to a secretory defect. reminiscent of the clinical effect of thiazides on bone.386 This is reminiscent perhaps of the polydipsia that has been implicated in thiazide-associated hyponatremia. in addition to acidosis and hypercalciuria.394 Regardless.g.221. due to the loss of electrogenic H+ secretion (with enhanced K+ secretion to maintain electroneutrality in the distal nephron). phosphate. cidofovir. and phosphate wasting.399 Magnesium deficiency is also a common concomitant of hypokalemia. Important contemporary causes include aristolochic acid.286 . Intracellular Mg2+ plays a key role in inward rectification. hereditary defects in subunits of H+-ATPase are associated with profound hypokalemia. and adefovir). glycosuria with a normal plasma glucose concentration. proximal RTA occurs in the context of multiple proximal tubular transport defects. NCCdeficient mice develop considerable polydipsia and polyuria on a K+-restricted diet. however. with a subsequent increase in outward conductance. however. decreased luminal Ca2+ in NCC deficiency may augment baseline ENaC activity. loss of H+-K+-ATPase activity.389 Patients have also been reported with ocular choroidal calcification. Associated defects include proximal RTA. in part because associated tubular disorders (e. hypomagnesemia.388 An interesting association has repeatedly been described between chondrocalcinosis. As discussed earlier with regard to thiazides. Hypokalemia does not occur in NCC–/– mice on a standard rodent diet. The associated hypokalemia can be truly profound. the increased circulating aldosterone and CNT hypertrophy likely compensate. often resulting in marked weakness and respiratory arrest. several lines of evidence suggest that the hypocalciuria of Gitelman’s syndrome and thiazide treatment is due to increased absorption of Na+ by the proximal tubule.
or a patient with hepatic encephalopathy). etc.. These patients may have a constellation of associated symptoms and signs.410 mutations in the cystic fibrosis gene (CFTR). associated conditions and settings (e.405. A TTKG of less than 2 to 3 separates patients with redistributive hypokalemia from those with hypokalemia due to renal potassium wasting.235. rhabdomyolysis. and this clue can often yield the diagnosis.Chapter 17 Disorders of Potassium Balance rectification of ROMK. including dental erosion and depression.g.222. which increases outward conductance and increases K+ secretion.413 Although replacement therapy is usually limited to patients with a true deficit. The timing and evolution of hypokalemia is also helpful in differentiating the cause. and Cl– is high in patients who abuse diuretics. The cause of hypokalemia is usually obvious from the history.414. physical examination. etc. a systematic approach reveals the underlying cause (Figure 17-11). however. For example. laxatives.405 Alternatively.406 mostly in those with surreptitious vomiting (bulimia) or laxative abuse (the purging269 subtype of anorexia nervosa). it has been suggested that the repletion of intracellular K+ is impaired in hypomagnesemia. are generally unremarkable in unselected. so as to tailor therapy to the pathophysiology involved. A rapid drop to less than 2.).392 Finally. which can be verified using urinary drug screens. volume status.279 Patients with Gitelman’s syndrome are also invariably hypomagnesemic.19.g.. hypokalemic periodic paralysis) when serious complications such as muscle weakness. a complete blood count. a patient with heart failure taking digoxin. hypokalemia due to transcellular shift usually occurs in a matter of hours.407 Hypokalemic patients with bulimia will have an associated metabolic alkalosis. It is also crucial to diagnose and eliminate the underlying cause.265 theophylline overdose. and cardiac arrhythmias are present or imminent. it should be considered in patients with hypokalemia due to redistribution (e. Plasma K+ levels thus remain normal at the expense of intracellular K+. and cardiac arrhythmias).g. due to the increase in urinary calcium excretion. Initial laboratory tests should include plasma electrolyte. because hypocalciuria is a distinguishing feature of the former. In most cases.. and patients taking digoxin or antiarrhythmic drugs. The urgency of therapy depends upon the severity of hypokalemia. urinary Cl– concentration is typically less than 10 mmol/L. During the physical examination.416 and acute head injury. mostly normokalemic patients with bulimia. Plasma and urine osmolality are required for calculation of the TTKG161 (see “Urinary Indices of Potassium Excretion” section).415 When increased sympathetic tone or increased sympathetic response is thought to play a dominant role. particularly in hospitalized patients. The relevant causes of hypokalemia include TPP.19.166 Treatment of Hypokalemia The goals of therapy in hypokalemia are to prevent lifethreatening conditions (diaphragmatic weakness. with the potential for fatal hyperkalemic arrhythmias. diarrhea). osmolality. ECG changes.221 In these high-risk patients. the risk of overcorrection or rebound hyperkalemia in patients with hypokalemia caused by redistribution is particularly high.404 The most common causes of chronic.5 mmol/L poses a high risk of cardiac arrhythmias and calls for urgent replacement. and the rate of decline in plasma K+ concentration. urea.374.407 Urinary excretion of Na+.26. persistent hypokalemia despite appropriate initial intervention requires a more rigorous workup..409 Differentiation of Gitelman’s syndrome from Bartter’s syndrome requires a 24-hour urine collection to assess calcium excretion.235 .165 Further tests such as urinary Mg2+ and Ca2+ and plasma renin and aldosterone levels may be necessary in specific cases (see Figure 17-11). patients with evidence of organic heart disease. and electrolyte levels. K+. and creatinine levels. and associated symptoms (e. and urinary pH. rhabdomyolysis. creatinine level.287. and/or results of basic laboratory tests.408 Urinary electrolyte levels. and diuretic abuse. diet and dietary supplements (e. plasma Mg2+ and Ca2+ concentrations. herbal medications). nephrocalcinosis is very common in furosemide abuse.403 This phenomenon is particularly important in patients with cardiac disease who are taking both diuretics and digoxin. to replace any K+ deficit.411 or Sjögren’s syndrome with tubulointerstitial nephritis. Hypokalemia was found to occur in 5. albeit not to the levels seen in Gitelman’s syndrome. particular attention should be paid to blood pressure. and to diagnose and correct the underlying cause. who will have TTKG values that are above 4. with an obligatory natriuresis accompanying the loss of bicarbonate. and signs suggestive of specific disorders associated with hypokalemia (hyperthyroidism. The history should focus on medications (e. Marked variability in urinary electrolyte levels is an important clue to diuretic abuse.267. However.g. an increased incidence of arrhythmias may occur at even mild to modest degrees of hypokalemia.) suggestive of an impending emergency that requires immediate treatment. likely due to reduced intracellular blockade of inwardly rectifying K+ channels (increased efflux) and inhibition of Na+-K+-ATPase (decreased influx).400 Decreased intracellular Mg2+ enhances K+ efflux from the cytoplasm of cardiac and perhaps skeletal myocytes. Cushing’s syndrome. even in normokalemic patients. Finally. surreptitious vomiting.412 Acquired forms of Gitelman’s syndrome have been reported after cisplatin therapy391 and in patients with Sjögren’s syndrome. licorice). although laxative abuse is perhaps a less common cause of chronic hypokalemia.g.400. the use of nonspecific β-adrenergic blockade with propranolol generally avoids this complication and should be considered. an associated acidosis suggests the diagnosis of hypokalemic distal or proximal RTA.5% of patients with eating disorders in an American study in the mid-1990s. an accompanying metabolic acidosis with a negative urinary anion gap should raise suspicion for this diagnosis.. plasma osmolality. antibiotics. In such patients hypokalemia and arrhythmias will respond to correction of magnesium deficiency and potassium supplementation. Clinically. Bartter’s syndrome must be differentiated from pseudo–Bartter’s syndrome due to gentamicin toxicity.400 661 Clinical Approach to Hypokalemia The initial priority in the evaluation of hypokalemia is an assessment for signs and/or symptoms (muscle weakness. for example. difficult-to-diagnose hypokalemia are Gitelman’s syndrome. diuretics.414 The risk of arrhythmia from hypokalemia is highest in older patients.
the deficit and the rate of correction should be estimated as accurately as possible.418 so that plasma K+ drops by approximately 0. HTN. BP. the total deficit correlates with plasma K+ concentration. blood pressure.20 • Loop diuretic • Bartter Syndrome High • Cushing Syndrome Normal • Liddle Syndrome • Licorice • AME • Thiazide diuretic • Gitelman Syndrome FIGURE 17-11 Clinical approach to hypokalemia. hypertension.222.222. RAS. GRA. familial hypokalemic periodic paralysis. TTKG. diabetic ketoacidosis. primary hyperaldosteronism. transtubular potassium gradient. PA. medications.15 Urine Ca/Cr (molar ratio) 0. gastrointestinal. To prevent hyperkalemia due to excessive supplementation. However. CCD.399 and concomitant Mg2+ deficiency should always be addressed with oral or parenteral repletion. Apparent mineralocorticoid excess. renin-secreting tumor.417 The goal is to raise the plasma K+ to a safe range rapidly and then replace the remaining deficit at a slower rate over days to weeks.414 In the absence of abnormal K+ redistribution. Renal function. RTA. K+ replacement is the mainstay of therapy in hypokalemia. renal tubular acidosis. Physical Examination and Basic Laboratory Tests Clear evidence of transcellular shift No Yes Treat accordingly Urine K 15 mmol/day Extrarenal loss/Remote renal loss Acid-base status 15 mmol/day Renal loss TTKG • Insulin excess • β2-adrenergic agonists • FHPP • Hyperthyroidism • Barium intoxication • Theophyline • Chloroquine Metabolic Acidosis • Gl K loss Normal • Profuse sweating Metabolic Alkalosis • Remote diuretic use • Remote vomiting or stomach drainage • Profuse sweating 4 ↑ Distal K secretion BP and/or volume 3 ↑ Tubular flow • Osmotic diuresis Non-reabsorbable anions other than HCO3 • Hippurate • Penicillins Low OR Normal Variable Acid-base status Metabolic alkalosis Urine Cl (mmol/l) High • Ras • RST • Malignant HTN High Renin Low • PA • GRA High Aldosterone Low Cortisol Metabolic acidosis • Proximal RTA • Distal RTA • DKA • Amphotericin B • Acetazolamide 20 10 • Vomiting • Chloride• losing diarrhea 0. cortical collecting duct. renal artery stenosis. to gauge the risk of overcorrection. Arbitrary adjustments in the dose of administered K+-Cl– replacement based on estimated GFR can potentially reduce the risk of hyperkalemia. RST. AME. in hypomagnesemic patients hypokalemia can be refractory to K+ replacement alone. glucocorticoid-remediable hyperaldosteronism.221. See text for details. GI.662 Section II Disorders of Body Fluid Volume and Composition Move to therapy Yes Emergency? No Hypokalemia (Serum K 3.414.5mmol/l) Pseudohypokalemia? No Yes No further workup Treat accordingly and re-evaluate Yes Clear evidence of low intake No History. and comorbid conditions such as diabetes (with a risk of both insulinopenia and autonomic neuropathy) should also be considered. FHPP. DKA.27 mmol/L for every .
plasma K+ concentration should be maintained at 4.421. since bicarbonaturia associated with volume expansion may aggravate renal K+ wasting and hypokalemia. or ischemic heart disease. since infusion through upper body central lines can acutely increase the local concentration of K+ with deleterious effects on cardiac conduction. a rapid increase in plasma K+ concentration associated with ECG changes may occur with higher rates of infusion (e. irritation.433 . diuretics) or upper gastrointestinal tract (e.414 The vehicle solution should be dextrose free to prevent a transient reduction in plasma K+ level of 0. Loss of 400 to 800 mmol of body K+ results in a reduction in plasma K+ concentration of approximately 2.426 Higher concentrations of K+-Cl– (up to 400 mmol/L.g. however. volume expansion should be performed cautiously and with close follow-up of plasma K+ levels. The easiest and most straightforward method of oral K+ supplementation is to increase dietary intake of potassium-rich foods222 (Table 17-4). In high-risk patients (i. rapid correction of hypokalemia through oral supplementation is possible and may be faster than intravenous K+ supplementation. potassium chloride raises plasma K+ concentration at a faster rate than does potassium bicarbonate.414 Although the recommended rate of administration is 10 to 20 mmol/hr.414 In patients infused at such high rates.2 to 1. and lack of information on acid-base status. First.419. relatively short duration.0 mmol/L. in patients with moderate to severe hypokalemia and Cl–-responsive metabolic alkalosis.g.221.429 These solutions are best given through a large central vein.428.414 Potassium phosphate is indicated when phosphate deficit accompanies K+ depletion (e. and potassium gluconate. One study compared the effectiveness of diet versus medication supplementation in cardiac surgery patients receiving diuretics in hospital and found no difference between the two groups with respect to maintenance of plasma K+ concentration. For example. potassium phosphate.4 mmol/L in 663 60 to 90 minutes after the oral intake of 75 mmol of K+424.0 to 1. and sclerosis. this study had limitations. cardiac arrhythmias. as 40 mmol in 100 mL of normal saline) have been used in life-threatening circumstances. The usual intravenous dose is 20 to 40 mmol of K+-Cl– in a liter of vehicle solution. rates of 40 to 100 mmol/hr or even higher (for a short period) have been used in patients with life-threatening conditions. myocardial infarction. a factor that is crucial in patients with marked hypokalemia and related symptoms.228 Patients with severe hepatic disease may not be able to tolerate mild to moderate hypokalemia due to the associated augmentation in ammoniagenesis.414 Potassium chloride should otherwise be the default salt of choice for most patients. including a small number of subjects. for several reasons. the maximum possible intravenous infusion of K+ should be administered acutely for symptom control.222.224 Plasma K+ concentration should also be closely monitored during replacement. In all likelihood. those with heart failure. potassium bicarbonate may offset the benefits of K+ administration by aggravating concomitant alkalosis.5 to 3. independent of the associated antihypertensive effect. such estimates are just an approximation of the amount of K+ replacement required to normalize plasma K+ concentration.413 A combination of potassium phosphate and potassium chloride may be necessary to correct hypokalemia effectively in these patients.e. and thus plasma K+ should be maintained at approximately 4.429 As a general rule.428 In these cases.425 The oral route is thus both effective and appropriate in patients with asymptomatic severe hypokalemia.221. diabetic ketoacidosis). the rate of infusion should be decreased to the standard dosage of 10 to 20 mmol/hr. the ingestion of approximately 125 to 165 mmol of K+ as a single oral dose can increase plasma K+ by approximately 2. supplementation is recommended for patients with a plasma K+ concentration lower than 3 mmol/L.427.413 In patients with combined severe hypokalemia and hypophosphatemia (e.418 These values can be used to estimate replacement goals. metabolic alkalosis typically accompanies chloride loss from the kidney (e. If the patient is experiencing lifethreatening signs and symptoms of hypokalemia. close monitoring of the appropriate physiologic consequences of hypokalemia is essential.429-431 However. followed by rapid oral supplementation. and those taking digoxin).5 mmol/L.. which keeps the K+ in the extracellular fluid compartment.0 mmol/L221 and potassium supplementation should be considered when plasma K+ falls below 3.222 In this setting. However. this faster rise in plasma K+ occurs because Cl– is mainly an extracellular fluid anion that does not enter cells to the same extent as bicarbonate. and K+ replacement withdrawn or adjusted if necessary.. However. due to limitations in the rapidity with which intravenous K+ can be infused. it usually does not suffice. However. Third.5 mmol/L in 60 to 120 minutes.5 mmol/L or higher.g..420 In asymptomatic patients with mild to moderate hypertension.422 Potassium is available in the form of potassium chloride. Because dietary K+ is mainly in the form of potassium phosphate or potassium citrate.427..g.0 mmol/L or higher221 or even at 4. ≥80 mmol/hr).414 Potassium bicarbonate (or its precursors) should be considered in patients with hypokalemia and metabolic acidosis.4 mmol/L due to an enhanced endogenous insulin secretion induced by the dextrose. Femoral veins are preferable.Chapter 17 Disorders of Potassium Balance 100-mmol reduction in total body stores.432 Intravenous administration of K+ at a rate of more than 10 mmol/hr requires continuous ECG monitoring. and to avoid venous pain. prospective studies have shown an inverse relationship between dietary potassium intake and both fatal and nonfatal stroke. 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. replacing chloride along with K+ is essential in treating the alkalosis and preventing further kaliuresis. Although the treatment of asymptomatic patients with borderline or low-normal plasma K+ concentration remains controversial. in diabetic ketoacidosis)..221 Notably.423 Parenteral (intravenous) K+ administration should be limited to patients unable to utilize the enteral route or patients experiencing associated signs and symptoms of hypokalemia.g. the amount of K+ per intravenous bag should be limited (e. However.. Second. 20 mmol in 100 mL of saline solution) to prevent inadvertent infusion of a large dose.g.429 It is important to remember that. potassium bicarbonate or its precursors (potassium citrate. which makes its results less than conclusive and not generalizable.0 mmol/L.428.. with as much as a one in six risk of overreplacement. potassium acetate).221. intravenous K+ phosphate can be used. concentrations of more than 60 mmol/L should not be given through a peripheral vein. after these effects have abated. vomiting) and contributes significantly to renal K+ wasting. an attempt should be made to maintain plasma K+ concentration above 4. plasma K+ concentration can be increased by 1.
1998. strategies to minimize K+ losses should be considered. Arch Intern Med 160:2429-2436. ARBs. and using a combination of non–K+-sparing and K+-sparing medications (e.3% to 41%)26.435 Potassium chloride is also available in either liquid or tablet form (Table 17-5). K+ supplementation alone may be ineffective in these settings.5 mmol]/100 g) Dried fruits (dates.442 although in some studies levels of 5.443 Hyperkalemia has been reported in 1.664 Section II Disorders of Body Fluid Volume and Composition TABLE 17-4 Foods with High Potassium Content Highest content(>1000 mg [25 mmol]/100 g) Dried figs Molasses Seaweed Very high content(>500 mg [12. the pathophysiology of hyperkalemia is multifactorial. few gastrointestinal tract erosions.437-439 In patients with hypokalemia due to loss through upper gastrointestinal secretion (continuous nasogastric tube suction. In the 10% of patients who remain hypokalemic. with reduced renal function. the prevalence of hyperkalemia is 5% to 10%. 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. these tablets are less irritating to the stomach and less likely to induce vomiting.222 Liquid forms are less expensive but are less well tolerated.222 The chance of overdose and hyperkalemia is higher with slow-release formulations.4 mmol/L qualify for the diagnosis. less adherent and less cohesive Fewer gastrointestinal tract erosions than with wax-matrix tablets Inexpensive.445 In most hospitalized patients.73 m2 to less than 20 mL/min/1. divided into 2 or 3 doses. more gastrointestinal tract erosions than with microencapsulated formulas Potassium chloride (effervescent tablets) for solution Wax-matrix extended-release tablets From Cohn JN. continuous or self-induced vomiting). increasing the oral dose or adding a K+-sparing diuretic is an appropriate choice. immediate effect Convenient. this risk is rather low.73 m2 in one study. which have been ascribed to local accumulation of high concentrations of K+.449 The risk of hyperkalemia . but more expensive than elixir. K+-sparing diuretics.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. Hyperkalemia Epidemiology Hyperkalemia is usually defined as a potassium level of 5.0 mmol/L).442 and accounted for approximately 1 death per 1000 patients in one case series in the mid-1980s. proton pump inhibitors are reportedly useful in helping to correct the metabolic alkalosis and reduce hypokalemia. however.222. Slow-release forms are more palatable and better tolerated.1% to 10% of all hospitalized patients. These measures may include minimizing the dose of non–K+-sparing diuretics and restricting Na+ intake more rigorously instead. ACE inhibitors. the available preparations are well absorbed.441 Hyperkalemia has been associated with a higher mortality rate (14. unlike the immediate-release forms. prunes) Nuts Avocados Bran Cereals Wheat germ Lima beans High content(>250 mg [6.221 The use of a K+-sparing diuretic is of particular importance in hypokalemia resulting from primary hyperaldosteronism and related disorders. poor patient adherence. N Engl J Med 339:451-458. et al: New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice. Whelton PK. Each gram contains 10 to 13 mmol of K+434.200.200. This dosage is effective in maintaining plasma K+ concentration in up to 90% of patients.440 Care should be taken when discontinuing these agents. need to be counseled regarding the appropriate amount and the potential for hyperkalemia.441. in patients taking diuretics222 (K+Cl– can be toxic in doses of more than 2 mmol/kg436).222 In addition to potassium supplementation.446-448 The prevalence increased from 2% to 42% as GFR decreased from 60 to 90 mL/min/1.221 In general.g.222 Salt substitutes are an inexpensive and potent source of K+-Cl–. immediate effect Easier to swallow.193. they have been associated with gastrointestinal ulceration and bleeding. Most patients therefore need to combine a high-K+ diet with a prescribed dose of K+-Cl–. and lower still when the microencapsulated forms are used. however. particularly those with an impaired ability to excrete potassium.429 Notably.442 In patients with ESRD.436 The usual dose is 40 to 100 mmol of K+ (as K+-Cl–) per day.0% of patients (8% to 10% of hyperkalemic patients) having significant hyperkalemia (≥6. Kowey PR.441.. such as Liddle’s syndrome and AME. patients.0 to 5. medications.441-444 with approximately 1. 2000. and hyperglycemia being the most common contributing factors. tastes bad.5 mmol/L or higher. TABLE 17-5 Oral Preparations of Potassium Chloride SUPPLEMENT Controlled-release microencapsulated tablets Encapsulated controlled-release microencapsulated particles Potassium chloride elixir ATTRIBUTES Disintegrate better in stomach than encapsulated microparticles. older age (≥60 years). β-blockers). Regardless.441.
due to the abnormal K+ permeability of erythrocytes. Alarmingly. with approximately 25% of the patients lacking any follow-up. which leads to normal values in hyperkalemic patients and/or to spurious hypokalemia in patients who are normokalemic. presumably due to as-yet-uncharacterized cardiac adaptation to chronic hyperkalemia.26 This phenomenon leads to “seasonal pseudohyperkalemia and pseudohypokalemia”26. Finally. mutations in the red cell Rh A glycoprotein (RhAG) have been linked to the monovalent cation leak associated with overhydrated hereditary stomatocytosis.464 may provoke severe hyperkalemia in individuals free of predisposing factors. which is thought to function as an NH3 or NH4+transporter RhAG. Abnormal red cell morphology. For example. such as K+-penicillin.448 and renal failure is the most common cause of hyperkalemia diagnosed in the emergency room. marked intake of K+. can cause spurious hyperkalemia. but in many kindreds there are no overt hematologic consequences.436 Such pills are radiopaque and may thus be seen on radiographs. there are several hereditary subtypes of pseudohyperkalemia. thrombocytosis.3 mmol/L within 3 hours.461 The mutations that were detected all cluster within exon 17 of the gene.461 between transmembrane domains 8 and 10 of the AE1 protein.451 665 Pseudohyperkalemia Factitious hyperkalemia.460 with fluctuations in outpatient samples as a function of season and ambient temperature.434 alternative medicines.448 Notably. which encodes the band 3 anion exchanger. pneumatic tube transport was shown to induce pseudohyperkalemia in a specimen from one patient with leukemia and massive leukocytosis.468 to a susceptible patient. and temperature-dependent loss of red cell K+ were found to have heterozygous mutations in the SLC4A1 gene on chromosome band 17q21.446 The prevalence of marked hyperkalemia (K+ ≥ 5.26.465 and alternative diets.61 Fourth. and/or perinatal edema can accompany hereditary pseudohyperkalemia. Sustained-release K+-Cl– tablets can cause hyperkalemia in suicidal overdoses. for example in sports beverages.461 The disorder is genetically heterogeneous. electrocardiography performed in only 36% of cases.224 or administration of a potassium-containing medication. the oral administration of 32 mmol to a diabetic patient with hyporeninemic hypoaldosteronism resulted in an increase in plasma K+ concentration from 4. forearm contraction. is an artifactual increase in plasma K+ concentration due to the release of K+ during or after venipuncture. which has led to the practice in some laboratories to perform EDTA assays on samples with a plasma K+ level of more than 6 mmol/L when K+-EDTA was used as an anticoagulant. Plasma K+ concentration increases in pseudohyperkalemia patient samples that have been left at room temperature. the management of outpatient hyperkalemia is often suboptimal. Very rarely. as can occur commonly in hypokalemic patients.200. There are several potential causes for pseudohyperkalemia. the risk of death from hyperkalemia is reduced as CKD progresses.8 mmol/L) is approximately 1% in a general medicine outpatient setting.Chapter 17 Disorders of Potassium Balance is higher in males with chronic kidney disease (CKD) and is tripled by treatment with ACE inhibitors or ARBs.458 Cooling of blood prior to the separation of cells from plasma or cooling of plasma is also a wellrecognized cause of artifactual hyperkalemia. Fifth.454 leukocytosis. acute anxiety during venipuncture may provoke respiratory alkalosis and hyperkalemia due to redistribution. sample contamination with potassium ethylenediaminetetraacetic acid (K+-EDTA). For example.449 It has been argued that hyperkalemia accounts for or contributes to 1. or pseudohyperkalemia. based on differences in the temperature-dependence curve of this red cell leak pathway.9 mmol/L to a peak of 7.466 Geophagia with ingestion of K+-rich clay26 and cautopyreiophagia467 (ingestion of burnt matchsticks) are two forms of pica that have been reported to cause hyperkalemia in dialysis patients.450 Hyperkalemia is the reason for emergency hemodialysis in 24% of patients with ESRD who are receiving hemodialysis.463 Increased intake or changes in intake of dietary sources rich in K+ (see Table 17-4) may also provoke hyperkalemia in susceptible patients. Pseudohyperkalemia in these patients thus results from a genetic event that endows AE1 with the ability to transport K+.50-52. however. whole bowel irrigation should be used for gastrointestinal decontamination.461 More recently. Other occult sources of K+ must also be considered. Second. caused by an increase in the passive K+ permeability of erythrocytes.26 Of particular interest. with a characterized gene on chromosome band 17q21 and uncharacterized loci on chromosome bands 16q23-ter and 2q3536. and frequent delays in repeating plasma K+ determinations.9% to 5% of deaths among patients with ESRD. pseudohyperkalemia.26.230 This issue is particularly important for samples drawn in the outpatient primary practice setting that are transported offsite and analyzed at a central facility. Red cell transfusion is . AE1.459 The converse is the risk of increased uptake of K+ by cells at high ambient temperatures. varying degrees of hemolysis. Several subtypes have been defined.462 These mutations cause an exaggerated cation leak in the RhAG. including salt substitutes. eleven pedigrees of patients with autosomal dominant hemolysis.457 There are several mechanisms for sample contamination with K+-EDTA during blood draws or sample handling.453 fist clenching. used as a sample anticoagulant for some laboratory assays. Excess Intake of Potassium and Tissue Necrosis Increased intake of even small amounts of K+ may provoke severe hyperkalemia in patients with predisposing factors.19 or tourniquet use452 may increase K+ efflux from local muscle and thus raise the measured plasma K+ level. with the novel acquisition of a nonselective transport pathway for both Na+ and K+.452 First. These mutations reduce anion transport in both red cells and Xenopus oocytes injected with AE1. lesser contamination is less obvious.457 Gross contamination with K+-EDTA usually results in spurious hypocalcemia and hypomagnesemia.455 and/ or erythrocytosis456 may cause pseudohyperkalemia due to release of K+ from these cellular elements. That single point mutations can convert an anion exchanger to a nonselective cation channel serves to underline the narrow boundaries that separate exchangers and transporters from ion channels. mechanical and physical factors may induce pseudohyperkalemia after blood has been drawn. Third.436 Iatrogenic causes include simple overreplacement with K+Cl–.
medications (statins. Hypokalemia is an important metabolic predisposing factor in rhabdomyolysis (see “Consequences of Hypokalemia” section). although the transport pathways involved are unknown.474-476 Diabetic patients are prone to severe hyperkalemia in response to intravenous administration of hypertonic glucose in the absence of adequate coadministration of insulin.480. for whom intravenous glucose infusions with or without insulin are appropriate measures to prevent the development of hyperkalemia. Patients with DKA typically present with plasma K+ levels that are within normal limits or moderately elevated.19. ESRD patients maintained on dialysis did not have an exaggerated increase in plasma K+ concentration with maximal exercise. typically with an acute dilutional hyponatremia. indicated for the treatment of digoxin overdoses. the use of central venous infusion and/or pressure pumping. Although exercise is a well-described cause of acute hyperkalemia. due the enormous store of K+ in muscle (see Figure 17-1).484 Insulin stimulates the uptake of K+ by several tissues. military combat support hospital in Iraq.19 Muscle plays a dominant role in extrarenal K+ homeostasis. thus digoxin overdose can result in hyperkalemia. which is structurally similar to the cardioactive glycoside digoxin. Redistribution and Hyperkalemia Several different mechanisms can induce an efflux of intracellular K+. volume depletion. so that fluoride poisoning is typically associated with hyperkalemia.469 Whereas 7-day-old blood has a free K+ concentration of approximately 23 mmol/L. and the hyperosmolar effect of severe hyperglycemia. which results in the efflux of K+ through acetylcholine receptors (AChRs) and a rapid.490 Succinylcholine depolarizes muscle cells. since bufadienolide is immunologically similar to digoxin. The direct ingestion of such toads488 or of toad extracts can result in fatal hyperkalemia.19. and aldosterone responses to exercise and/or to their preexisting hyperkalemia.19. generates an increase in plasma K+concentration. in particular). severe hyperkalemia.471 Tissue necrosis is an important cause of hyperkalemia. contain appreciable amounts of toad venom and have lead to several case reports of poisoning in the United States. is a well-described complication of mannitol administration for the treatment or prevention of cerebral edema.40. however.486 due to a variety of potential factors: insulinopenia.19.477.26. The skin and venom gland of the cane toad Bufo marinus contains high concentrations of bufadienolide.5 mmol/L) is not uncommon in DKA. in particular. due to a similar osmotic effect.482 The results and design of this and other studies of exercise-associated hyperkalemia in ESRD have been criticized by a more recent report. the acute osmolar load was the likely cause of the acute hyperkalemia in these patients.472 Potential mechanisms include dilutional acidosis with subsequent shift in K+. one would expect the development or worsening of hyperkalemia in dialysis patients exposed to large volumes of hyperosmolar contrast dye.666 Section II Disorders of Body Fluid Volume and Composition a well-described cause of hyperkalemia. but usually transient. The infusion of hypertonic mannitol or saline.489 Finally. but with profound whole-body potassium deficits. Hyperkalemia due to rhabdomyolysis is particularly common. resulting in hyperkalemia. Dialysis patients are susceptible to modest increases in plasma K+ concentration after prolonged fasting. renal dysfunction. However. In many cases. acidosis. perhaps due to greater insulin. and hyperglycemia. with low cardiac output.38. hypernatremia and hyponatremia. a retrospective report documented considerable increases in plasma K+ concentration after intravenous injection of contrast dye in five patients with CKD. . due to the relative insulinopenia in this setting. but not hypertonic bicarbonate. with such a complication typically seen in children or in patients receiving massive transfusions. fluoride ions also inhibit Na+-K+-ATPase.43 Reduction in circulating insulin level is thus an important factor or cofactor in the generation of hyperkalemia in diabetic patients.463 Two reports have appeared regarding the risk of hyperkalemia with the use of ε-aminocaproic acid (Amicar).483 In any event. massive release of K+ and other intracellular contents may occur as a result of acute tumor lysis.484 This may be clinically relevant in preoperative ESRD patients. this effect is usually transient. acute hemolysis. the use of irradiated blood.36 Digoxin inhibits Na+-K+-ATPase and thus impairs the uptake of K+ by skeletal muscle (see “Factors Affecting Internal Distribution of Potassium” section). the concentration rises to the 50-mmol/L range in 42-day-old blood. primarily via stimulation of Na+-K+-ATPase activity. exercise-associated hyperkalemia is not a major clinical cause of hyperkalemia.469. and metabolic predisposition contribute to the genesis of rhabdomyolysis.478 Finally. and the use of older blood. four being maintained on dialysis and one with stage 4 CKD. hyperkalemia. In one study.489 The toxin may be detected in the plasma of such patients using standard digoxin assays. The use of this agent is contraindicated in patients with thermal trauma.479 Again. others include hypophosphatemia. significant hyperkalemia (plasma K+ > 6. may be effective and life-saving in bufadienolide toxicity. Administration of digoxin-specific Fab fragment.471 Although red cell and/or blood product transfusion plays an important role. The implications of this provocative study are not entirely clear. and its clinical relevance is difficult to judge.245 Finally.0 to 6. and other factors contributing to the risk of hyperkalemia in patients with severe trauma. increased passive exit of K+ due to an increase in intracellular K+ activity from intracellular water loss.485.470 Hyperkalemia is a common occurrence in patients with severe trauma. Those patients with hypokalemia-associated rhabdomyolysis in whom redistribution is the cause of hypokalemia are at particular risk of subsequent hyperkalemia as the rhabdomyolysis evolves and renal function worsens. Cationic but not anionic amino acids induce efflux of K+ from cells. catecholamine. with a period prevalence of 29% seen in massively traumatized patients at a U. Risk factors for transfusion-related hyperkalemia include a higher rate and volume of transfusion.474 Regardless of the cause. hypocalcemia. primarily via regulated uptake by Na+-K+-ATPase.473. and a “solvent drag” effect as water exits cells. which linked abnormal extrarenal K+ homeostasis to increased fatigue in ESRD.485-487 Inhibition of insulin secretion by the somatostatin agonist octreotide can also cause significant hyperkalemia in both anephric patients35 and patients with normal renal function. this and other studies indicate a complex pathophysiology for resuscitative hyperkalemia. Certain herbal aphrodisiac pills.S.481 a cationic amino acid that is structurally similar to lysine and arginine.
thus enhancing and prolonging the K+ efflux after paralysis has subsided. with increased extrajunctional AChRs (α1.Chapter 17 Disorders of Potassium Balance neuromuscular injury (upper or lower motor neuron). by medications. with a temporal hypokalemic response to the KATP inhibitor glibenclamide (glyburide). In addition. The α7-containing AChR is a homomeric. with loss of the normal clustering at the neuromuscular junction.491 These disorders share a 2. and aldosterone level. however. β1. The daring. including severe hyperkalemia. Richtsfeld M: Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms. mucositis.491 Depolarization of these upregulated AChRs by succinylcholine results in an exaggerated efflux of K+ through the receptor-associated cation channels that are spread throughout the muscle cell membrane (Figure 17-12).492 A report of three patients suggested the possibility that drugs which share the ability to open KATP channels may have an underappreciated propensity to cause hyperkalemia in critically ill patients. and nicorandil. neuronal-type α7-AChRs. angiotensin II level. (From Martyn JA. with DAX-1 deficiency leading to hypogonadotropic hypogonadism499 and SF-1 deficiency causing maleto-female sex reversal. including in skeletal muscle. This leads to a modest transient hyperkalemia. when patients either show delayed puberty (see later) or experience an adrenal crisis. it still remains to be seen whether this is a common or important mechanism for acute hyperkalemia.491 Depolarization of α7-AChRs in response to choline is not subject to desensitization. Both genes are involved in gonadal development.498 The X-linked disorder adrenal hypoplasia congenita is caused by loss-of-function mutations in the transcriptional repressor DAX-1 (dosage-sensitive sex-reversal. and ε [multicolored]) acetylcholine receptors (AChRs). succinylcholine interacts with the entire plasma membrane. Anesthesiology 104:158-169. and this may explain in part the hyperkalemic effect that persists in some patients well after the paralytic effect of succinylcholine has subsided. disuse atrophy. in part by inhibiting cellular uptake but also through the hyporeninemic hypoaldosteronism induced by the effect of these drugs on both renal renin release and adrenal aldosterone release (see “Regulation of Renal Renin and Adrenal Aldosterone” section). is a particularly common cause of hyperkalemia in susceptible patients. 2006. due to the upregulation and redistribution of these AChRs. is also required for adrenal development in both mice and humans.497 Primary hypoaldosteronism may be genetic or acquired. isoflurane. β-blockers cause hyperkalemia. Concomitant upregulation of the neuronal α7-subunit of the AChR has also been observed in denervated muscle.495 However. in addition to adrenal insufficiency. Patients with adrenal hypoplasia congenita present with primary adrenal failure and hyperkalemia either shortly after birth or much later in childhood. critical region on the X chromosome. adrenal hypoplasia congenita.497 Concomitant hyporeninemic hypoaldosteronism is frequent26. the efflux of K+ induced by succinylcholine is enhanced in these patients and can result in significant hyperkalemia. The isolated loss of pituitary secretion of ACTH leads to a deficit in circulating cortisol.to 100-fold upregulation of AChRs at the plasma membrane of muscle cells. or by isolated deficiency of ACTH. and gonadal steroids. variable defects in other pituitary hormones are likely secondary to this reduction in cortisol level. a functional partner for DAX-1. there is a considerable upregulation of muscle AChRs.494 KATP channels are widely distributed. hyperkalemia is less common in secondary hypoaldosteronism than in Addison’s disease. Steroidogenic factor 1 (SF-1). δ. Depolarization of denervated muscle leads to an exaggerated K+ efflux. However.19 The disorder manifests in early infancy with adrenal crisis. In innervated muscle. With denervation. choline generated from the metabolism of succinylcholine maintains the depolarization mediated by α7-AChRs. glucocorticoids. Labetalol. β1. off-label use of glibenclamide was presumably 667 instigated by the senior author’s observation that cyclosporine activates KATP channels in vascular smooth muscle. Reduced steroidogenesis causes two other important forms of primary hypoaldosteronism. but depolarizes only the junctional (α1. Aldosterone release from the adrenal glands may be reduced by hyporeninemic hypoaldosteronism and its multiple causes.491 Consistent perhaps with this neuromuscular pathophysiology.500 Genotypically male 46. if patients survive the early neonatal period the diagnosis will then be missed until much later in life. or prolonged immobilization in an intensive care unit setting.19.499 This bimodal presentation pattern does not appear to be influenced by DAX1 genotype. rather.498 Congenital lipoid adrenal hyperplasia is a severe autosomal recessive syndrome characterized by impaired synthesis of mineralocorticoids. a broadly reactive sympathetic blocker. gene 1).493 These patients exhibited hyperkalemia that resisted the usual therapies (insulin/dextrose with or without hemofiltration).) . Reduced Renal Excretion of Potassium 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 “Aldosterone” section). δ. so that activation of such channels is indeed a plausible cause of acute hyperkalemia.496 so that β-blockade in general increases susceptibility to hyperkalemia. patients with renal failure do not appear to have an increased risk of succinylcholine-associated hyperkalemia. pentameric channel that depolarizes in response to both succinylcholine and choline. Finally. The implicated drugs included cyclosporine.XY patients with congenital lipoid adrenal hyperplasia have female external genitalia due to the Innervated Muscle SCh or Choline K K Myonucleus SCh or Choline Denervated Muscle K K K K K K K K K K K K K Extracellular fluid K K K Extracellular fluid Myonucleus FIGURE 17-12 Increase in succinylcholine-induced efflux of potassium in denervated muscle. and γ [multicolored]) and acquisition of homomeric. both nonspecific and cardiospecific β-blockers have been shown to reduce PRA. its metabolite.
511 Antiphospholipid syndrome may also cause bilateral adrenal hemorrhage and adrenal insufficiency.503 21-Hydroxylase is a cytochrome P450 enzyme encoded by the gene CYP21B that is involved in the bioconversion of progesterone to 11-deoxycorticosterone. adrenal insufficiency may be precipitated by stress. many diabetic patients appear to be volume expanded.19.523.220 Although the cause of this acidosis is clearly multifactorial.26. a shared precursor for aldosterone and cortisol. this suggests a defect in the normal processing of prorenin. Acquired hyperreninemic hypoaldosteronism has been described in association with critical illness. patients tend to become asymptomatic in adulthood. the conversion of prorenin to active renin is impaired in some diabetic patients.506 and amyloidosis due to familial Mediterranean fever. a small mitochondrial protein that helps shuttle cholesterol from the outer to the inner mitochondrial membrane and thus initiates steroidogenesis. the incidence is likely 50% to 60%.518 multiple myeloma.166. Third.19 type 2 diabetes. patients should show suppression of PRA and aldosterone level.502 The classical salt-wasting form of congenital adrenal hyperplasia due to 21-hydroxlase deficiency is associated with marked reductions in both cortisol and aldosterone levels.516 First. Concomitant overproduction of androgenic steroids results in virilization in female patients with this form of congenital adrenal hyperplasia.507 as well as after metastasis of carcinoma to the adrenal gland.19. degenerative. Several factors account for the reduced PRA in diabetic patients with hyporeninemic hypoaldosteronism. renin is physiologically rather than pathologically suppressed.19 Failure to respond to isoproterenol with an increase in PRA. Contemporary estimates of the risk of hyperkalemia in patients with Addison’s disease are lacking.159. Histologic findings in experimental animals include a marked diminution in the size of the zona glomerulosa and an attenuated hyperplastic response to salt depletion.512 Another renal syndrome in which there should be a high index of suspicion for adrenal insufficiency is renal amyloidosis. which leads to adrenal insufficiency. as is the case with perhaps all patients with hyporeninemic hypoaldosteronism (see later). with a 7% incidence of hyperkalemia associated with heparin therapy.19 Hyporeninemic hypoaldosteronism has also been described in patients with systemic lupus erythematosus. aldosterone synthesis is selectively reduced by heparin. drugs such as ketoconazole that inhibit steroidogenesis. and many respond to either Na+-Cl– restriction or furosemide with an increase in PRA. despite an adequate cardiovascular response. however. a positive urinary anion gap. The most common cause of adrenalitis in HIV disease is cytomegalovirus. however.509 heparin can cause hyperkalemia.26 Classically.19. suggests a postreceptor defect in the ability of the juxtaglomerular apparatus to respond to β-adrenergic stimuli19 (see also “Regulation of Renal Renin and Adrenal Aldosterone” section). many patients have an associated autonomic neuropathy. although genetic heterogeneity has been reported. or the acute withdrawal of steroid agents such as megestrol. which then exerts a negative effect on both renal renin release and adrenal aldosterone release (see also “Regulation of Renal Renin and Adrenal Aldosterone” section).501 Some patients may alternatively have mutations in the side-chain cleavage P450 enzyme.515 Approximately 50% of patients have an associated acidosis. Megestrol is a progesterone derivative with antineoplastic properties used in the treatment of advanced carcinoma of the breast and endometrium that can increase appetite at higher dosages. which do not respond to typical maneuvers such as furosemide administration or sodium restriction.525 which is also an indicator of their underlying volume expansion. A high-K+ diet and high peritubular K+ concentration serve to increase apical Na+ reabsorption and K+ secretion in the CNT and CCD (see “Renal Potassium Excretion” section). human immunodeficiency virus (HIV) infection has surpassed tuberculosis as the most important infectious cause of adrenal insufficiency.159.520 and experimental216 evidence suggests that hyperkalemia per se is the dominant factor. Congenital lipoid adrenal hyperplasia is caused by loss-of-function mutations in steroidogenic acute regulatory protein. Hyperkalemia due to prophylactic subcutaneous administration of unfractionated heparin (5000 U twice daily) has also been reported. either in Addison’s disease or in the context of a polyglandular endocrinopathy. and infiltrative processes may involve the adrenal glands in these patients.504 The disorder typically manifests in childhood with volume depletion and hyperkalemia.5. Isolated deficits in aldosterone synthesis with hyperreninemia are caused by loss-of-function mutations in aldosterone synthase.498.516 the elderly.220.505 Much as in pseudohypoaldosteronism due to loss-of-function mutations in the mineralocorticoid receptor (see later). in most patients with reductions in circulating aldosterone this homeostatic mechanism appears to be sufficient to regulate plasma K+ concentration to within normal limits. with impaired release of renin during orthostatic challenges.19 Finally. that is. The most attractive current hypothesis for the suppression of PRA in hyporeninemic hypoaldosteronism is that primary volume expansion increases the level of circulating ANP.519 strong clinical219.516 despite adequate release of prorenin in response to furosemide19. Patients who respond . which results in hyperreninemic hypoaldosteronism. overlapping subsets of hyperkalemic patients: diabetic patients. with reduced renal excretion of NH4+.19 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. and a urine pH of less than 5.508 Most primary adrenal insufficiency is due to autoimmunity. Hyporeninemic Hypoaldosteronism Hyporeninemic hypoaldosteronism515 is a very common predisposing factor in several large.517 and patients with renal insufficiency. Second.522-524 Patients with hyporeninemic hypoaldosteronism due to a diversity of underlying causes have elevated ANP levels.508 Both unfractionated508 and low-molecular-weight19. with subsequent suppression of PRA.26 and acute glomerulonephritis.514 Although the adrenal involvement in HIV disease is usually subclinical.513 Finally.510 Heparin reduces the adrenal aldosterone response to both angiotensin II and hyperkalemia.668 Section II Disorders of Body Fluid Volume and Composition developmental absence of testosterone. due to competitive inhibition of NH4+ transport in the TAL and reduced distal excretion of NH4+521 (see also “Consequences of Hyperkalemia” section). a long list of infectious. There is evidence that these patients are volume expanded.
which can occasionally be very severe531. unlike in ENaC-deficient mice. and reduced bone density. Medication-Related Hyperkalemia Cyclooxygenase Inhibitors Hyperkalemia is a well-recognized complication of the use of nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit cyclooxygenases.5. the syndrome does not improve in adulthood.533 FHHt behaves like a gain of function in the thiazide-sensitive Na+-Cl– cotransporter NCC. NSAIDs will reduce its activity and the flow-dependent component of K+ excretion. more recently. suppressed PRA and aldosterone. hypercalciuria. large intronic deletions in the WNK1 gene result in increased expression.147.127 A key insight from study of the mechanisms of FHHt is that the activation of NCC in the DCT in this syndrome serves to reduce Na+ delivery to principal cells in the downstream CNT and CCD.530 The recessive form of PHA-1 is caused by various combinations of mutations in all three subunits of ENaC.527-529 Classical causes include systemic lupus erythematosus. or FHHt) is in every respect the mirror image of Gitelman’s syndrome.541 which implies NSAID-like effects on renal pathophysiology. hyperkalemic distal RTA is associated with a normal or increased aldosterone level and/or PRA. however.539 Finally. as familial hyperkalemia with hypertension.19.340 Patients with this syndrome show severe salt wasting. . the activation of NCC by the AT1 angiotensin II receptor appears to require the downstream activation of SPAK by WNK4. the infusion of exogenous ANP can suppress the adrenal aldosterone response to both hyperkalemia159 and dietary Na+-Cl– depletion.534 WNK-dependent phosphorylation and activation of the downstream SPAK and OSR1 (oxidative stress–responsive kinase 1) kinases leads to phosphorylation of a cluster of N-terminal threonines in NCC.538 The administration of indomethacin to normal volunteers thus attenuates furosemide-induced increases in PRA. hence the designation WNK (with no lysine [K]). resulting in impairment in its channel activity. hypotension. the shared label pseudohypoaldosteronism. mutations in two related serine-threonine kinases were detected in various kindreds with FHHt.1. the flow-activated apical maxi-K/BK channel in the CNT and CCD is activated by prostaglandins536.526 669 Acquired Tubular Defects and Potassium Excretion Unlike hyporeninemic hypoaldosteronism. however. NSAIDs cause hyperkalemia by a variety of mechanisms. which leads to hyperkalemia. with resolution of the hypertension.535 In particular. as would be predicted from the relevant physiology. Pseudohypoaldosteronism type 1 (PHA-1) has both an autosomal recessive and an autosomal dominant form.535 For example.26 Patients with recessive PHA-1 may have pulmonary symptoms. The autosomal dominant form is due to loss-of-function mutations in the mineralocorticoid receptor.158 The physiology reviewed earlier in this chapter (see “Regulation of Renal Renin and Adrenal Aldosterone” section) suggests that COX-2 inhibitors would be equally likely to cause hyperkalemia. which results in activation of Na+-Cl– cotransport1 (see also Figure 17-6). the lifelong increases in circulating levels of aldosterone.525 FHHt is an autosomal dominant syndrome. and they are unable to increase acid or K+ excretion in response to furosemide. coexpression of WNK4 with NCC reveals an additional inhibitory influence of the kinase on NCC. Na+-SO42–. and hyperkalemia in the neonatal period.68 This and other effects of the WNK pathways on distal K+ secretion were discussed earlier in this chapter (see “Potassium Intake” section). Whereas WNK1 localizes to the cytoplasm and basolateral membrane. However. angiotensin II.74. aggressive salt restriction decreases ANP levels and increases PRA. hyperkalemia. hyperchloremic metabolic acidosis. COX-2 inhibitors can clearly cause sodium retention and a decrease in GFR. The clinical phenotype includes hypertension. which is at least partially dependent on prostaglandins acting though prostaglandin EP2 receptors and cAMP. By decreasing GFR and increasing sodium retention they decrease distal delivery of Na+ and reduce distal flow rate. Indeed.523 Furthermore.19 Hereditary Tubular Defects and Potassium Excretion Hereditary tubular causes of hyperkalemia have overlapping clinical features with hypoaldosteronism. as in the hypoaldosteronism due to mutations in aldosterone synthase. hence.68 These competing. with as many as four genetic loci.527 sickle cell anemia.534 The catalytic sites of these kinases lack specific catalytic lysines conserved in other kinases.340 One unexpected result in the physiologic characterization of ENaC is that mice with a targeted deletion of the α-ENaC subunit were found to die within 40 hours of birth due to pulmonary edema.532 Pseudohypoaldosteronism type 2 (PHA-2. Whereas FHHt mutations in WNK4 affect the C terminus of the coding sequence.340 Of interest. Both kinases are expressed within the distal nephron in both DCT and CCD cells. hyperkalemia. they typically become asymptomatic in adulthood.19 In a landmark paper. Urine pH in these patients is higher than 5.370 NSAIDs are also a classical cause of hyporeninemic hypoaldosteronism.533 FHHt is an extreme form of hyporeninemic hypoaldosteronism due to volume expansion. the inhibitory effects of WNK4 appear to dominate in mouse models with overexpression of wild-type WNK4 compared with those with FHHt mutant WNK4. hence.Chapter 17 Disorders of Potassium Balance to furosemide with an increase in PRA exhibit a concomitant decrease in ANP.540. WNK4 protein is found at the apical tight junctions. the modest residual activity associated with heteromeric PHA-1 channels is generally sufficient to mediate pulmonary Na+ and fluid clearance in humans with loss-of-function mutations in ENaC. and treatment with thiazides typically results in resolution of all clinical manifestations.537.529 and amyloidosis. Moreover. and renin seen in this syndrome do not appear to have untoward cardiovascular consequences. NSAIDs would not cause hyperkalemia with such regularity if they did not also blunt the adrenal response to hyperkalemia. divergent mechanisms can be reconciled by the likelihood that the physiologic context determines whether WNK4 will have an activating or inhibitory effect on NCC. also known as Gordon’s syndrome and. it appears that. effects that are blocked by FHHt-associated point mutations in the kinase. or fludrocortisones.530 These patients require aggressive salt supplementation during early childhood. In contrast to the autosomal dominant form of PHA-1. and metabolic acidosis.
a protease inhibitor widely used in Japan for pancreatitis and other indications. Aliskiren beta-blockers Angiotensin-I ACE Angiotensin-II ACE inhibitors ARBs Aldosterone Spironolactone.105 ACE Inhibitors and Mineralocorticoid and Angiotensin Antagonists Hyperkalemia is a predictable and common effect of ACE inhibition. drospirenone Amiloride. thus reducing transcription of the α-subunit of ENaC. In a study of hospitalized patients treated with standard doses of trimethoprim. with severe hyperkalemia (>5.550 in addition to basolateral Na+-K+-ATPase.19.19 Treatment FIGURE 17-13 Pharmacologic inhibition of the epithelial sodium channel (ENaC). It causes hyporeninemic hypoaldosteronism. circulating PRA and/or aldosterone levels have been reduced in hyperkalemia associated with COX-2 inhibitors.543. COX-2 inhibitors.19. eplerenone. as are drugs that inhibit epithelial sodium channels (ENaCs) in the renal tubule (collecting segment [CNT] or cortical collecting duct [CCD]).551 A provocative but preliminary report has linked acute hyperkalemia secondary to cyclosporine administration to indirect activation of KATP channels (see also earlier)493. pentamidine Nafamostat Renal tubule FIGURE 17-14 Medications that target the renin-angiotensin-aldosterone axis are common causes of hyperkalemia. this side effect is not restricted to high-dose intravenous therapy.558 Although trimethoprim and pentamidine directly inhibit ENaC.552-554 Trimethoprim thus inhibits Na+ reabsorption and K+ secretion in perfused CCDs. in contrast to the reported effect of aldosterone. Renin NSAIDS.104 Aldosterone induces expression of the membrane-associated proteases CAP1 to CAP3 (see “Aldosterone” section).26 so that hypovolemic patients may be particularly prone to hyperkalemia in this setting. triamterene Trimethroprim. . Nafamostat.101 Thus inhibition of the protease activity of CAP1 by nafamostat appears to abrogate its activating effect on ENaC (Figure 17-13) and may reduce expression of the protein in the CCD.147 Salt restriction potentiates the hyperkalemia seen in dogs treated with COX-2 inhibitors.19.5 mmol/L) in 21%. this is particularly intriguing given the reported response of cyclosporine-associated hyperkalemia to KATP inhibition with glibenclamide infusion.554 who are otherwise predisposed to hyperkalemia. cyclosporine causes redistribution of K+ and hyperkalemia.19 Finally. clinical reports have begun to emerge of hyperkalemia and acute renal failure associated with the use of COX-2 inhibitors.556 hyporeninemic hypoaldosteronism. The risk of sustained hyperkalemia may be higher in renal transplant patients treated with tacrolimus than in those treated with cyclosporine.548 due in part to its inhibitory effect on COX-2 expression in the macula densa.670 Section II Disorders of Body Fluid Volume and Composition COX-2–derived prostaglandins stimulate renal renin release19 and COX-2 inhibitors reduce PRA in both dogs26 and humans.547 Cyclosporine is perhaps the most versatile of all drugs in the variety of mechanisms by which it causes hyperkalemia.544 of rats with nafamostat was also shown to reduce the urinary excretion of CAP1/prostasin. Nafamostat – + – CAP ENaC + + Spironolactone Eplerenone – MLR Inhibition of the Epithelial Sodium Channel Inhibition of apical ENaC activity in the distal nephron by amiloride and other K+-sparing diuretics predictably results in hyperkalemia. which can also inhibit ENaC. a novel indirect mechanism for ENaC inhibition associated hyperkalemia has been reported. Whereas amiloride and related compounds directly inhibit the channel. thus indirectly inhibiting the channel. the protease inhibitor nafamostat inhibits membrane-associated proteases such as CAP1 (channel-activating protease 1). Amiloride Triamterene Trimethoprim Pentamidine Cyclosporine and Tacrolimus Both cyclosporine545 and tacrolimus546 cause hyperkalemia. canrenone. and several other target genes (see text for details). Spironolactone and related drugs inhibit the mineralocorticoid receptor. significant hyperkalemia occurred in more than 50%. direct renin inhibition.549 Cyclosporine inhibits apical SK secretory K+ channels in the distal nephron. Amiloride is structurally similar to the antibiotics trimethoprim and pentamidine.556 Risk factors for hyperkalemia due to normal-dose trimethoprim include renal insufficiency. the ENaC-activating kinase SGK (serum. which inhibits the mineralocorticoid receptor560 and can potentially cause hyperkalemia in susceptible patients.544 Where the data have been reported. is known to cause hyperkalemia.26. However.555 Both trimethoprimsulfamethoxazole (Bactrim) and pentamidine were reported to cause hyperkalemia during high-dose treatment of Pneumocystis pneumonia in HIV patients.557 and concomitant use of ACE inhibitors and ARBs.and glucocorticoid-regulated kinase).542 Not surprisingly. The oral contraceptive agent Yasmin 28 and related products contain the progestin drospirenone.104 Indirect evidence suggests that the mechanism involves inhibition of amiloride-sensitive Na+ channels in the CCD. and antagonism of the mineralocorticoid and angiotensin receptors559 (Figure 17-14). particularly when used in combination with β-blockers. The COX-2 inhibitor celecoxib and the nonselective NSAID ibuprofen have equivalent negative effects on K+ excretion after a defined oral load.
the following approach is recommended to prevent or minimize the occurrence of hyperkalemia in response to medications that interfere with the RAAS26. and/or mineralocorticoid receptor blockers should be stopped and the patient should be treated for hyperkalemia. B. The adrenal release of aldosterone due to increased K+ is clearly dependent on an intact adrenal renal-angiotensin system.. reduce the drug dosage and reassess the possible contributing factors.559 in part due to the use of higher than recommended dosages. Cockcroft-Gault equation. volume depletion. for that matter. and CKD increase the risk of hyperkalemia from these agents. albeit in conjunction with spironolactone.6 mmol/L. diet and dietary supplements (e. heart failure.) K. patients with diabetes.563. The patients at risk for the development of hyperkalemia in response to drugs that target the RAAS. H. This should be followed by a comprehensive workup to determine the cause (Figure 17-15).565 Heart failure.73m2.572 It should also be emphasized that the development of hyperkalemia—or. blood pressure. If the plasma K+ concentration is above 5.Chapter 17 Disorders of Potassium Balance As with many other causes of hyperkalemia. . I. are those in whom the ability of the 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 671 CCD (as in congestive heart failure. Aliskiren has also been reported to cause acute renal failure with acute hyperkalemia. given the increasing indications for combining spironolactone or aliskiren with ACE inhibitors and/or ARBs in renal and cardiac disease. (4) chronic tubulointerstitial disease. NSAIDs. and volume status. K+-sparing diuretics) and.567 In these susceptible patients. that induced by pharmacologic targeting of the RAAS axis depends on concomitant inhibition of adrenal aldosterone release by hyperkalemia.g. reduction in urine output. COX-2 inhibitors. Overall. A combination of a mineralocorticoid receptor blocker and either an ACE inhibitor or an ARB should not be prescribed to patients with stage 4 or 5 CKD (estimated GFR of <30 mL/min/1. NSAIDS.573: A. salt substitutes. singly or in combination therapy. (2) decreased circulating aldosterone level (hyporeninemic hypoaldosteronism. Juurlink and colleagues569 studied the correlation between the rate of prescription of spironolactone for Canadian patients with heart failure who were taking ACE inhibitors and the occurrence of hyperkalemia and associated morbidity before and after publication of the results of the Randomized Aldactone Evaluation Study (RALES). licorice) and prescribe a low-potassium diet. discontinue these agents.566.19 Notably.566. The history and physical examination should focus on medications (e. (3) inhibition of amiloride-sensitive Na+ channels in the CNT and CCD. and (5) increased potassium intake (salt substitutes. by coadministration of trimethoprim-sulfamethoxazole. and/or mineralocorticoid receptor blockers. ARBs. the association remained statistically significant for admissions in which hyperkalemia was the primary diagnosis. Continue or initiate use of loop or thiazide-like diuretics depending upon the GFR. ACE inhibitors. with associated dysfunction of the distal nephron. salt substitute). Inquire about diet and dietary supplements (e. etc. ARB. and/or mineralocorticoid receptor antagonists. C.). and/or 24-hour creatinine clearance. F. G. the presence of predisposing factors for hyperkalemia—does not appear to mitigate the mortality benefits of eplerenone in treatment of heart failure.. all but one should be stopped and potassium level rechecked.g.5 mmol/L). Clinical Approach to Hyperkalemia The first priority in the management of hyperkalemia is to assess the need for emergency treatment (e. if appropriate. etc. trimethoprimsulfamethoxazole).567 The prevalence of hyperkalemia associated with the combined use of mineralocorticoid receptor antagonists and ACE inhibitors and ARBs appears to be much higher in clinical practice (approximately 10%)568 than that reported in large clinical trials.).559. risk factors for kidney failure. pentamidine.g.). If the plasma K+ concentration is increased but is less than 5.561 ACE inhibitors and ARBs have the additional potential to cause acute renal failure and acute hyperkalemia in patients with an angiotensindependent GFR. a study in the United Kingdom found a similar increase in spironolactone use after the publication of RALES results. ARBs. Estimate GFR using the Modification of Diet in Renal Disease (MDRD) equation. particularly those that can interfere with renal K+ excretion (e.. Dual treatment with lisinopril and spironolactone in patients with CKD is also associated with a reduction in extrarenal potassium disposition.571 However.559. E. K+ ≥ 6. Correct acidosis with sodium bicarbonate. diabetes. with a temporal correlation with increases in the rate of hyperkalemia in patients admitted to hospital569. given that reduced K+ excretion alone does not explain the substantial increase in plasma K+ after a defined oral potassium load. etc.570 Their provocative study found an abrupt increase in the rate of prescription of spironolactone after release of the RALES findings. followed by another measurement 1 week later. and/or CKD are at particular risk for hyperkalemia from RAAS inhibition. drugs such as heparin or ketoconazole. so that this response is abrogated by systemic ACE inhibitors and ARBs153 (see “Regulation of Renal Renin and Adrenal Aldosterone” section). high-potassium diet. presence of ECG changes. Check plasma K+ concentration 3 to 5 days after initiation of the therapy and after each dosage increment. Initiate treatment with a low dose of only one of the following agents: ACE inhibitor. ARBs.567 Given the mounting evidence supporting the combined use of ACE inhibitors. it is prudent to systematically adhere to measures that will minimize the chance of associated hyperkalemia and therefore allow patients to benefit from the cardiovascular and renal effects of these agents.562 RAAS inhibitors are an increasingly important cause of hyperkalemia.. or amiloride. The dosage of spironolactone in combination with ACE inhibitors or ARBs should be no more than 25 mg/day. Inquire about medications used. D..6 mmol/L. or mineralocorticoid receptor antagonist. but without an increase in hyperkalemia or hyperkalemia-associated admissions to hospital. If the patient is taking a combination of ACE inhibitors. J.g.564 in addition to the development of mineralocorticoid receptor antagonists with perhaps a greater potential for causing hyperkalemia.g. ACE inhibitors.
ECG. in part because there is no universally accepted definition for mild. Serial measurements of blood potassium concentration are key to appreciating the kinetics of any changes and assessing the response to therapy. depend on many other variables .g. and creatinine. NSAIDs. mannitol) • Hyperglycemia • Succinylcholine • ε-aminocaproic acid • Digoxin • β-blockers • Metabolic acidosis (non-organic) • Arginine infusion • Hyperkalemic periodic paralysis • ↓ Insulin • Exercise 8 Reduced tubular flow 5 Reduced distal K secretion (GFR 20 ml/min) Advanced kidney failure (GFR 20 ml/min) Reduced ECV α-Fludrocortisone TTKG 8 (Tubular resistance) TTKG 8 Low aldosterone Drugs • Amiloride • Spironolactone • Triamterene • Trimethoprim • Pentamidine • Eplerenone • Calcineurin inhibitors Other causes • Tubulointerstitial diseases • Urinary tract obstruction • PHA type I • PHA type II • Sickle cell disease • Renal transplant • SLE Renin High • Primary adrenal insufficiency • Isolated aldosterone deficiency • Heparin/LMW heparin • ACE-I/ARB • Ketoconazole Low • Diabetes mellitus • Acute GN • Tubulointerstitial diseases • PHA type II • NSAIDs • β-Blockers FIGURE 17-15 Clinical approach to hyperkalemia. plasma aldosterone level. TTKG. pseudohypoaldosteronism. PHA. plasma osmolality. ECV.5 mmol/l) Pseudohyperkalemia? No Yes No further action Treat accordingly Yes Evidence of increased and re-evaluate potassium load No History. GFR. See text for details. Treatment of Hyperkalemia Indications for the hospitalization of patients with hyperkalemia are poorly defined.0 or K ECG changes No Hyperkalemia (Serum K 5. SLE. Initial laboratory tests should include plasma levels of electrolytes. or severe hyperkalemia. Plasma and urine osmolality are required for calculation of the transtubular K+ gradient (see “Urinary Indices of Potassium Excretion” section). ACE-I. creatinine level. and urinary pH. cortical collecting duct. angiotensin receptor blocker.. systemic lupus erythematosus. blood urea nitrogen. human immunodeficiency virus. GN. transtubular potassium gradient. moderate. low-molecular-weight. effective circulatory volume. CCD. and the response of the TTKG to fludrocortisone may be necessary to determine the specific cause of an inappropriately low TTKG in hyperkalemia. plasma Mg2+ and Ca2+ levels. nonsteroidal antiinflammatory drugs. glomerular filtration rate. glomerulonephritis. LMW. Physical Examination and Basic Laboratory Tests Evidence of transcellular shift: No Yes Treat accordingly and re-evaluate Decreased urinary K excretion ( 40 mmol/day) Decreased distal Na delivery Urine NA 25 mmol/L Urine electrolytes TTKG • Hypertonicity (e. Plasma renin activity. electrocardiogram.672 Section II Disorders of Body Fluid Volume and Composition Emergency therapy Yes 6. The clinical sequelae of hyperkalemia. a complete blood count. which are primarily cardiac and neuromuscular. HIV. and electrolyte levels. osmolality. ARB. Angiotensin converting enzyme inhibitor.
of adrenergic activity.446.578 Calcium should be used with extreme caution in patients taking digitalis.Chapter 17 Disorders of Potassium Balance (e.575. hyperkalemia in patients with any ECG manifestation should be considered a true medical emergency and treated urgently.587 The effect of insulin on plasma K+ levels is independent of age. Antagonism of Cardiac Effects Intravenous calcium is the first-line drug in the emergency management of hyperkalemia. and immediate treatment.448.174 Calcium is available as calcium chloride or calcium gluconate (10-mL ampules of 10% solutions) for intravenous infusion.585. Plasma K+ ≥ 8. respectively. infused intravenously over 2 to 3 minutes and under continuous ECG monitoring..0 mmol/L. particularly into skeletal myocytes and hepatocytes (see “Factors Affecting Internal Distribution of Potassium” section).580 Administration of calcium also alters the relationship between Vmax and the resting membrane potential.575. continuous ECG monitoring.586 The recommended dose of insulin with glucose infusion is 10 U of regular insulin in 500 mL of 10% dextrose. acute deterioration of renal function.590 The effect of insulin on K+ level begins in 10 to 20 minutes. Given the limitations of ECG changes as a predictor of cardiac toxicity (see “Consequences of Hyperkalemia” section).581 Calcium gluconate582 is less irritating to the veins and can be administered through a peripheral intravenous line. even in patients with CKD and ESRD584-586 and in those in the anhepatic stage of liver transplantation.583 However. calcium chloride can cause tissue necrosis if it extravasates and must be administered through a central line. such as intravenous antibiotics. whereas bicarbonate is the most controversial.587. Each milliliter of 10% calcium gluconate and calcium chloride has 8. β2-agonists.g.591 In almost all patients.2 mmol/L after this treatment. peaks at 30 to 60 minutes.197. The necessary measures to treat the underlying conditions causing hyperkalemia should be undertaken to minimize the factors that are contributing to the hyperkalemia and to prevent future episodes. maintaining a more normal Vmax at less negative resting membrane potentials and thus restoring myocardial conduction.5 to 7.580 To prevent the precipitation of calcium carbonate. However. (2) rapid reduction in K+ concentration by redistribution into cells. further studies in vitro. The effect of the infusion starts in 1 to 3 minutes and lasts 30 to 60 minutes. acid-base status. and lasts for 4 to 6 hours. 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. .588).0 mmol/L) in the absence of ECG changes should be managed aggressively.26 Insulin can be administered with glucose as a constant infusion or as a bolus injection. However. The treatment of hyperkalemia is generally divided into three categories: (1) antagonism of the cardiac effects of hyperkalemia.579 Calcium raises the action potential threshold to a less negative value without changing the resting membrane potential.576-578 Urgent management of hyperkalemia constitutes recording of a 12-lead ECG.9 mg (0. 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.443. which is removal of K+ from the body.444 However.197.585. and during the anhepatic stage of liver transplantation have shown equal and rapid dissociation of ionized calcium from equal doses of calcium chloride and calcium gluconate.582 In this case.26 The recommended dose is 10 mL of 10% calcium gluconate (3 to 4 mL of calcium chloride). in animals.576 Adequate management and serial monitoring of plasma K+ concentration generally requires hospital admission.174.468 should not be overlooked.578 The dose should be repeated if there is no change in ECG findings or if the ECG abnormalities recur after initial improvement.591 The dose can be repeated as necessary. and (3) removal of K+ from the body. concentration dependent. the plasma K+ drops by 0. ECG changes other than peaked T waves. and the rate of change in plasma K+ concentration201-204). they are all temporary measures and should not be substituted for the definitive treatment of hyperkalemia.448. patients with severe hyperkalemia (K+ ≥ 6. and the existence of additional medical problems have been suggested as appropriate criteria for hospitalization. insulin with glucose is the most constant and reliable. plasma calcium level. in addition to the absolute value of the plasma K+ level. Of these treatments. and insulin with glucose all are used in the treatment of hyperkalemia to induce a redistribution of K+.585.577. so that less ionized calcium would be bioavailable in cases of liver failure or diminished hepatic perfusion. even in patients with normal calcium levels. which in fact may be impaired in patients with CKD and/or ESRD.68 mmol) of elemental calcium.22 mmol) and 27. which indicates that the release of ionized calcium from calcium gluconate is independent of hepatic metabolism.590.448. because hypercalcemia potentiates the toxic effects of digitalis on the myocardium.197 The recommended dose is 10 U of regular insulin administered intravenously followed immediately by 50 mL of 50% dextrose (25 g of glucose). given over 60 minutes (there is no further drop in plasma K+ concentration after 90 minutes of insulin infusion580. Redistribution of Potassium into Cells Sodium bicarbonate.174. The mutually antagonistic effects of Ca2+ and K+ on the myocardium and the protective role of Ca2+ in hyperkalemia have long been known.588 and of its hypoglycemic effect.197 Dietary restriction (usually 60 mEq/ day) with emphasis on the K+ content of total parenteral nutrition solutions and enteral feeding products (typically 25 to 50 mmol/L) and adjustment of medications and intravenous fluids are necessary. reproducible.5 to 1.583 This finding was attributed to a requirement for hepatic metabolism for the Insulin and Glucose Insulin has the ability to lower plasma K+ level by shifting K+ into cells.586. particularly under emergency conditions. admission to the hospital. calcium should not be administered in solutions containing bicarbonate. restoring the usual 15-mV difference between resting and threshold potentials reduces myocyte excitability. a bolus injection is easier to administer.577.448 and effective.589.574 These factors are likely to influence management decisions. 673 release of ionized calcium from calcium gluconate. in humans with normal hepatic function. Hidden sources of K+.444. This effect is reliable.443.2 mg (0.
674 Section II Disorders of Body Fluid Volume and Composition Despite glucose administration.484.580 Combined treatment with β2-agonists.5 0 p < 0.4 mmol/L.593 Its K+-lowering effect starts in few minutes. therefore. hypoglycemia may occur in up to 75% of patients treated with the bolus regimen described earlier.52. which is not available in the United States.5 to 1.477.5 mmol/L in total.0 Dialysis –1.585 Of note. a selective β2-agonist.) .446 To prevent this.598 in which bicarbonate was typically administered as a long infusion over many hours (not by intravenous push.592 and lasts for 2 to 6 hours. in addition to providing a synergistic effect with insulin in lowering plasma K+.591 A subset of patients with ESRD (approximately 20% to 40%) are not responsive to the K+-lowering effect of albuterol (ΔK+ ≤ 0.596 Treatment with albuterol may result in an increase in plasma glucose level (approximately 2 to 3 mmol/L) and. Shaw S.596 The results showed a significant decline in plasma K+ levels in almost all patients (mean = 1.1 ± 6. 1988.592 There is no significant increase in systolic or diastolic blood pressure with nebulized or intravenous administration of albuterol. The increase in heart rate is more pronounced with the intravenous form (approximately 20 beats/min) than with the inhaled form (approximately 6 to 10 beats/min). concluded that the K+lowering effect of bicarbonate is independent of changes in pH.4 mmol/L. there is.586.4 mmol/L).484 Administration of glucose in the absence of insulin may in fact increase plasma K+ concentration by increasing plasma osmolality.585. For example. one study tested the effects of weight-based dosing on plasma K+ levels.585. is the most widely studied and used. the use of glucose-containing solutions. It is available in oral.446 The recommended dose for inhaled albuterol is 10 to 20 mg of nebulized albuterol in 4 mL of normal saline.5 mmol/L.01 10 20 30 40 50 60 Duration of treatment. which later became the routine).597 Its use to treat acute hyperkalemia was based mainly on the results of small.599 One of these studies.484 In an attempt to reduce pharmacokinetic variability.595 Albuterol (in inhaled or parenteral form) and insulin with glucose have additive effects in reducing plasma K+ levels.599-601 sodium BicArBonAte Bicarbonate Plasma Potassium mmoL/L 0 Epinephrine –0.592 The recommended dose for intravenous administration. as noted earlier. after Ca2+. Its kaliopenic effect starts at about 30 minutes. given over 10 to 15 minutes.589 Administration of glucose without insulin is not recommended. confounding variables included the duration of infusion. range = 0. in heart rate.0 mmol/L446. Weidmann P. is maximal at about 30 to 40 minutes592. an effect of isotonic bicarbonate at 4 to 6 hours.599. Albuterol (Salbutamol). inhaled. and infrequent monitoring of plasma K+ level. They exert their effect by activating Na+-K+-ATPase and the NKCC1 Na+-K+-2Cl– cotransporter.5 beats/min (range = 6.60. the combined regimen may increase the heart rate by 15.2 to 1.589 In hyperglycemic patients with glucose levels of 200 to 250 mg/dL or more.585 β2-Adrenergic Agonists β2-Agonists are an important but underutilized group of agents for the acute management of hyperkalemia.9 to 1. inhaled over 10 minutes585 (nebulized levalbuterol is as effective as albuterol594).5 Insulin/glucose –1. et al: Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure. epinephrine.31 ± 0. or insulin in glucose.8 ± 10. heart rate increased by an average of 25.599 These observations were later confirmed by others. Am J Med 85:507-512.446. albuterol administered by metered-dose inhaler with spacer reduces plasma K+ level by approximately 0. because the endogenous insulin release may be variable.0 beats/min.3 mmol/L) in 30 to 90 minutes. and during hemodialysis. is 0.593 and lasts for 2 to 6 hours. and can decrease plasma K+ concentration by approximately 1. (From Blumberg A.585 The likelihood of hypoglycemia is greater when the dose of glucose given is less than 30 g. older. may reduce the level of hypoglycemia. it was ranked as the second-line treatment. (min) FIGURE 17-16 Changes in serum K+ during intravenous infusion of bicarbonate.5 to 2.592. both the intravenous and inhaled or nebulized forms are effective.478.592 Inhaled albuterol reduces plasma K+ levels by approximately 0. uncontrolled clinical studies with a very limited number of patients.592 However. reaches its peak at about 90 minutes. albuterol (or other β2-agonists) should not be used as a single agent in the treatment of hyperkalemia.446.5 mg of albuterol in 100 mL of 5% dextrose. it is prudent to use these agents with caution in patients with ischemic heart disease.5 to 48). which is frequently quoted.575.601 Blumberg and colleagues compared different K+-lowering modalities (Figure 17-16) and showed that bicarbonate infusion (isotonic or hypertonic) for up to 60 minutes had no effect on plasma K+ level in their cohort of ESRD patients on hemodialysis586.446 Bicarbonate prevailed as a preferred treatment modality for hyperkalemia for decades.60 However. infusion of 10% dextrose at 50 to 75 mL/hr and close monitoring of the blood glucose levels is recommended. of note. however.580. who failed to show any acute K+-lowering effects (within 60 to 120 minutes) for bicarbonate. in a survey of nephrology training program directors in 1989. typically 1 hour after the infusion.60. and intravenous forms. insulin should be administered without glucose and with close monitoring of plasma glucose level.448.446 It reduces plasma K+ levels by approximately 0. using 7 μg/kg of subcutaneous terbutaline (a β2agonist) in a group of ESRD patients.600 The role of bicarbonate in the acute treatment of hyperkalemia has been challenged. shifting K+ into hepatocytes and skeletal myocytes (see also “Factors Affecting Internal Distribution of Potassium” section).
issues of relevance in patients with renal failure. this requires large.618 Calcium-cycled resins may have other potential benefits. this regimen reduces plasma K+ concentration by 0.g. it may be of some benefit in this setting. the 11β-HSD2 enzyme protects colonic epithelial cells from illicit activation of the mineralocorticoid receptor by cortisol. has been reported with oral administration of SPS in water. hydrogen.617 Occasional constipation. however.608 However.3 mg/day of fludrocortisone.577 When bicarbonate administration is used to treat hyperkalemia.606 In patients with impaired renal function. (e.622 even though cAtion-exchAnge resins minerAlocorticoids . Treatment with glycyrrhetinic acid significantly increased the plasma ratio of cortisol to cortisone.575 Of note. versus 24% in the placebo phase. perhaps due to the lower median plasma K+ level. They are capable of binding to a variety of monovalent and divalent cations.611.614 The long-term safety of fludrocortisone treatment in patients with ESRD has not been established. 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.Chapter 17 Disorders of Potassium Balance A few studies have shown that metabolic acidosis may attenuate the physiologic responses to insulin and β2agonists.. (2) intravenous agents (short-term treatment) with the least hepatic metabolism (e.613.603.612 The recommended dose is 0.338 As in other aldosterone-sensitive epithelia.617 which made the sodium-cycled resins preferable. bicarbonate infusion may have a limited role in the subacute control of hyperkalemia. SPS exchanges Na+ for K+ in the gastrointestinal tract. in those with systemic lupus erythematosus.586 675 Removal of Potassium Diuretics have a relatively modest effect on urinary K+ excretion in patients with CKD.472 it has been reported to cause hypernatremia. with 70% of predialysis values in the normal range (3.5 to 4.1 to 0.610 and in ESRD patients maintained on hemodialysis who have interdialytic hyperkalemia. doses of resin619.575. hydrogen.7 mmol/L and has not been associated with significant changes in blood pressure or weight (as a surrogate for fluid retention).620 The dominant resin clinically available in the United States is sodium polystyrene sulfonate (SPS).338 Plasma renin activity and aldosterone levels also dropped. Cation-exchange resins are classified based on the cation (i.. consistent with successful inhibition of 11β-HSD2. (3) combinations of loop and thiazide-like diuretics for better efficacy.601 In addition. Flinn and colleagues added sorbitol to the resin.1 mg/day of fludrocortisone in patients receiving long-term hemodialysis have shown statistically significant but clinically inconsequential effects on plasma K+ concentration.197. although this may decrease GFR due to activation of tubuloglomerular feedback. torsemide) and the least renal metabolism.3 mg of fludrocortisone is equal to 1 mg of prednisone with regard diuretics to glucocorticoid activity). ammonium.448.607 Limited data are available on the role of mineralocorticoids in the management of acute hyperkalemia.615 However.605.26.617 To prevent constipation and to facilitate the passage of the resin through the gastrointestinal tract. sodium.621 and has been shown to increase the fecal excretion of K+. the authors recommend isotonic infusion of sodium bicarbonate.601 The combined effect of bicarbonate and insulin with glucose has been studied with conflicting results.. use of the following agents is recommended: (1) oral diuretics with the highest bioavailability (e. Farese and colleagues tested the effect of the drug in a double-blind. these medications are useful in correcting hyperkalemia in patients with the syndrome of hyporeninemic hypoaldosteronism604 or selective renal K+ secretory problems (e. however.609 in kidney transplant patients taking cyclosporine. approximately half of this effect is due to volume expansion. moreover.603 particularly in an acute setting.610-612 In patients with ESRD maintained on hemodialysis. these resins have been associated with hypercalcemia. these agents have been used to treat chronic hyperkalemia in patients with hypoaldosteronism with or without hyporeninism. potentially toxic. more recent studies of a regimen of 0.601 In summary. bicarbonate and albuterol coadministration failed to show any additional benefit over albuterol alone.617. placebo-controlled trial involving 10 ESRD patients.599 Regardless of the mechanism.607 Use of the maximal effective “ceiling” dose is recommended. This effect was associated with a significant reduction in mean plasma K+ concentration. potassium. more extensive clinical testing is clearly required before widespread utilization.448.and ammoniumcycled resins were associated with metabolic acidosis616 and mouth ulcers.5 to 0. Prolonged infusion of isotonic bicarbonate in ESRD patients does reduce plasma K+ concentration at 5 to 6 hours by up to 0.g...7 mmol/L. or calcium) that is cycled during the synthesis of the resin to saturate sulfonic or carboxylic groups. Pharmacologic inhibition of 11β-HSD2 with glycyrrhetinic acid has also been tested as a novel mechanism to control hyperkalemia in patients with ESRD. easily controlled with enema or cathartics. furosemide rather than bumetanide). administration of bicarbonate. torsemide. after transplantation or administration of trimethoprim). mainly in the colon. the infusion of sodium bicarbonate may reduce serum ionized calcium levels and cause volume overload.578 However.e. bumetanide) to minimize the chance of accumulation and toxicity.g.611 However. although hypertonic sodium bicarbonate does not increase plasma K+ level. a synthetic glucocorticoid with potent mineralocorticoid activity and modest glucocorticoid activity (0. and given the minimal effect on plasma K+ concentration the authors do not recommend its use for the management of interdialytic hyperkalemia. Glycyrrhetinic acid is thus a promising agent for long-term management of plasma K+ in ESRD patients. has no role in the contemporary treatment of acute hyperkalemia. for example in the nondialytic management of patients with severe hyperkalemia.g.26. including a phosphate-lowering effect. In 1950 Elkinton and colleagues successfully used a carboxylic resin in ammonium cycle in three patients with hyperkalemia. however. especially as a single agent. Hypothesizing that glycyrrhetinic acid would activate extrarenal potassium secretion by the colon and other tissues.602 The acute effect of bicarbonate infusion on plasma K+ level in severely acidemic patients is not clear.7 mmol/L) in the glycyrrhetinic acid phase of the trial.
However. which can compete with potassium for binding to the resin. the effect occurs within 4 to 6 hours of administration. data demonstrating the efficacy and safety of these laxatives when used with SPS are not available. at best. although SPS is used in this chapter to denote sodium polystyrene sulfonate.577. Furthermore.625 Notably.625 The discrepancy is caused in part by the binding of small amounts of other cations.627 An increasing concern with oral SPS in sorbitol is intestinal necrosis caused by the administration of this preparation623. It should be administered warm (body temperature). SPS . Food and Drug Administration (FDA) removed recommendations for concomitant or postdosing use of sorbitol from the labeling of SPS in 2005. however. cases of intestinal necrosis have also been described with this preparation. SPS can be administered rectally as a retention enema in patients unable to take or tolerate the oral form.577. as noted earlier. It has since become routine to administer SPS with sorbitol. Many pharmacies and hospitals stock only SPS premixed with sorbitol.626 SPS in sorbitol should not be used for enemas. used multiple doses of the exchange resin orally or rectally as an enema and were associated with declines in plasma K+ levels of 1 mmol/L and 0. Regardless. The recommended dose is 30 to 50 g of resin as an emulsion in 100 mL of an aqueous vehicle (e.623 However.623 In response to these reports. flushed with an additional 50 to 100 mL of non–sodium-containing fluid. stating that concomitant administration of sorbitol is not recommended. clinicians must carefully consider whether emergency treatment with SPS is actually necessary for the management of hyperkalemia. if the patient has existing vascular access for hemodialysis the risk of intestinal necrosis outweighs that of the dialysis procedure. If a laxative other than sorbitol is coadministered. 20% dextrose in water) every 6 hours. In patients with advanced renal failure. has also been reported.578.578. the FDA allowed continued marketing of the most frequently used premixed SPS in sorbitol suspension.623.631 which directly implicates SPS in the intestinal injury. given the delayed hypokalemic response and the risk of potentially fatal intestinal necrosis. retained for at least 30 to 60 minutes.624. Clinicians must weigh the relative risk of using this preparation in the management of acute hyperkalemia. this is frequently a fatal complication.628 Notably. if SPS is judged to be appropriate in the management of hyperkalemia (see later). without sorbitol.623.617. In patients with intact renal function alternative measures such as hydration to increase distal tubular delivery of Na+ and distal tubular flow rate.g. SPS is in fact also a brand name for sodium polystyrene sulfonate in sorbitol.2 mEq of K+ in exchange for 2 to 3 mEq of Na+. including some associated with the use of SPS in 33% sorbitol.623 Although there are indications that SPS preparations with 33% sorbitol carry a lesser risk. SPS crystals can often be detected in human pathologic specimens. out of 117 patients who received SPS with sorbitol within a week of surgery. the use of SPS is reasonable as a temporizing maneuver while awaiting hemodialysis. adherent to the injured mucosa.676 Section II Disorders of Body Fluid Volume and Composition the occurrence of constipation and impaction had not been reported in an earlier study618 of SPS use cited by these authors. The risk of intestinal necrosis appears to be greatest when SPS is given with sorbitol within the first week after surgery.8 mmol/L in 24 hours.S. One study of healthy subjects compared the rate of fecal excretion of K+ by different laxatives with or without 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. given the risk of colonic necrosis. however.617 This temporal limitation should be taken into consideration when deciding whether or not to administer SPS in acute hyperkalemia. it has become common to order only a single dose of resin-cathartic in the management of acute hyperkalemia.623 As a result. however. which indicates the frequency with which these agents are administered together. One study has addressed the efficacy of this practice. SPS without sorbitol is typically available as a powder that must be reconstituted with water.617 With the advent of routine hemodialysis. it should not contain potassium or other cations such as magnesium or calcium. given that it contained only 33% sorbitol. if hemodialysis is available within 1 to 4 hours the authors question the need for SPS. and/or administration of diuretics are often sufficient for potassium removal. given the role of the SPS resin itself in this complication.617 The oral dose is usually 15 to 30 g.629-631 SPS without sorbitol is rarely available in the United States.630 A case of colonic necrosis following oral SPS alone.627-630. two patients developed intestinal necrosis. only 2 out of 11 confirmed cases occurred in the postoperative setting. the laxative should not contain phosphorus. in a recent case series examining intestinal necrosis associated with SPS in sorbitol. and followed by a cleansing enema (250 to 1000 mL of body-temperature tap water).623 Given these serious concerns.632 There are minimal data on the efficacy of SPS within the first 24 hours after administration for hyperkalemia623.629. however.5 to 1. the U. which can be repeated every 4 to 6 hours.623 In any case.578. repeated doses are usually required for an adequate effect. in September 2009 the FDA changed the safety labeling for SPS powder.629 Although most cases of intestinal necrosis have occurred in patients receiving SPS in 70% sorbitol it has also been reported in patients receiving SPS in 33% sorbitol.629 Studies in experimental animals suggest that sorbitol is required for the intestinal injury627. after a cleansing enema with body-temperature tap water.617 The hypokalemic effect may be due partly to the coadministered laxative. After this labeling change. the preparation ideally should not contain sorbitol. None of the regimens used reduced the plasma K+ concentration below the initial baseline.576 It should also be noted that administering SPS without sorbitol might not eliminate the risk of intestinal necrosis. evaluating the effect of four different single-dose resin-cathartic regimens on the plasma K+ levels of six patients with CKD on maintenance hemodialysis. For example. respectively. Reasonable laxatives for this purpose include lactulose and some preparations of polyethylene glycol 3350. mostly before the era of long-term hemodialysis. In patients with renal insufficiency. Each gram of resin binds 0.578.576.576 The effect of ingested SPS on plasma K+ concentration is slow. with approximately 5 million doses administered annually in the United States alone. The emulsion should be introduced by gravity. through a rubber tube placed at about 20 cm from the rectum with the tip well into the sigmoid colon. If SPS is administered. it may take from 4 to 24 hours to see a significant effect on plasma K+ level. more cases of intestinal necrosis were reported. the subjects in this study were normokalemic..627.624 Earlier studies of SPS.623 Notably.
with concomitant intracellular shift of K+. However.638 An average 3.641. The use of a high concentration of bicarbonate was associated with a more rapid decline in plasma K+ level.580 However.626 All modes of acute renal replacement therapy are effective in removing K+. blood flow rate. although neither of these differences was statistically significant.650 Several studies have found an increased incidence of significant arrhythmia with hemodialysis. the total amount of K+ removed was higher with the low-bicarbonate dialysate (116. although not very effective in an acute setting.616 interference with lithium absorption.653 However. has been used effectively in cases of cardiac arrest complicating acute hyperkalemia. the insulin level is 50% lower when glucose-free dialysates are used. Continuous hemodiafiltration is increasingly used in the management of critically ill and hemodynamically unstable patients.637 Peritoneal dialysis is capable of removing significant amounts of K+ (5 mmol/hr or 240 mmol in 48 hours) using 2-L exchanges.641 Discrepencies among reported findings are likely due to differences in the glucose content of the dialysate utilized.634 volume overload.e.6 mmol per dialysis) than with the standard-bicarbonate dialysate (73. Continuous cardiac monitoring for all patients undergoing dialysis with a 0. 35 mmol/L (standard).645 Many nephrologists use the “rule of 7s” to set the dialysate K+ concentration: the plasma K+ concentration plus the dialysate K+ concentration should equal approximately 7. then dialysate with a K+ concentration of 0. dialysates with a very low K+ concentration may increase the risk of significant arrhythmia. coronary artery disease.642.635 and iatrogenic hypokalemia.8 mmol per dialysis) and high-bicarbonate dialysate (80. in turn. an acute decrease in plasma K+ level can be associated with rebound hypertension (i. it seems prudent to recommend that dialysates with a very low K+ concentration (0 or 1 mmol/L) be used cautiously.650-652 An incidence of up to 76% has been reported.640 Glucose-free dialysates are more efficient in removing K+.640 Furthermore.650 The K+ concentration of the .657 In this regimen. however.649 Finally.639 which is attributed in part to the peripheral vasoconstriction that is a direct result of the change in plasma K+ concentration. this difference was statistically significant for comparisons of both high-bicarbonate versus standard-bicarbonate dialysates 677 diAlysis and high-bicarbonate versus low-bicarbonate dialysates at 60 and 240 minutes. examining the effect of dialysate bicarbonate concentration on both plasma K+ level and K+ removal. occurring during and immediately after treatment. or high systolic blood pressure. these findings imply that K+ removal may be greater if hemodialysis is performed with the patient in a fasting state.9 ± 15.636 Peritoneal dialysis. an alternative approach has been proposed for the treatment of significant hyperkalemia. Dialysates with K a lower K+ concentration are more effective at reducing plasma K+ concentration. about 40% of the difference in removal cannot be explained by the aforementioned factors and may instead be related to the relative distribution of K+ between intracellular and extracellular spaces. with each exchange taking almost an hour.638 The change in pH during dialysis has been thought to have no significant effect on K+ removal. Dialysates with bicarbonate concentrations of 39 mmol/L (high). dialysis duration.26.26. and plasma/dialysate K+ gradient.639 This vasoconstriction. differences in circulating insulin may have had additional. prospective study did not confirm this finding.2 to 1.or 1-mmol/L K+ bath is strongly recommended. and those of advanced age.638-645 Approximately 15% of the total K+ removal results from ultrafiltration.641. this advantage is potentially mitigated by a lower total removal of the ion over the course of a typical treatment session. which will immediately lower the plasma K+ concentration in a slower and perhaps safer manner.640. A rapid decline in plasma K+ concentration due to the use of 0K or 1K dialysate can have deleterious effects due to several mechanisms.2 ± 12. and the remainder is from intracellular compartments.645. If this rule were followed. a significant increase in blood pressure 1 hour after dialysis).643 This effect may be caused by alterations in endogenous insulin levels.643 In most patients.638.to 4-mEq/L K+ bath.to 5-hour hemodialysis session removes approximately 40 to 120 mmol of K+.4 mmol per dialysis). the plasma K+ concentration usually reaches its nadir at about 3 hours. and 27 mmol/L (low) were utilized. particularly in patients at high risk. One of the major determinants of total K+ removal is the + gradient between the plasma and dialysate.26 although a randomized. This definition includes patients receiving digitalis.642 The amount of K+ removed depends primarily on the type and surface area of the dialyzer used.654-656 Some have suggested that a relationship exists between decreases in plasma K+ concentration. although at significantly lower rate. left ventricular hypertrophy. However. dialysate flow rate. and renal transplant recipients. patients with a history of bowel obstruction.448.448 Given the risk of inducing arrhythmias with very low-K+ dialysates.Chapter 17 Disorders of Potassium Balance with sorbitol should not be used in patients at higher risk for intestinal necrosis. Finally. although high-bicarbonate dialysis may acutely have a more rapid effect on plasma K+ level. the greatest decline in plasma K+ (1. K+ removal continues until the end of the hemodialysis session.4 ± 21.650 Despite the controversy. hemodialysis is the preferred mode when rapid correction of a hyperkalemic episode is desired. including postoperative patients.640. those with a history of arrhythmia. which promotes arteriolar constriction. although the clinical significance of these findings is not known. and the incidence of significant arrhythmias.633 Other potential complications include reduction of plasma calcium level. oral SPS with sorbitol can also injure the upper gastrointestinal tract.5 mmol/L) and the largest amount of K+ removal occur during the first hour. may reduce the efficiency of dialysis.646 A recent study evaluated this issue in detail. with the remaining clearance from dialysis. patients with ischemic bowel disease.646 Of the total K+ removed.646 Treatment with β2-agonists also reduces the total K+ removal by approximately 40%. a low plasma K+ concentration can alter the rate of tissue metabolism—the so-called Solandt effect648—and decrease tissue oxygen consumption.642.639 Second. patients with slow intestinal transit. about 40% is from extracellular space. First.0 or 1. unrelated effects on muscle blood flow. many investigators do not consider the hemodialysis procedure to be significantly arrhythmogenic.. Despite a relatively constant plasma K+ concentration thereafter.647 Therefore. dialysis is initiated with a 3.0 mEq/L (“0K” or “1K” bath) would need to be used for patients with plasma K+ concentrations exceeding 6 to 7 mmol/L. dialysate K+ concentration.
23. Dotin LN. This phenomenon can be especially marked in cases of massive release from devitalized tissues (e. with less effect on ventricular ectopy. Effect of insulin on renal potassium metabolism. 2006. Zandi-Nejad K. 1980.13(4):209-216. 3rd ed. Ryan DP. Impairment of extrarenal potassium disposal by α-adrenergic stimulation. 12. Epstein FH. 2. et al. et al. Proc Natl Acad Sci U S A. Clausen T. Graf D. 7th ed. Wang Q. 24. We recommend restricting the upfront use of these low-K+ baths to patients with life-threatening hyperkalemic arrhythmias and/or life-threatening conduction abnormalities. Nielsen JJ. Warnock DG. even removal of potassium658 than dialysis using a fixed-K+ bath (2. et al. Clinical and therapeutic significance of the Na+. Wong JA. Clausen T.657-659 For the management of severe hyperkalemia (plasma K+ ≥ 7. 8. Am J Physiol.14:497-501. Skeletal muscle regulates extracellular potassium. Serum immunoreactive insulin and growth hormone response to potassium infusion in normal man. Leong PK.646 a high predialysis plasma K+ concentration. Woo AL. 25. 36. Severe hyperkalaemia resulting from octreotide use in a haemodialysis patient. McKenna MJ. DeFronzo RA.103:2805-2808.282:20207-20212. rhabdomyolysis) and requires frequent monitoring of plasma K+ and further hemodialysis. 1984. Boini KM. Gamba G. Independent stimulation of glucose metabolism and Na+-K+ exchange by insulin in the human forearm. 1978. Yu M. K-pump in skeletal muscle.643:69-77.642 particularly in those patients with a high predialysis K+ concentration. et al. Effects of training on potassium homeostasis during exercise. Brenner and Rector’s the kidney. 21. J Clin Invest. 2000. 1972. However. Phosphoinositide-3 kinase binds to a proline-rich motif in the Na+. Knight KK. Larsen JS. Rossetti L. I. Lingrel JB. Zandi-Nejad K. 32. J Mol Cell Cardiol. Sargent AI. Disorders of potassium balance. et al.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Significance of sodium pump isoforms in digitalis therapy. et al. et al. Li D. Thomason DB. 42. ed. Philadelphia: Saunders. Extrarenal potassium metabolism. 2006. N Engl J Med. 33. kidney transport. J Biol Chem. 28. 15.77:1063-1069. K+ supplementation increases muscle [Na+-K+-ATPase] and improves extrarenal K+ homeostasis in rats. Am J Physiol. A more sophisticated approach uses potassium profiling to maintain a constant K+ gradient during dialysis. Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC. 20. Rosa RM. Liddle’s syndrome mutations increase Na+ transport through dual effects on epithelial Na+ channel surface expression and proteolytic cleavage. ACTH-induced hypertension is dependent on the ouabain-binding site of the α2-Na+-K+-ATPase subunit. Crambert G. 18. Am J Physiol Renal Physiol.282:F967-F974. et al. et al. Duality of G protein–coupled mechanisms for β-adrenergic activation of NKCC activity in skeletal muscle. Effects of terbutaline and isoproterenol on hyperkalemia in nephrectomized rabbits.554:857-870. In: Brenner BM. 26. 1995. K-ATPase isozymes. 38. tumor lysis. Akimova O.27:1001-1009. Klein-Robbenhaar G. et al. Am J Physiol Heart Circ Physiol. Silva P.0 mEq/L) the authors favor the use of stepped reduction or potassium profiling of dialysate K+ concentrations. K+-ATPase alpha subunit and regulates its trafficking. Knochel JP.644 16. K-ATPase. Am J Physiol Regul Integr Comp Physiol.3:555-563. In: Brenner BM.657-659 Potassium profiling results in more sustained. Schoder R. Kuhl D. Zhou R. K+-ATPase activity in kidney proximal tubule cells depends on phosphorylation of the α-subunit at Tyr-10.311:145-149. Mechanisms of sodium pump regulation. Ferrannini E. 43. 2002. Youn JH. Juel C. despite technically adequate treatment. Molecular physiology of cation-coupled Cl– cotransport: the SLC12 family. et al. 10. J Biol Chem. Koechig I. James PF. J Mol Cell Cardiol. 31.51:242-255. 2003. Identification of a specific role for the Na. McDonough AA. Kidney Int. et al. Clin Sci (Lond). 4.10:2847-2859. 44.278:R400-R406.252:F60-F64. Wang J. Insulin-induced stimulation of Na+.447:580-593. Choi CS. 9.. Brenner and Rector’s the kidney. Pflugers Arch. 14. 2001.5 mEq/L). 2000. Acta Physiol Scand Suppl.457:955-961. . Croyle ML. Studies with somatostatin in normal dogs and in normal and diabetic human beings. 45. 1988. eds. Am J Physiol.642 and higher dialysate Na+ concentrations. Gitman M. Disorders of potassium balance. Am J Physiol Cell Physiol. Adabala M. et al.97:6556-6561. Pharmacotherapy. J Clin Invest. Octreotide-induced hyperkalemia. et al. Giebisch G.58:721-730. Hamburger RJ. Kidney Int. Gosmanov AR. Mechanisms of potassium depletion. Briggs AP.25:924-927. Effect of graded doses of insulin on splanchnic and peripheral potassium metabolism in man. Welling PA. et al. FEBS Lett. 34. 2010. Philadelphia: Lippincott Williams & Wilkins. et al. Olson DR. 1934. 1978. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. 1997. McDonough AA. 5.238:E421-E427. K-ATPase alpha 2 isoform as a regulator of calcium in the heart. et al.25:3439-3442. J Physiol. Ligand binding sites of Na. Pathophysiology. Delpire E. 30. 2000:1552-1573. Scand J Urol Nephrol. Nielsen JJ. 3. Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines. Doisy EA. 1995. Bubien JK. 19. Hebert SC. 2006. Mol Cell. Dluhy RG.82:393-398.280:F95-F102. Overton CC. Farley RA.and alpha(2)-subunit isoforms.279:C541-C566. Bundgaard H. Cell. food consumption early in the dialysis session. 1999. Yudowski GA. DeFronzo RA. Therien AG. Factors that attenuate K+ removal and thus increase the risk and magnitude of postdialysis rebound include pretreatment with β2-agonists. 22. Thompson CB. Multigene kinase network. et al. J Biol Chem. 2008.12:35-38. 29. Williams ME. Everts ME. Mount DB. Mutations in potassium channel Kir2.33:22-26. Giebisch G.95:3-17. Kuwik RJ. A rebound increase in plasma K+ concentration can occur after hemodialysis. 2007:547587. K(+)-ATPase trafficking in skeletal muscle: insulin stimulates translocation of both alpha(1). 13. 41. References 1. 1999. 2009. 1924. 2010. Am J Physiol. and salt in essential hypertension. Chang YP. Modest dietary K+ restriction provokes insulin resistance of cellular K+ uptake and phosphorylation of renal outer medulla K+ channel without fall in plasma K+ concentration. a rebound increase may also occur in ESRD patients during regular maintenance hemodialysis. 17. Rosa RM. Al-Khalili L. The Na+/K+-ATPase as [K+]o sensor: role in cardiovascular disease pathogenesis and augmented production of endogenous cardiotonic steroids. 1999.82:1136-1144. Na(+). Lorenz JN.638 pretreatment with insulin and glucose. Nat Genet.678 Section II Disorders of Body Fluid Volume and Composition dialysate may then be lowered in a stepwise fashion with each subsequent hour of dialysis. SGK1 dependence of insulin induced hypokalemia. 1987. Williams GH. 1994.255:E953-E958.27:941-949. K+ pump*. J Appl Physiol.295:H273-H280. which we also avoid at the beginning of dialysis sessions for treatment of acute hyperkalemia. J Appl Physiol. Philadelphia: Saunders. Mount DB. Chibalin AV. 39. 37. 2000. Effects of high-intensity intermittent training on potassium kinetics and performance in human skeletal muscle. Pathophysiology of intense physical conditioning in a hot climate. D’Silva JL. The kidney: physiology and pathophysiology. Chen P. Am J Physiol Cell Physiol. Some changes in the composition of blood due the injection of insulin. 2004.35:372-376. 2000. Nephrol Dial Transplant. 2010. 2009. et al. Ferrannini E.290:C1355-C1363. 1998. Interstitial K(+) in human skeletal muscle during and after dynamic graded exercise determined by microdialysis. The action of adrenaline on serum potassium. 2003. 2004. Influence of basal insulin and glucagon secretion on potassium and sodium metabolism. Guo J. ed. et al. 6. 7. 27. J Physiol.35:1-13. Zhou R. et al. In: Seldin DW. Axelrod L. Feraille E. 11. Thompson CB. 1998. 2004:997-1040. 2007.119:2745-2757. Mol Biol Cell. Felig P. et al.275:1976-1986.140:88-98.g. Persson S. Patel SV. We rarely encounter the need to use 1K or 0K dialysate baths. Am J Physiol Cell Physiol. Hamet P. Blostein R. Regulation of the Na.536:198-202. 2002. 1995. Sweeney G. J Clin Invest. Tremblay J. Pflugers Arch. Mount DB.61:472-479. Liddle’s syndrome: a public health menace? Am J Kidney Dis. Schmidt TA.276:H2109-H2116. Jhaveri KD. Proc Natl Acad Sci U S A. Am J Physiol Renal Physiol. et al. Olsson AM. et al. 35. Snyder PM. et al. 40. Pilegaard H. vol 2. 1989. et al. Participation of PI3K and atypical PKC in Na+-K+-pump stimulation by IGF-I in VSMC. Transport and pharmacological properties of nine different human Na.283:C1025-C1032. Short-term K(+) deprivation provokes insulin resistance of cellular K(+) uptake revealed with the K(+) clamp. 1972. Kahle KT.
A controlled randomized trial. 2004. 107. 71. Kidney Int. et al. Lin DH. Orringer CE. Kleyman TR. Cleaveland ES. Palmer LG.106:11800-11805. 67.284:F381-F388. et al. et al. J Am Soc Nephrol. Gennari FJ. 2006. Bailey MA.284:35659-35669. 1998. Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach. J Biol Chem. Changes in plasma potassium concentration during acute acid-base disturbances. 1985.246:C415-C421. Canessa CM. 2006. 70. et al. An epithelial serine protease activates the amiloride-sensitive sodium channel. Proc Natl Acad Sci U S A. Lewis DW. and this transcriptional response is mediated via distinct cis-elements in the 5′-flanking region of the gene. Jaeger NF. Acute metabolic acidosis: characterization and diagnosis of the disorder and the plasma potassium response. Regulation of apical K channels in rat cortical collecting tubule during changes in dietary K intake. Rubidium absorption and proton secretion by rabbit outer medullary collecting duct via H-K-ATPase. 1959. 2001. Grimm PR. J Am Soc Nephrol. AF17 competes with AF9 for binding to Dot1a to up-regulate transcription of epithelial Na+ channel alpha. Snyder PM. 1994. Malnic G. Adrogué HJ. 86. Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK.263:F849-F857. 2003. Am J Physiol. 105. Vallet V.62:1-9. Grafe P. 52.241:F395-F402. et al. 59. Lutz T.146:5079-5085. Am J Physiol Renal Physiol. Hyperkalemia: an adaptive response in chronic renal insufficiency. et al. BK channels in the kidney: role in K(+) secretion and localization of molecular components.93:15370-15375. Williams ME. 69. Castro A. 51. 2009.15:575-588. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. 85. 2001.and glucocorticoid-regulated kinase (Sgk1) in Xenopus oocytes. Tauxe C. Catecholamine modulation of rapid potassium shifts during exercise. 97. Loffing J. 1979. Olson DR.71:456-467. 2005. Fraley DS. Hughey RP. Wingo CS. Am J Physiol Renal Physiol. 1964. J Gen Physiol.35:935-939. Gamba G. 2002. Am J Physiol. 2004. 65. sgk is an aldosteroneinduced kinase in the renal collecting duct. et al. 102. 1992. . Fulop M. Aldosterone and potassium secretion by the cortical collecting duct.75:566-573. Irsik DL.277:5-8. Miner Electrolyte Metab. Loffing J. Fenn WO. 48. ENaC at the cutting edge: regulation of epithelial sodium channels by proteases. Perez G.280:F675-F682.297:796-799. Muto S. 49. Vallet V. 106. Acute respiratory acidosis does not increase plasma potassium in normokalaemic anaesthetized patients. Serum potassium in lactic acidosis and ketoacidosis. The effect in humans of extracellular PH change on the relationship between serum potassium concentration and intracellular potassium. J Am Soc Nephrol. Kidney Int. Fay FS. 99. et al. Adler S. 2002. Correction of hyperkalemia by bicarbonate despite constant blood pH. 2002. Identification and localization of BK-β subunits in the distal nephron of the mouse kidney. J Biol Chem. Am J Physiol Renal Physiol. et al. Effects on epithelial Na+ channels. 1999. Vuagniaux G.281:F469-F477. Gaeggeler HP. 1988.82:1071-1074. Giebisch GH. Am J Physiol Renal Physiol. 679 78. 2006. Sansom SC. Madias NE. 2002. 2004. A trail of research on potassium. Madias NE. Grimm PR.62:14981512. Wulff P. Thomas BC. Frindt G. et al. 55. 56. Findling JW.312:823-827. et al. Oster JR. Naray-Fejes-Toth A. 79. Giebisch G. Eur J Anaesthesiol. J Clin Endocrinol Metab. 100. 2001. Wiederseiner JM. Kidney Int. 1997. Nature. Wunsch CD. 1999. Musa-Aziz R. Edvinsson J. Am J Physiol. Armitage FE.and low-Na diets. Role of luminal anion and pH in distal tubule potassium secretion. Potassium transport in the mammalian collecting duct.286:F669-F674.81:85-116. 1934. Kidney Int. Natalini G. Raff H. J Am Soc Nephrol.38:1124-1132. 91. Renal potassium transport: mechanisms and regulation. J Clin Invest. Kidney Int. 92. 2001. Iwashita K.206:674-686. 2003. Adrogué HJ. 1997. Vlassopoulos D. Muser J. Hansson JH.197:319-326. 2000. Am J Physiol Renal Physiol.28:411-418. Endocrinology. Palmer LG. Kidney Int. Canessa C. et al. 1995.12:354-360. 2001. et al. Frindt G. 2004. Am J Physiol Renal Physiol. Klose RM. 73. J Biol Chem. Lalioti MD. Loffing J. J Biol Chem.222:506-515. 64. et al. Carattino MD. 88.277:F805-F812.47:217-224. Mount DB. 2001. Amorim JB. Am J Physiol.Chapter 17 Disorders of Potassium Balance 46. et al. 1994. 81. 80. 84. Lu M. et al. 2004. Rieg T. Narikiyo T. 94. 1984. J Clin Invest. Settles DC. 76. 62. Frindt G. Abrams WB.17:629-656. 1951. Nature. 2004. J Gen Physiol.104:693-710.274:16973-16978.297:F389F396. 2009. Am J Med Sci. Long-term management of sevelamer hydrochloride–induced metabolic acidosis aggravation and hyperkalemia in hemodialysis patients. Kamynina E. Impaired regulation of renal K+ elimination in the sgk1knockout mouse. Brenner R. Am J Physiol. Proc Natl Acad Sci U S A.283:F923-F933. The effect of acidosis and alkalosis on the plasma potassium concentration and the electrocardiogram of normal and potassium depleted dogs. Burnell JM. 2002. Curr Opin Nephrol Hypertens. J Biol Chem. Krapf R. Am J Physiol Renal Physiol. Staub O. 1981.287:F593-F601. 2007. Micropuncture study of renal potassium excretion in the rat.110:1263-1268. Palmer LG. Plasma potassium response to acute metabolic acidosis induced by mineral and nonmineral acids. 101. Palmer LG. 103. Eustace JC. et al. 57. 1980. Potassium secretion by cortical collecting tubule: relation to sodium absorption. 90. Protein tyrosine kinase is expressed and regulates ROMK1 location in the cortical collecting duct. 2000. Am J Physiol Renal Physiol. Regulation of apical K and Na channels and Na/K pumps in rat cortical collecting tubule by dietary K. Scheid CR.296:F347-F354. Warnock DG. Pflugers Arch. Am J Physiol Renal Physiol. et al.14:11-16. Hypertension of Kcnmb1–/– is linked to deficient K secretion and aldosteronism. Changes in intracellular ion activities induced by adrenaline in human and rat skeletal muscle. Ren Fail. 89.279:F252-F258. Uyeno BT. Cobb DM.293:F350-F359. et al. Chraibi A.109:401-408. et al. et al.262:F488-F493. 54. 95. Wagdi P. J Clin Invest.120:191-201. Nat Genet. Active potassium absorption by the renal distal tubule. and transepithelial voltage. Meneton P. 83. et al. Differential subcellular localization of ENaC subunits in mouse kidney in response to high. 1977. 2009. and mCAP3) and serum. Am J Physiol Renal Physiol. et al. mCAP2. Fujita T. N Engl J Med. 53. N Engl J Med. Pluznick JL. Shah A. et al. Inhibition of prostasin secretion by serine protease inhibitors in the kidney. N Engl J Med. Acid-base alterations and plasma potassium concentration.332:687. 2002. 2002. Firsov D. 75. et al. 2007. PCO2 and [K+]p in metabolic acidosis: certainty for the first and uncertainty for the other. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. 1995. Antonian L. 50. 68. J Gen Physiol.15:885-891. Physiol Rev. Renal K-Cl cotransporters. 2004. A model for the study of an anion-gap acidosis not associated with hyperkalemia.274:F817-F833. The potassium equilibrium in muscle. Nielsen J. Am J Physiol. Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. Plasma potassium response to acute respiratory alkalosis. Snyder PM. 1981. et al. Simmons DH. The role of the BK channel in potassium homeostasis and flow-induced renal potassium excretion. Palmer LG. Ballanyi K. Velazquez H.367:463-467. 87. Frindt G. The α-subunit of the epithelial sodium channel is an aldosterone-induced transcript in mammalian collecting ducts. et al. Unwin RJ. et al. 63. 1977. 1956. 74. Mol Endocrinol. 2009. Kitagawa H. 98. et al. Regulation of prostasin by aldosterone in the kidney.300:1087-1089. Am J Physiol Renal Physiol. Bellet S. Impaired renal Na(+) retention in the sgk1-knockout mouse. Sodium transporter abundance profiling in kidney: effect of spironolactone. Frindt G. Am J Physiol. Mick VE. 2002. Am J Med. 104. Segal AS. K+ secretion in the rat kidney: Na+channel–dependent and –independent mechanisms. Hyperkalemia due to nafamostat mesylate. Minireview: regulation of epithelial Na+ channel trafficking. 66. 77. et al. Reisenauer MR. Okusa MD. Stokes JB. 2009. Frindt G. Natural history of lactic acidosis after grand-mal seizures. Am J Physiol. Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1. N Engl J Med. Frindt G. Am J Physiol Renal Physiol. Dietary K regulates ROMK channels in connecting tubule and cortical collecting duct of rat kidney. Metaxaki P.286:F881-F892.284:20447-20451. Am J Physiol Renal Physiol. Na channels in the rat connecting tubule.15:16671668. Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation. et al. et al. Avedon M.291:F517-F529. Foutz RM.389:607610. 58. Sonikian M. Palmer LG.10:685-692. Sodium and potassium handling by the aldosterone-sensitive distal nephron: the pivotal role of the distal and connecting tubule. Villamill MF. luminal sodium concentration. Absence of small conductance K+ channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter’s) knockout mice. Chang H. 93. 1996. Liddle’s syndrome: prospective genetic screening and suppressed aldosterone secretion in an extended kindred. Huang DY. Beta-adrenergic stimulation of 42K influx in isolated smooth muscle cells. 1992. Apical potassium channels in the rat connecting tubule. 60. 96. 82. Giebisch G. Caduff P.277:37881-37887.287:F1030-F1037. 61. 47.4:28-36.411:283-288.15:1589-1596. 72.18:394-400.57:1324-1328.
K depletion increases protein tyrosine kinase-mediated phosphorylation of ROMK. Zavilowitz B. et al. Cherradi N. Angiotensin II inhibits the ROMKlike small conductance K channel in renal cortical collecting duct during dietary potassium restriction. 151. Emmett M. Brown NJ. 118. Am J Kidney Dis. 116. 2003.237:1618-1620. Terada Y.276:F674-F683. et al.and β2-adrenergic receptors in rat kidney. Role of cGMP-kinase II in the control of renin secretion and renin expression. 120. et al.289:F922-F932. Choi MJ.31:575-581. et al. Kurtz A. 2009. Wang JL. Activation of the succinate receptor GPR91 in macula densa cells causes renin release. 142. Babilonia E. 165. et al. Am J Physiol Renal Physiol. 2002. potassium. 163. 121. 2005. Kang JJ. Wade JB. Muller M. 114. Harris RC. Chacko M. Role of gp91phox-containing NADPH oxidase in mediating the effect of K restriction on ROMK channels and renal K excretion. Am J Physiol. Vargas SL. Kuchel O. J Am Soc Nephrol. et al. 2010. et al. Evidence for an electroneutral sodium chloride transport pathway. Bayliss DA. J Am Soc Nephrol. J Nephrol.680 Section II Disorders of Body Fluid Volume and Composition 108. et al. Delaloy C. 147. Am J Physiol Renal Physiol. et al. Lin SH. Transtubular potassium concentration gradient (TTKG) and urine ammonium in differential diagnosis of hypokalemia. 146. 1992. Underwood RH. TASK channel deletion in mice causes primary hyperaldosteronism. 2007:156-213. J Clin Invest. Yu AS. Direct demonstration of macula densa–mediated renin secretion. Henrich WL. Malendowicz LK. J Am Soc Nephrol.67:S78-S83.103:8558-8563. Liu Z. Hypertension. et al. Ruth P. 139. Proc Natl Acad Sci U S A.282:6455-6462. 2007. Am J Physiol Renal Physiol. 2008.297:F704-F712. Weinstein AM. Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells. Am J Physiol Renal Physiol. Inhibition of protein-tyrosine phosphatase stimulates the dynamin-dependent endocytosis of ROMK1. Am J Physiol Renal Physiol. Pfeifer A. et al. 2000. 141.32:47-51. Wei Y. J Clin Invest. 1987. Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway.33:1025-1030. WNK1 kinase isoform switch regulates renal potassium excretion. 122. et al.102:1576-1582.120:1627-1635. Mol Endocrinol. Control of the renal renin system by local factors. 133. et al. Schroth J. Marhauer V. 2003. et al. 2009. Regulation of aldosterone and cortisol production by the transcriptional repressor neuron restrictive silencer factor. 150. Tumor necrosis factor-α inhibits renin gene expression. The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice. Kramer BK. Am J Physiol Cell Physiol. Macula densa sensing and signaling mechanisms of renin release. II. Pisano JJ. Proc Natl Acad Sci U S A. Pihakaski-Maunsbach K. potassium. et al. Clark I. 2000. et al. 130. Wagner C. Wei Y.260:F486-F493.105:2203-2208. 136. Kramer BK.293:F662-F669. 129. 1987. Am J Physiol. Knepper MA. J Am Soc Nephrol. Transport of inorganic solutes: sodium. San-Cristobal P. Cheng HF. Hypertension. et al. 2000. Fordtran JS.295:F780-F788. Proc Natl Acad Sci U S A.75:399-403. Stichtenoth DO. Hanke CJ.21:1093-1096.283:C1522-C1529. Chen XL. et al. Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform. Rewolinski D. 2005. 131. Lazrak A. Markowska A. Direct inhibitory effect of atriopeptin III on renin release in primate kidney. Mount DB. A role for T-type Ca2+ channels in the synergistic control of aldosterone production by ANG II and K+. et al. Am J Physiol Renal Physiol. 8th ed. Expression and phosphorylation of the Na+-Cl– cotransporter NCC in vivo is regulated by dietary salt. 124.143:3651-3657. Zhang MZ. Franco-Saenz R. J Am Soc Nephrol. 1997. and phosphate. Clark BA. J Biol Chem.283:R1046-R1051. Vallon V. Am J Physiol Renal Physiol. 2004. Calmodulin-dependent kinase I regulates adrenal cell expression of aldosterone synthase. Prostaglandin E2–induced aldosterone release is mediated by an EP2 receptor. 2007. 152. et al. Joo KW. Dluhy RG. 1998. 125. J Clin Endocrinol Metab. Physiology (Bethesda). Smith PB. Decrease in dietary K intake stimulates the generation of superoxide anions in the kidney and inhibits K secretory channels in the CCD.20:140-146. Endocrinology. 1967. 1999. 132. Gordon RD. 113. 140. 160. Wang ZJ. et al. Endocrinology. Immunofluorescent imaging of β1. Kidney Int. 1998. Wagner C. Inhibition of angiotensin type 1 receptor impairs renal ability of K conservation in response to K restriction. 145. 1972. 144. 162. et al.68:2197-2207. 1999.51:1950-1957.49:2119-2127. Mol Cell Biol. Ring AM. 156. Somekawa S. et al. Effects of vasopressin and bradykinin on anion transport by the rat cortical collecting duct. Am J Physiol. J Biol Chem. 1998. Bloom P. 137.59:515-531. A mathematical model of rat cortical collecting duct: determinants of the transtubular potassium gradient. Schnermann J. Role of the sympathetic nervous system in regulating renin and aldosterone production in man. 154. et al. 2001. Atrial natriuretic peptide inhibits calcium-induced steroidogenic acute regulatory protein gene transcription in adrenal glomerulosa cells. 2010.277: 4317-4323. Li YC. Najjar F. Jensen BL. 111.164:1561-1566. et al. Yue P. et al. 110. et al. Wagner C. 1998.51:2246-2251. et al. et al. and fractional excretion of potassium. J Clin Invest. et al. 1998.283: F671-F677. et al. Bull MB. 164. et al. J Clin Invest. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. 159. 2007. et al. and SGK1. Am J Physiol Regul Integr Comp Physiol. Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man. Kidney Int Suppl. Burg MB. 2009. Hilbers U. et al. et al. J Clin Invest. 148. et al. Todorov V. Regulation of the adrenal renin angiotensin system in cultured bovine zona glomerulosa cells: effect of catecholamines. Lin DH. Lin DH. 123. 1. 2007. J Clin Invest. Science. Satlin LM.20:1002-1011. ed. Thiazide-sensitive NaCl absorption in rat cortical collecting duct.281:F206-F212.104:4025-4029.259:F519-F528. J Biol Chem. Boivin V. 2002. 2002. Philadelphia: Saunders. Am J Physiol Endocrinol Metab. Sterling H. Estilo G. et al. Tsikas D. et al. 2006. Effect of mineralocorticoid activity on transtubular potassium gradient. Sealey JE. Lorenz JN. McAlister EA. Kaplan NM. 1970. Csukas S. Effects of specific COX-2inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers. et al. 117.46:599-605. 155. et al. 1990. Src family protein tyrosine kinase (PTK) modulates the effect of SGK1 and WNK4 on ROMK channels. 158. 127. Dietary K+ regulates apical membrane expression of maxi-K channels in rabbit cortical collecting duct. Brenner and Rector’s the kidney. O’Reilly M.280:F1072-F1092. Supuran CT. Hypertension. Effect of dietary potassium and acute potassium infusion.296:F1179-F1184.18:2037-2045. Renin release from isolated juxtaglomerular apparatus depends on macula densa chloride transport. et al. 138. Davies LA. Tomita K. Wang Y. Axelrod L. Proc Natl Acad Sci U S A.41:259-264.23:9208-9221. 2009.19:424-426. 2005. Potassium balance and the control of renin secretion. 2009. Studies of the control of plasma aldosterone concentration in normal man. magnesium. Sandberg MB.280:10790-10796. ANG II provokes acute trafficking of distal tubule Na+-Cl– cotransporter to apical membrane. Arch Intern Med. Babilonia E. Epstein FH.29:1148-1155. Wang WH. 2008. Sterling H. 128. 2001. 134. Adrenocortical steroidogenesis: the effects of prostaglandins.12:962-972. Preserved macula densa– dependent renin secretion in A1 adenosine receptor knockout mice. Sterling D. Toma I. 135. 2002. Life Sci. Laboratory tests to determine the cause of hypokalemia and paralysis. Leviel F. 115. Kidney Int. 2008. Lang F. Schweda F. Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride. Endocrinology. urinary [K]/[Na] ratio. et al. 143. The protein tyrosine kinase-dependent pathway mediates the effect of K intake on renal K secretion. . 109. Fern RJ. Role of adrenal renin-angiotensin system in the control of aldosterone secretion in sodiumrestricted rats. Gupta P. Adrenomedullin stimulates renin release and renin mRNA in mouse juxtaglomerular granular cells. 1986. 2002.17:2402-2413. Wang ZJ.103:1615-1620.130:2129-2134.13:120-125.25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. In: Brenner BM. Ziyadeh FN. Weihprecht H. 2006.150:3110-3117. An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Schweda F. 161. Superoxide anions are involved in mediating the effect of low K intake on c-Src expression and renal K secretion in the cortical collecting duct.106:681-688. 2006. Condon JC. Jin Y. 1991.278:E1027-E1030. Effect of dietary K intake on apical small-conductance K channel in CCD: role of protein tyrosine kinase. Huang CL.77:136-141. 2002. Lin D. Liddle GW.284:F770-F777. Saruta T. Briggs JP. calcium. 2001.106:15061-15066. Am J Physiol Renal Physiol. Gu R. 2005. 1972. Am J Physiol Renal Physiol. Am J Physiol Renal Physiol. J Clin Invest. Effect of aldosterone on BK channel expression in mammalian cortical collecting duct.106:4384-4389.110:229-238. Pezzi V. The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II. 1992. Brown RS. 157. et al. Kramer BK. et al. Drummond BM. Riquier AD. Proc Natl Acad Sci U S A. 119. Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Proc Natl Acad Sci U S A. Skott O. 112. J Clin Invest. 126. 2010. 2009.298:F1515-F1522. 153. 149. Mulrow PJ. et al. Jensen BL. J Clin Invest. Mazzocchi G. Peti-Peterdi J.
194. Am J Kidney Dis.97:1960-1968. The hyperkalemic Brugada sign. Am J Emerg Med.38:390-394.279:F655-F663. Hypokalemia induces renal injury and alterations in vasoactive mediators that favor salt sensitivity. 2005. Acker CG. 196. 2001. Salakhov E.4 and is associated with periodic paralysis.281:2203-2210. J Clin Invest. 2001. Biermann KM. The prominent T wave: electrocardiographic differential diagnosis.260:F680-F687. Buller GK. Electrocardiography is unreliable in detecting potentially lethal hyperkalaemia in haemodialysis patients. Hoorn EJ. Carnegie A. Kaplan NM. and results of an attempt to improve physician compliance with published therapy guidelines. Multicenter Study of Perioperative Ischemia Research Group. Secondary hyperkalaemic paralysis. Am J Physiol Renal Physiol. Nephrol Dial Transplant. et al. Effects of electrolyte disorders on renal structure and function. et al. Testa D. Early polyuria and urinary concentrating defect in potassium deprivation. 176. et al. Stimulation by in vivo and in vitro metabolic acidosis of expression of rBSC1. Clin J Am Soc Nephrol. et al. Am J Physiol Renal Physiol. et al. Profound hyperkalemia without electrocardiographic manifestations. Jurkat-Rott K.286:1189-1192. 2007. 218. Chronic potassium depletion induces renal injury. Friedman EA. 179. Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature. Curr Opin Neurol. Physiol Rev. DuBose Jr TD. Struthers AD. et al. Roden DM. Tannen RL. On the mechanism of polyuria in potassium depletion. 224. Good DW. 209. Giebisch G. Kowey PR. Kidney Int. Fish FA. Hizon M. Fale AD. Jenkins R. Correlating phenotype and genotype in the periodic paralyses.18:721-729.63:1647-1655. 1977. 175. Alderman MH. 167. TSC. Arch Intern Med. N Engl J Med. Ann Emerg Med. et al. 1998.43:155-161. Lidocaine-induced conduction disturbance in patients with systemic hyperkalemia. Levi M. Weiss J. et al. Szerlip HM. Safety of exercise stress testing in patients with abnormal concentrations of serum potassium.281:F620-F629. Shafi T. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. 2010. Wedell E. Modesto KM. N Engl J Med. Berl T. J Hypertens. 213. 1996. 217. Ouellette JR. Bourgeois S. 212. 1998. Aisenbrey GA.19:301-306. Slovis C. Am Heart J. 2005. Am J Kidney Dis. 1986. Miller 3rd ER. Relman AS. Cornelio F. et al.79:1317-1372.90:1443-1449.7:112-119. 215. 1999.261:F767–F673. Tziviskou E. Hemodynamic and electrocardiographic effects of hyperpotassemia.22:545-547. 226. NHE4 is critical for the renal handling of ammonia in rodents.97: 1247-1249. 192.294:361-365. et al. 191.18:46-57. Nephrol Dial Transplant. Cohen HW.60:548-554. 222. 1985. Evers S. Rosenberg J. et al. The cardiovascular implications of hypokalemia. Perron AD. Torres VE. Crop MJ. McBride D. Buller GK. Potassium restoration in hypertensive patients made hypokalemic by hydrochlorothiazide.149:2677-2681. 1998. 169. Mazzoleni A. McLean SA.312:1652-1653. Hypokalaemia-induced acute renal failure. 207. Br J Anaesth. Am J Physiol Renal Physiol.283:F1376-F1388. 203. 2005. Muscle Nerve. Whelton PK. JAMA. Madhavan S.70:226-267. 208. He FJ. A practical approach to torsade de pointes. Young Jr WF. New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice. Annu Rev Physiol. 200. 193. Arch Intern Med. 2002. Hypertension.312:746-749. Katz AI.322:345-351. et al. adequacy of treatment. J Clin Invest. Abbott GW.56:623-647. 187. 1985. Matsuda O. Heart Rhythm.Chapter 17 Disorders of Potassium Balance 166. 2003. Chen Q. Fortnightly review: beneficial effects of potassium. 180.2:304-306. et al. 1967. 1988. Tang NL. 1989. Littmann L. Mehdirad AA. Brady WJ. Electrocardiographic manifestations of hyperkalemia. 216.45:233-247.273:33681-33691. J Clin Invest. Wahr JA. Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter. Management of severe hypokalemia in hospitalized patients: a study of quality of care based on computerized databases. In: Seldin DW. 1991. Retrospective review of the frequency of ECG changes in hyperkalemia.318:594-599. 2005. N Engl J Med. Wong KM. and renal cysts. Lehmann-Horn F. et al. et al.23:466-476. Changes in serum potassium mediate thiazide-induced diabetes. serum potassium and ventricular arrhythmias in the Multiple Risk Factor Intervention Trial. 2004. 1997. Semin Nephrol. Good DW. 172.8:17-21. 2006. et al.323:497-501. Gennari FJ. Voltage-gated ion channels and hereditary disease. 2000. Diabet Med. Hyperkalemia: treatment options. Frokiaer J. Am J Cardiol. Jacob Holler on potassium deficiency in diabetic acidosis (1946). 2002. Hypokalemic metabolic acidosis attributed to cough mixture abuse. 2008. 1998. 1993. vol 2.20:285-290. Macdonald JE. Greenberg A. BMJ. Perazella MA. J Electrocardiol. Darbar D. 182. Miller TM.160: 2429-2436. Paul ID. 1999. High and low serum potassium associated with cardiovascular events in diuretic-treated patients. Gustafsson F.276:383-389:contd. et al. 223. Moore R. Am J Physiol. 201. 2001. MacGregor GA. Cohen E. Lawson N. Role of hyperkalemia in the metabolic acidosis of isolated hypoaldosteronism. A paper which changed clinical practice (slowly). DuBose Jr TD. Taylor 3rd L. 2008. 1999. et al. Marples D. Severe hypokalemic myopathy in Gitelman’s syndrome.40:53-59. Paltiel O. Johnson JP. Neurology. Cardiovasc Drugs Ther.324:1320-1323. 183. 1983. 1976. and hypertension in young rats. Attmane-Elakeb A. Linas SL. 220.3:324-330. 197. Chlebus H. BMJ. Parham WA. Spector PS. Am J Emerg Med. 188. Menahem SA. et al. 1994. Clin Nephrol. Effects of chronic hyperkalemia on renal production and proximal tubule transport of ammonium in rats. 219. Ifudu O. Chronic hyperkalemia impairs ammonium transport and accumulation in the inner medulla of the rat. Br Med J (Clin Res Ed). Tattersall RB. 225. Muscular paralysis and ventilatory failure caused by hyperkalaemia. Differences in response to slow and rapid increases in concentration of plasma K. Somers MP. 2001. Renal adaptation to a high potassium intake. Int Urol Nephrol. Hypokalemia-induced downregulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. Bock KD. McDonald LA. Appel LJ. Am J Cardiol. 227. Neaton JD. Hyperkalaemia in patients in hospital.35:429-434. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. Prevalence and pathogenesis of hypokalemia in patients on chronic peritoneal dialysis: one center’s experience and review of the literature. J Clin Invest. Monroe MH. Suga SI.158:917-924. 221. 185. Gray JM. Int J Eat Disord. MiRP2 forms potassium channels in skeletal muscle with Kv3. ABC of clinical electrocardiography: conditions not primarily affecting the heart. Cremer W. Hyperkalemia revisited. 214. 1999. Chaimowitz C. 210. Mattu A. Hyperkalemia in hospitalized patients: causes. salt sensitivity.59:1850-1858. Prineas RJ. Tex Heart Inst J.49:203-209. Liu XH. Coca SG. Paice B. Ray PE. et al. Association of hypokalemia. et al. et al. Hanna MG. BSC-1. Potassium deficiency. 1967. Skeletal muscle channelopathies: nondystrophic myotonias and periodic paralysis. The role of hydrogen ion. Mujais SK. 174. Offord KP. et al. et al. 178.60:620-625. 177. 202. 2007. Ammonium transport by the thick ascending limb of Henle’s loop. 205. Raja Rayan DL. 170. Preoperative serum potassium levels and perioperative outcomes in cardiac surgery patients. 1990. Arch Intern Med. et al. 184. Raskin P. et al. Schnaper HW. Better OS. Arch Intern Med.52:2089-2101.19:1315-1323. et al. Elkjaer ML. Altered expression of renal NHE3. 173. et al. and ENaC subunits in potassium-depleted rats.38:383-385. 211. Am J Kidney Dis. Cohn JN. Am J Physiol. Singer I. Schwartz WB. 195. 228. Congenital long QT syndrome aggravated by salt-wasting nephropathy. 206. Amlal H. Potassium depletion myopathy: a clinical and morphological study of six cases. 1977. Diuretics. the Na-K(NH4)-2Cl cotransporter of the rat medullary thick ascending limb.7:461-465.104: 217-231. N Engl J Med. 2002. Sile S. High ambient temperature: a spurious cause of hypokalaemia.339:451-458. 2001. Marenah CB. aldosteronism. eds. Krane CM. et al. Suga S. Surawicz B.120:1895-1904. The role of polydipsia. Engelien A. BMJ. Freeman SJ. Lindemans J. 1992.161:1089-1095. Philadelphia: Lippincott Williams & Wilkins. The kidney: physiology and pathophysiology. Palevsky PM. 3rd ed. Brady WJ. 2000.36:615-618. 1999. Masters PW. Comi G. 171. 2001. Karsch V.14:2216-2218.16:978-984. 2006. Szylman P. J Biol Chem. Robinson DA. Clin Cardiol. Hypokalemia. Muscle Nerve. et al. 681 199. Primary role of hyperkalemia in the acidosis of hyporeninemic hypoaldosteronism.20: 243-251. 2000:1615-1646. 1973. 1991.22:3471-3477.33:40-47. Galatius S. Montague BT. J Neurol Neurosurg Psychiatry.17:1639-1642. “End-stage kidney” in longstanding bulimia nervosa. J Clin Invest. 2002. N Engl J Med. Nephrol Dial Transplant. Ronen I. 2000. Good DW. N Engl J Med. et al. 181. What is the optimal serum potassium level in cardiovascular patients? J Am Coll Cardiol. et al. Symptoms and course of chronic hypokalemic nephropathy in man. 186. et al. 2001.52:1022-1029. Hypokalaemia and subsequent hyperkalaemia in hospitalized patients. 189.64:249-252. Cell.73:647-664. 2010. 198. 1988. et al. Cohen JD. Dorup J. Yasuhara D. 204. 190. et al. 1998. et al. . 2004. 229. et al. Dowling J. Nephron. et al. et al. Aslam S. Perry GJ. 1996. Preisig PA. 1987. 2000. Batlle DC. 168.
243.352:1680-1681. Ann Emerg Med. Edwards F. Chow CC. Chest. Admission serum potassium in patients with acute myocardial infarction: its correlates and value as a determinant of in-hospital outcome. et al.40:10-18. Addis GJ. 269.51:1867-1875. Rice JE. Kerner JA. 1988. Life-threatening hypokalaemia and lactate accumulation after autointoxication with Stacker 2. Koch BC. Aristolochic acid–induced Fanconi’s syndrome and nephropathy presenting as hypokalemic paralysis. Chilimuri SS. Azuma KK. 282. Malingre MM. Blondon H. Kher KK. Nephrol Dial Transplant. 2002.19:78-79. Gonzalez-Buitrago JM. Mutations in Kir2. Sigue G. Excessive cola consumption as a cause of hypokalaemic myopathy. 1999. Severe hypokalaemia secondary to dicloxacillin. 288. et al. 268. Sandle GI. Emerg Med J. 2002. 278. Modulation of force development by Na+. Crapo LM. Desrame J. Plaster NM. Schaefer M.105:511-519. 244. 247. Electrolyte losses associated with the taking of purges investigated with aid of sodium and potassium radioisotopes. and acidosis. Am J Physiol. Yeung CK.25:329-330. 2008. Milionis HJ. 233. 2000. 2007. Pakravan N. 1998. Br J Clin Pharmacol. Pflugers Arch. de Wijkerslooth LR. Over-expression of colonic K+ channels associated with severe potassium secretory diarrhoea after haemorrhagic shock. Gentamicin-induced Bartter-like syndrome. 290. Kao MC. 2000. Chan A. Z Gastroenterol. Hypoglycaemia and associated hypokalaemia in diabetes: mechanisms. 1997.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. 259.283:836-840. Goddard J. 2003. Am J Kidney Dis. 258. et al. Juurlink DN.44:466-470.89:463-468. Gastroenterology.75:193-197. Lin SH.23:3350-3352. 2001. 257. Ritodrine. 2010. 1990. 1990. Kelly K.27:296-315. 253.97:9549-9554. et al. 275. Vale JA. 1999. Tricarico D. 238. 2005. 261. 2000. Bourantas CL.30:324-326. 281. J Pediatr. Schwartz WB.303: 1096-1099. Insulin modulation of ATPsensitive K+ channel of rat skeletal muscle is impaired in the hypokalaemic state.19:175-177. Jacobs IA.16:56-61. Diekmann F. Thyrotoxic periodic paralysis and intravenous propranolol in the emergency setting. Secretory diarrhoea with high faecal potassium concentrations: a new mechanism of diarrhoea associated with colonic pseudo-obstruction? Report of five patients. et al.41:285-288. Hensley CB. Martin-Ruiz C. Intern Med J. 231.120:38-43:[see comments].62:201-207.66:728-731. 1991. Salbutamol induced hypokalaemia: the effect of theophylline alone and in combination with adrenaline. 260. et al. Molecular investigation and long-term clinical progress in Greek Cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene. 237. 2000. Ruff RL. Novel thiazide-sensitive Na-Cl cotransporter mutation in a Chinese patient with Gitelman’s syndrome presenting as hypokalaemic paralysis. 286. 284. 234. Lancet. 249.2:75-82. Miller RF. Conte Camerino D. 235. Nichols CA.56:1201-1210. Gaeta TJ. Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current.118:904-913. Stimulated active potassium secretion in a patient with colonic pseudo-obstruction: a new mechanism of secretory diarrhea. The response of normal man to selective depletion of hydrochloric acid. 2000. Suicidal ingestion of barium-sulfide– containing shaving powder. Intern Med J. 1995. 1997. et al. Jurkat-Rott K.106:4036-4041. Clin Genet. Na+ K+ pump and KATP channel during muscular activity. 2000. et al. Apical extracellular calcium/polyvalent cation–sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. Fatal dysrhythmia following potassium replacement for hypokalemic periodic paralysis. hypokalemia. Cell.52:548-553. Hawley CM. Ho JM. 242. West J Emerg Med. Hypokalemia following polyethylene glycol–based bowel preparation for colonoscopy in older hospitalized patients with significant comorbidities. Braden GL. Germain MJ. Coghill NF. 1959. Intensive Care Med.64:824-832. Ulahannan TJ.11:57-59. Reid C. 276. Poisoning as a result of barium styphnate explosion. Can J Appl Physiol. Fatal hypokalaemia associated with ifosfamide/ mesna chemotherapy.99:1399-1405. Husband DJ. 2009. 1999. Arch Intern Med. Inter-relationship between serum potassium and plasma catecholamines and 3′:5′ cyclic monophosphate in alcohol withdrawal. Wolf I. Servidei S. Siamopoulos KC. 279. Pediatr Clin North Am. Hannemann L. Cheng NL. Lin YF. Malkowska AM. K+-dependent paradoxical membrane depolarization and Na+ overload. Basic Clin Pharmacol Toxicol. 2000. 1988.1:14-19. Tang MJ. et al.18:1005-1008. 1999. Ruff RL. Drug-induced Fanconi’s syndrome. Adrenaline-induced colonic K+ secretion is mediated by KCa1. Feldman M. 1995. Propranolol rapidly reverses paralysis. Orman RA. Thyrotoxic periodic paralysis: reports of seven patients presenting with weakness in an Asian emergency department.and beta 2-isoforms. Landau D.1 (BK) channels. Factors in the genesis of persistent gastric alkalosis. Tonali P.437:235-240. Simon M. et al. et al. Sorensen MV. Kassirer JP. Capriulo R. Am J Emerg Med. Whyte KF. Am J Kidney Dis. Am J Med.37:620-623. Goh SH. 1970. Birkhahn RH. Pediatr Nephrol. Suki WN. 280.33:295-310. Acute treatment of hypercalcemia with furosemide. 2002. Am J Physiol. Foote JA. Postgrad Med J. Hsu YD. et al. 248.6:214-218.109:599-600. Isnard-Bagnis C. and hypophosphatemia in thyrotoxic periodic paralysis. 2008.53:1556-1563. Kirrane BM. Apical potassium (BK) channels and enhanced potassium secretion in human colon. J Infect. From profound hypokalemia to life-threatening hyperkalemia: a case of barium sulfide poisoning. et al.26:183-188. Thyrotoxic periodic paralysis in a Chinese population. et al. Cavalcanti RB. et al. 2008. Excessive hypokalemia and hyperkalemia following head injury. In vivo and in vitro sodium pump activity in subjects with thyrotoxic periodic paralysis. Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. 232. Sands JM. Waring WS. Acute barium poisoning treated with hemodialysis.32:357-358. 2001. 246. 251. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. Hunter M. Ann Pharmacother. 1992. Thyroid hormone specifically regulates skeletal muscle Na(+)-K(+)-ATPase alpha 2. 2000. McAllen PM. 2010. et al.265:C680-C687. Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Proc Natl Acad Sci U S A. 2008. QJM. Am J Forensic Med Pathol. 285.129:1268-1273. 255. 1995. Tse HF. Wood KE.1:1116. clinical implications and prevention. Disturbances of potassium homeostasis in poisoning. et al. 266. 1999. 250. Am J Hematol. Milling D. Lovejoy Jr FH.258: F423-F428. From profound hypokalemia to fatal rhabdomyolysis after severe head injury. Refeeding syndrome. Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis. Lewis Jr JB. 2002. 283. Sachdev A.41:292-309. 2008. 241. Renaud JM. Tricarico D.102:325-328.103:675-682.11:737-740. Marcus SM.103:85-89. Am J Emerg Med. Hypokalaemic paralysis. Taddeo J. 2003. Link J. Laso FJ. 264. et al. Diabetes Obes Metab. et al. Bettinelli A. Adult celiac disease presented with celiac crisis: severe diarrhea. Gastroenterol Clin Biol. 254. Ahlawat SK. 1993. et al. Bateman DN. Foscarnet-induced hypokalaemia. Robinson RT. Shinde R. Drug Alcohol Depend. et al. 274. et al.31:317-318. Mouallem M. Proc Natl Acad Sci U S A. BMJ. Hypokalemic nephropathy after pelvic pouch procedure and protective loop ileostomy. BMJ. et al. 287. Bechade D. van Dinter Jr TG. 1999. et al. Luminal calcium regulates potassium transport by the renal distal tubule. Amitai Y. 245. 265. Acute acetaminophen overdose is associated with dose-dependent hypokalaemia: a prospective study of 331 patients. 262. Am J Ind Med. 252. Stephen AF. 263. Chu P. 272. Farfel Z. major and reversible contributors to weakness by ion channel leaks. Hoffman RS. N Engl J Med. Am J Kidney Dis. Br J Clin Pharmacol.149:1193-1194. 239. Arch Intern Med. Lancet. Nephrol Dial Transplant.97:9832-9833. Ko GT. Effect of acute paracetamol overdose on changes in serum and urine electrolytes. Acid-base and electrolyte abnormalities in patients with acute leukemia. Ambient temperatures and potassium concentrations.69:135-144. Ellison DH. 236. J Clin Invest. et al. K+. Flaccid quadriparesis associated with Yersinia enterocolitis-induced hypokalemia. Velazquez H. 1988. Izzedine H. 277.18:199-202. 1996. Am J Med. Kidney Int. et al. hypokalemia. et al. 1997. 2002. Keenan J. Fuentebella J. J Emerg Med. Proc Natl Acad Sci U S A. 256. Chintalapally G. 1966.39:E14. Neurology. 2010. 289. et al. 267. 2009. J Toxicol Clin Toxicol. 2001. QJM. Okusa MD. 2001. et al.159: 601-606.21:235-237.32:401-404. Arch Intern Med. Launay-Vacher V. Madias JE. 273. Downs JC. Wells JA. Lin YF.” Br J Clin Pharmacol. Heller SR. 270. J Clin Invest.160:548-551. J Physiol. a “powerful slimming agent. Shah B. von Oeyen PT. 271. 240. Watkin SW. Melniker L. 2001. et al. Faunt JD. Jurkat-Rott K. J Clin Gastroenterol. Malin A. Kay TD. Manoukian MA. Bradberry SM. 2010. Skeletal muscle sodium current is reduced in hypokalemic periodic paralysis.and terbutalineinduced hypokalemia in preterm labor: mechanisms and consequences. 2006. McVittie J.588:1763-77. Hypokalemia in acute theophylline poisoning. 1992. Ahmed I.25:571-578.682 Section II Disorders of Body Fluid Volume and Composition 230. A descriptive study of an outbreak of clenbuterol-containing heroin. 1989. . Johnson DW. Yang SS.39:579-582.
298.344:1558-1559. 1986. et al. Lifton RP. 1993. Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2. and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. Proc Natl Acad Sci U S A. 2001. 683 320. 321. et al.1:657-663.104:545-556. White PC. Proc Natl Acad Sci U S A. 1999. Pseudoaldosteronism due to the concurrent use of two herbal medicines containing glycyrrhizin: interaction of glycyrrhizin with angiotensin-converting enzyme inhibitor. 1992. 1988. Science.32:503-507. 1997. et al. Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. 1992. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. Horton R. 308. et al. Kurtzman NA. et al. Ambrosius WT.Chapter 17 Disorders of Potassium Balance 291. Warnock DG. 328.66:607-618. 2010. Hypertension. 307. Geller DS. J Clin Endocrinol Metab. Hop WC.281:F1021-F1027. mineralocorticoid receptor. 1998.31:619-632:xi. Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. et al.16:1187-1191. The ectopic adrenocorticotropin syndrome: clinical features.63:370-379. Sinaiko AR. Endocrinol Metab Clin North Am. Pascoe L. Liddle’s syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit. 324. Liao C. Coolidge C. 1994. Montori VM. Ilias I. Pintar TJ. Groenestege WM. Ann Intern Med. Mutants of 11β-hydroxysteroid dehydrogenase (11HSD2) with partial activity: improved correlations between genotype and biochemical phenotype in apparent mineralocorticoid excess. 303. Brief report: Liddle’s syndrome revisited—a disorder of sodium reabsorption in the distal tubule. Meta-analysis of incidence and risk of hypokalemia with cetuximab-based therapy for advanced cancer. Steroid 11β-hydroxylase deficiency and related disorders. et al. et al. 345. Lifton RP. Am J Physiol Renal Physiol. White PC. 2003. Botero-Velez M. 1999. Lancet. 2000. N Engl J Med. Funder JW. A chimaeric 11β-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Curtis JJ. Diagnosis and management of ACTH-dependent Cushing’s syndrome: comparison of the features in ectopic and pituitary ACTH production. Wilson RC. Hannila-Handelberg T. Biller KJ. et al.21:887-890. 2006. Goldsmith O. Bunchman TE. Geller DS. 1998. Enhanced Na+/H+ exchange in Cushing’s syndrome reflects functional hypermineralocorticoidism.264:F565-F574. J Clin Invest. 2001. Molecular basis for hypertension in the “type II variant” of apparent mineralocorticoid excess. Clinical.34:638-642. Frindt G. Rich GM. 2006. 294. 2005. diagnosis. Eiam-Ong S. 2001. 2007. Science.117:2260-2267. Phillips PA. Unwin RJ. Dluhy RG. 323. Young WF.10:131-135. 300. Williams JS.82:3570-3573.20:2383-2390. Synergistic action of liquorice and cortisone in Addison’s and Simmond’s disease. Holder G. 2002. N Engl J Med. 2008. 297. J Clin Endocrinol Metab.93:3266-3281. J Clin Invest. et al. et al. A genetic defect resulting in mild low-renin hypertension. 310. de Jong FH. Isidori AM. Borst JGG. 2008. Clin Endocrinol (Oxf ). II. Use of plasma aldosterone concentration–to– plasma renin activity ratio as a screening test for primary aldosteronism. et al.121:877-885. 299. Dysfunction of the epithelial sodium channel expressed in the kidney of a mouse model for Liddle syndrome. Pradervand S. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. 309. . Torpy DJ. ‘Pseudo-aldosteronism’ induced by intravenous glycyrrhizin treatment of chronic hepatitis C patients.93:3117-3123. not receptor. Li A. Paraneoplastic hyperaldosteronism associated with non-Hodgkin’s lymphoma. 2002. Glucocorticoid-remediable aldosteronism. A systematic review of the literature. Endocr Res. 1994. Clin Exp Nephrol. Sukor N. 314. Primary aldosteronism: renaissance of a syndrome. Ann Intern Med.131:794-795. BMC Med Genet. Mullen N. Sabatini S. Feedback regulation of Na channels in rat CCT. 296. Hiltunen TP. The thiazide-sensitive Na-Cl cotransporter is an aldosterone-induced protein. 2002.14:2219-2228. 1998]. Mutations causing Liddle syndrome reduce sodium-dependent downregulation of the epithelial sodium channel in the Xenopus oocyte expression system. J Hypertens. et al. 311. Severe hypokalaemia: is one reason enough? Nephrol Dial Transplant. 1997. J Am Soc Nephrol. beta. 306. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy.91:2385-2392.76:877-884. New MI. Clin Endocrinol (Oxf ). 1998. et al. 327. Nunez BS. N Engl J Med. Ann Intern Med. Matsumoto K. 302. et al. 332. Distal tubular electrolyte transport during inhibition of renal 11β-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab. et al. Shirley DG. 313. 341. and long-term follow-up. Cancer Chemother Pharmacol. 11β-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. 333.104:R19-R23. Litchfield WR. J Hum Hypertens. 330. and gamma subunit proteins in rat kidney. Kim GH. J Hypertens. Loffing J. 1998. Mendonca BB.289:119-123. Am J Physiol Renal Physiol. 322. 2009.355:262-265. et al. Rabbia F. Kellenberger S. Kim GH.” Singapore Med J. Effects of inhibition of Na entry. Veglio F. 1995. 1994. Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoidremediable aldosteronism. Hypertension. 1997. 295. 326. J Clin Endocrinol Metab. 1993. J Clin Endocrinol Metab. et al. 334.280:F172-F179. Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension. 1995. Hamidon BB. Gautschi I. Pinet F. Pediatr Nephrol. 11β-Hydroxysteroid dehydrogenase activity in Cushing’s syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia. van Rossum TG. Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families. and thiazide-sensitive Na-Cl cotransporter expression by distal tubules. The 17-hydroxylase deficiency syndrome. Case detection. diagnosis. Lindop GB. 335.82:1507-1510. et al.970:134-144. et al. Endocr Rev. et al. Farese S. 344. Cao Y. 1999. 342. J Gastroenterol Hepatol. 1999. 315.91:371-377. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients.87:1805-1809. Hyperreninemic hypertension secondary to a subcapsular perinephric hematoma in a patient with polyarteritis nodosa. Unilateral renal ischemia causing the hyponatremic hypertensive syndrome in children—more common than we think? Pediatr Nephrol. 1998. Mune T. Stewart PM. et al. Bostanjoglo M. Pearce PT. 336. J Clin Endocrinol Metab.19:2914-2917. Kidney Int. Walker BR. Otsuka Y. Herrmann A. 2006. 1995.30:61-79:vi. Rossier BC. Blumenfeld JD. Zimmerman S. Am J Physiol. Solomon DH.101:2741-2750. 339. 318.4:169-170. 340. 292. Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoidremediable aldosteronism. 338.95:10200-10205. 2006. Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree.84:4341-4344. Howlett TA. de Vries LA. Exogenously-induced apparent hypermineralocorticoidism associated with ingestion of “asam boi. Haller H. Woywodt A. J Am Soc Nephrol. et al. et al. et al. Ann N Y Acad Sci. biochemical and genetic features of five extended kindred’s with glucocorticoid-suppressible hyperaldosteronism. 1999. Diagnosis and treatment of primary hyperaldosteronism.277:673-677. Corvol P. Jeyabalan V. et al. Koren W. Mulatero P. et al. 2001. J Clin Invest. et al. 319. Renovascular hypertension presenting with hypokalemic metabolic alkalosis. Liu L. Iida R. Jamieson A. et al. Smith R.47:156-158. Molecular mechanisms of human hypertension. 2004. Ringrose TR. 325. et al. J Clin Endocrinol Metab. 301. 11β-hydroxysteroid dehydrogenase. 316. et al. Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype. 1999. 2007. 329.20:129-136. Ten Holt SP. 1998. Lifton RP.9:1347-1358:[published erratum in J Am Soc Nephrol 9(11):2179. Mitchell C. J Clin Endocrinol Metab. et al. Nature.18:135-156. 1953. et al. et al.66:37-42. 1967. Am J Hum Genet. et al. 2001. Funder JW.26:1577-1582. et al.6:4. Endocrinol Metab Clin North Am. Agarwal AK. Am J Kidney Dis. et al. Regulation of collecting tubule adenosine triphosphatases by aldosterone and potassium. Geller DS. et al. 346. Gharavi AG. 304. Renin-secreting tumors. Mineralocorticoid action: target tissue specificity is enzyme. 305. Kotelevtsev Y. Silver RB. management. 337. Litchfield WR. 1990. 312. J Clin Invest. Nicholls MG.23:255-270.242: 583-585. Renin-secreting adenocarcinoma of the colon. Windhager EE. 2001. et al. J Clin Invest. 347. Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension. 317.80:3617-3620. Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. 331.16:789-795. et al. J Hypertens. 1998.330:178-181. Plouin PF.103:683-689. Cell. et al. Endocrinol Metab Clin North Am.34:631-637.116:813-820. 2002. 2008.96:22362246. 293. Aldosterone-mediated regulation of ENaC alpha. J Clin Invest. Masilamani S. 343.21:463-469.95: 14552-14557.24:699-713. Hypogonadism and mineralocorticoid excess. Young Jr WF. 2006. mediated.
Komhoff M. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies.45:221-225. Two types of K+ channels are present in the apical membrane of the thick ascending limb of the mouse kidney. Friedman E. et al. 1999. Selhi S. J Am Soc Nephrol. 366.39:299-315. 394.84:2560-2564. CFTR is required for PKA-regulated ATP sensitivity of Kir1. A new association? Ann Rheum Dis. Crow SJ. Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Colussi G. Hebert SC.414:558-561. Nat Genet. Simon DB. 2001. 379. 385. et al. 391.50:667-678. et al.290:F1416-F1420.152:60-63. Panichpisal K.684 Section II Disorders of Body Fluid Volume and Composition 348. 353.280:F786-F793. Am J Physiol. 2003. 2007. Loffing J. J Am Soc Nephrol. et al. Thiazide treatment of rats provokes apoptosis in distal tubule cells. Wang WH. 2000. hypokalaemic alkalosis with hypercalciuria.57:748749. 2002. Am J Physiol. et al. et al. Whang R. Flow-dependent K+ secretion in the cortical collecting duct is mediated by a maxi-K channel. Refractory potassium repletion due to cisplatin-induced magnesium depletion.70:51-59.272:F678-F688. Sun A. Am J Physiol. 1996. Am J Physiol Renal Physiol. 1997. Am J Physiol. 384. et al. BMC Nephrol. Am J Kidney Dis. 395.65:766-772. 404. Chen YC. et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel. 399. Simon DB. 368. 351. et al. Wilson TM. De Jong JC. et al. Quinlan DM. Refractory potassium repletion. 406.CLCNKB. et al.13:2259-2266. J Clin Invest.14:2957-2961. Vezzoli G. Jansen A. et al.286:F490-F495. Nephrol Dial Transplant. 377. Vandenberg CA. Foglia PE. Kim YG. 1995. 401. Am J Physiol Renal Physiol.112:183-190.145:1686-1689. Association between activating mutations of calciumsensing receptor and Bartter’s syndrome. Simon D.116:797-807. Lancet. 400. Young IS. Arch Intern Med. 370. Cobeta-Garcia JC.42:586-590. et al. 1970. Brochard K. Hoorn EJ. Karet FE. Altered renal distal tubule structure and renal Na+ and Ca2+ handling in a mouse model for Gitelman’s syndrome. Lu M. 1989. Maxi-K channels contribute to urinary potassium excretion in the ROMK-deficient mouse model of type II Bartter’s syndrome and in adaptation to a high-K diet. Finer G.120:83-94. 2005. the hypocalciuric variant of Bartter’s syndrome. 2004. An unusual cause of hypokalemic paralysis: aristolochic acid nephropathy with Fanconi syndrome. Normal prostaglandinuria E2 in Gitelman’s syndrome. Soldati L. 410. 2001. 2005. 2001. 2002. 392. et al. ROMK. 390.274:F611-F622. Morris RG. J Pediatr. Nijenhuis T. 1996. Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. Nat Genet. 2005. 1999. et al. et al. Ann Intern Med. et al. Hypokalaemic paralysis precipitated by distal renal tubular acidosis secondary to Sjögren’s syndrome.24:1455-1464. 361. is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Seyberth HW.30:279-287. Morris Jr RC. 1998. 398. 2006. Medullary nephrocalcinosis associated with long-term furosemide abuse in adults. Kleyman TR. Cyclooxygenase-2 expression is associated with the renal macula densa of patients with Bartter-like syndrome.15:2276-2288. 2007. et al.50:1180-1190. 2000.19:1398-1402. Greenfeld D.17:2136-2142. Angulo-Pernett F.12:24-30. 362. Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. A thiazide test for the diagnosis of renal tubular hypokalemic disorders. et al. Kidney Int. Lu M. Nat Genet. McSherry E. Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter’s syndrome. Urine electrolytes as markers of bulimia nervosa.17:171-178. 1999. Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome. Electrocardiogram with prolonged QT interval in Gitelman disease. Estevez R. 1978. 1996. Nephrol Dial Transplant. 2004.16:1066-1068. Comer DM. cause Bartter’s syndrome type III. J Clin Invest. J Am Soc Nephrol. et al. Kidney Int. 2002. 2000. Vargas-Poussou R. Kockerling A. Raymond J. Watanabe S. 1996. 2006.115:1651-1658. 371. Nephrol Dial Transplant. ROMK is required for expression of the 70-pS K channel in the thick ascending limb.264:C457C463. Mechanism of hypokalemia in magnesium deficiency. 376. Guay-Woodford LM. Am J Med. Kidney Int. Luthy C. Grossman EB. Bartter’s syndrome. et al. 1996. 389. 1997. 2006.330:153-155. et al. Rodriguez M. Hesling CM.149:2592-2594. Whang R. et al.105:151-161. Lu M. 2006. 2002. et al. Peters M. et al. Tsai CS. Nephrol Dial Transplant.129:519-528. Arch Intern Med.1 potassium channels in mouse kidney. 1993. Gladziwa U. Clin J Am Soc Nephrol. 356. Simon DB. 1997:F739-F748. et al. Hypokalemia in a mouse model of Gitelman’s syndrome. et al. Whang DD. Proc Natl Acad Sci U S A. et al.13:1442-1448. 372. is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Mickley D. 393. Bia MJ. Wang W. Knepper MA. A consequence of magnesium deficiency. 2008. 2001. et al. Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis. Lifton RP. Groeneveld JH. Kidney Int. J Pediatr. Bettinelli A. 363. Chondrocalcinosis and Gitelman’s syndrome. Bartter FC. Gitelman-like syndrome after cisplatin therapy: a case report and literature review. 369. 402. Kuo E. Thiazide-induced hyponatremia. Am J Physiol. 397. Mitchell JE. 2009. Reimann D. et al. et al. 2004. Lin SH.45:e41-e44. et al. 1989. et al. Riccardi D. 383. 2001. Chen HH. Cytochrome P-450 metabolites mediate extracellular Ca2+-induced inhibition of apical K+ channels in the TAL. et al. et al. Am J Kidney Dis. 2004. Functional expression of mutations in the human NaCl cotransporter: evidence for impaired routing mechanisms in Gitelman’s syndrome. 381.14:152-156. Woda CB.10:1607-1613. 1991. Am J Med.360:692-694. 1996. Am J Med Sci. Kidney Int. N Engl J Med. An unusual presentation of cystic fibrosis in an adult. QJM. 382. 354. Vandewalle A.36:855-858. Loffing J. Gitelman’s variant of Bartter’s syndrome. et al. Droogan AG. Lu M. Magnesium depletion as a cause of refractory potassium repletion. diagnosis-resistant hypokalaemia. Drug-induced secondary hyperaldosteronism in patients with pulmonary tuberculosis. J Membr Biol. 364. 358.18:2649-2652.62:253-260. et al. Holmes AM. Sebastian A. Herrmann A. Am J Med. Chronic. Am J Psychiatry. 373. Chronic hypokalaemia of adults: Gitelman’s syndrome is frequent but classical Bartter’s syndrome is rare. Localization and induction by dehydration of ClC-K chloride channels in the rat kidney. J Clin Invest. Localization of the extracellular Ca2+/polyvalent cation–sensing protein in rat kidney. Huang CL. Inactivating mutations in the Na-Cl cotransporter is associated with high bone density. et al.58:2420-2424. Dorup I. Arch Intern Med. 2003. 1995. 367. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Reproducibility by single dose rechallenge and an analysis of pathogenesis. Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Halkin H. Ryan MP. 352. Late-onset manifestation of antenatal Bartter syndrome as a result of residual function of the mutated renal Na+-K+-2Cl– Co-transporter.59:710-717. Schlingmann KP. Sijpkens YW. Nat Genet. Cruz D. 2005. Nephrol Dial Transplant. Vasopressin alters the mechanism of apical Cl– entry from Na+:Cl– to Na+:K+:2Cl– cotransport in mouse medullary thick ascending limb.7:10.142:318-323. 357.13:183-188. Am J Physiol Renal Physiol. Chen YC. Pressler CA. Bartter syndrome: unraveling the pathophysiologic enigma.2:454-460. Gill Jr JR. Am J Kidney Dis. Bragin A. 403. 365. et al. 1995. Gross P. Simon DB. et al. Shadel M. Primary Sjögren’s syndrome associated with Gitelman’s syndrome presenting with muscular paralysis. Transient neonatal hyperkalemia in the antenatal (ROMK defective) Bartter syndrome.271:C103-C111. Ann Clin Biochem. Bailey MA. 405. 1971. Xu JZ. Rosenberg ME. Dave S. Shaer AJ.98:305-316. McSherry E.21:84-90. Nephrol Dial Transplant. Kidney Blood Press Res. et al. Nature. et al. Mutations in the chloride channel gene. Choroidal calcifications in patients with Gitelman’s syndrome. inherited hypokalaemic alkalosis. Lombardi M.25:824828. Salt wasting and deafness resulting from mutations in two chloride channels. Am J Kidney Dis. 2002. 388. 359. 2006. et al. An approach to the patient with severe hypokalaemia: the potassium quiz. 1985. J Am Soc Nephrol. Barttin is a Cl– channel β-subunit crucial for renal Cl– reabsorption and inner ear K+ secretion. 1992. Clausen T. 378. 409. Impaired response to furosemide in hyperprostaglandin E syndrome: evidence for a tubular defect in the loop of Henle. Iglesias E. Kidney Int. 396. 355. 350. On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA). 1987. 375.16:2303-2309. 2002. J Am Soc Nephrol. Gascon A. Int J Eat Disord. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. 1971. Honney S. 386. 387.110:24-30. Morris Jr RC.62:580-584. Cruz DN. Nat Genet. 407.10:597A. et al. 360. Reinalter SC. 2001. 374. 1998.152:40-45. The tell-tale urinary chloride. .23:75-82. et al. 380. 1998. et al. 408. Eisenberger U. Hypokalemia in outpatients with eating disorders. et al.50:231-243. Correlation between magnesium and potassium contents in muscle: role of Na+-K+ pump. Q J Med. J Clin Invest. Woywodt A.350:1314-1319. Cardiac work up in primary renal hypokalaemiahypomagnesaemia (Gitelman syndrome). 349. Reinalter SC. Whang R. Sebastian A. J Am Soc Nephrol. Solanki DL.
Dunlay R. Br J Rheumatol.121:e1-e2.110:426-429. Sowinski KM.16:879. 1983.77:759-764. 1966. Hyperkalemia in hospitalized patients. Kew MC.196:401-403. Weinberger MH. 424. Cause of life-threatening hyperkalemia in a patient undergoing hemodialysis. 1985. Tumor lysis syndrome. Pseudohyperkalemia and extreme leukocytosis. Dosik H. Hyperkalaemia in patients in hospital. 2009. 1981. In: Rose BD. Factitious hyperkalemia.160:1605-1611.15:694-696. Case report.20:164-171. Hypokalaemia and hyperkalaemia. 433.30:246-250. Bailey RR. et al. et al. Potassium supplementation. Diabetic acidosis with initial hypokalemia. et al. Clin Pharmacol Ther. Moreno M. 420. 2001:836-887. 419. Ann Pharmacother. Early and intensive potassium replacement in diabetic acidosis. J Lab Clin Med. Zydlewski AW. Am J Kidney Dis. 1990. Timing of onset of CKD-related metabolic complications. Kim GH. 2001. Lancet. Griffing GT. 456.245:F593F600. 474. and fiber and risk of stroke among US men. Takasu N. Corish D. 472. Perkins RM. 428. Robinson LM.8:352-355. Anesth Analg.2:313-319. Salt substitutes as a source of potassium. 1981. 469. J Am Soc Nephrol. 417. 458. 1969. et al. Blood. 443. vol 1. Am J Med Sci. diet vs pills: a randomized trial in postoperative cardiac surgery patients. Cystic fibrosis presenting with hypokalemia and metabolic alkalosis in a previously healthy adolescent. Safety and effectiveness of a modification of diet in renal disease equation-based potassium replacement protocol. Pullen H. eds. Bruce LJ. 454. Brown JJ. Goldsmith C. Khaw KT. et al. Am J Med. 2009. Bussell S. da Silva JA. J Anesth. Intensive intravenous potassium replacement therapy. Young GA. Some effects of potassium salts in man. Sodi R. Bates CM. Mueller BA. Lambie AT. Mahfouz RA. magnesium. Quigley R.12:116-120. Barrett-Connor E.32:177-180. The management of hyperkalaemia in the emergency department. 2000. Gabduzda GJ. 459. Jaeger P.19:75-77. Sims EAH. Scott MK. Ammonium transport in rat cortical tubule: relationship to potassium metabolism. J Toxicol Clin Toxicol. 2008.85:660-664. Thiele A. Relation of potassium depletion to renal ammonium metabolism and hepatic coma. 2008. N Engl J Med.266:228-233. In: DuBose Jr TD.Chapter 17 Disorders of Potassium Balance 411. Arrambide K. Ann Intern Med. 426. N Engl J Med. 2000. Lancet. Copkney C.218:1201-1207. Hall 3rd PW. Cox M. Post TW. Bates GD. Stevens MS. Intake of potassium. Parisi A. et al. Kone BC. Hypokalemia. Clin Nutr.98:1198-1204. Rapid correction of hypokalemia using concentrated intravenous potassium chloride infusions. Chest. Rosenbaum BJ. Sanchez A. 422. Am J Med Qual.79:517-519. Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloridebicarbonate exchanger. 412. Nagasaki A.92(suppl 1):28-32. Davison AS. 439. Danger of salt substitutes that contain potassium in patients with renal failure. Ganguly A. Br Med J.150:613-617. 430. et al. Anesth Analg. Kellerman PS. Medicine (Baltimore). Triamterene-thiazide combination: alternative therapy for primary aldosteronism. BMJ. 1961.331:17-21. et al. 435. et al. 468. Am J Physiol. 475. Nephron. Charytan D.102:557-558. Su M.37:1258-1263. 2005. Manoguerra AS. 2009. aldosterone excess. Mahajan SK.31:56-61. 466.42:813818. 447. Ann Clin Biochem. 473. Hamill RJ. Use of a proton-pump inhibitor for metabolic disturbances associated with anorexia nervosa. Ackerman JD. Am J Physiol. Am J Kidney Dis. JAMA. 446. Chapman SA. 2006. plasma glucose and role for sodium-potassium-exchanging-ATPase. 461. 444. JAMA. Sopko JA. Abramson E. Doorenbos CJ. The phenomenon of seasonal pseudohypokalemia: effects of ambient temperature. Burchell HB. Clin J Am Soc Nephrol. Arky R. Sondheimer JH. Ahee P. Circulation. 1988. Am J Physiol. calcium. 1981. Bellevue R. Sustained-release potassium chloride overdose. Amiloride in primary hyperaldosteronism. 455. Anion effects on cation movements during correction of potassium depletion. Soleimani M. . 448. Clin Biochem. 427. Arch Intern Med. Kunzelman KS. 2003. The frequency of hyperkalemia and its significance in chronic kidney disease. 2002. 2002:381-394. 1998. Ponce SP. 434. A 12-year prospective population study. Curtis GP. Aboudara MC. 471. et al. The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein. 445. 1997.73:291-298. 2002. et al.169:1156-1162. AE1. Bartoli E. Spergel G. Thornbery JM. Medicine (Baltimore). Osterberg AE. Abu-Hamdan DK. Madias NE. 1967. N Z Med J. N Engl J Med. 462. Rehman HU. Factitial hyperkalemia due to icing before analysis. An unusual case of hyperkalaemia-induced cardiac arrest in a paediatric patient during transfusion of a “fresh” 6-day-old blood unit. Cardiac arrests associated with hyperkalemia during red blood cell transfusion: a case series. Hypothermia-induced hypokalemia. Thrombocytosis elevates serum potassium. Wiederkehr MR. 2007.38:900-902. Moranne O. Arch Intern Med. 451. Allon M. Kruse JA. Kearney TE. 2009. 2007. Transfus Med. Philadelphia: Saunders. J Sports Med Phys Fitness. Semin Nephrol.229:161-166. 1966. 470. 2004. Dunlay RW. 453. Cornes MP. Acid-base and electrolyte disorders: a companion to Brenner and Rector’s the kidney. 460. 1997. J Lab Clin Med. 432. 2008. 2000. Resuscitative hyperkalemia in noncrush trauma: a prospective.13:273-280. Gama R. Ann Intern Med.2:729–334. Vermeij CG.36:1125-1128. Severe hyperkalemia associated with “alternative” nutritional cancer therapy. et al. 2005. Arch Intern Med. Moore ML. Norris W. 1966. Eiro M. et al. Increase in serum potassium resulting from the administration of hypertonic mannitol and other solutions. Kaufenberg AJ. Crowe AV.19:694-699. Int Urol Nephrol.64:357-370. Doig A. 1977. Bruce LJ. Skiner S. 1966. Makoff DL. 449. Internal potassium balance and the control of the plasma potassium concentration. Hypertonic expansion: acidbase and electrolyte changes. Cautopyreiophagia. et al. Casatta L. acquired Gitelman’s and Bartter’s syndrome in chronic sialoadenitis. et al. Decrease in serum potassium concentrations and appearance of cardiac arrhythmias during infusion of potassium with glucose in potassium-depleted patients.346:140. 429. Complex ventricular arrhythmia induced by overuse of potassium supplementation in a young male football player. J Accid Emerg Med. Mil Med. Indications for hospitalization of patients with hyperkalemia. Han JS. et al. Farrow SJ. A cause of erroneous potassium levels. Surawicz B. 457.45:481-490. 1985. 1998. Nicolis GL. et al. Ahmed J. 1962. 440. et al. Hasbargen JA. Hyperkalemic cardiac arrest with hypertonic mannitol infusion: the strong ion difference revisited. Therapeutic approach to hypokalemia. 2006. 431. 1987. Nebulized albuterol for acute hyperkalemia in patients on hemodialysis. 418. 438. Jennings AE.14:348-356. Abbott KC. 1975.163:719-721. et al. 450. Therapeutic implications.326:35-36.2:809-811. Holmes E. Clinical physiology of acid-base and electrolyte disorders.102:766-769. Murphy C. Weisberg LS. 415. Two cases of hyperkalemia after administration of hypertonic mannitol during craniotomy. Wexler HR. 416. Freeman RM. 1989.125:404-409. Am J Med. et al.141:49-53. 1991. eds. 414. et al. J Am Soc Nephrol. Ascherio A. Deland EC. Hypokalemia. 2000.17:188-191. 1982. Follow-up of markedly elevated serum potassium results in the ambulatory setting: implications for patient safety. Subramani K. 685 442. Takamine W. New York: McGraw-Hill. Hypokalaemic alkalosis. Drug-induced hyperkalemia. Anderson P. 423.106:1062-1069.104:225-226. et al. 421. Watanabe T. 2009. Kanazi GE. et al. Seftel HC. Moore CR. Flynn BC. Arch Intern Med. Hyperkalemia in dialysis patients. Nat Genet. Efficacy and safety of potassium infusion therapy in hypokalemic critically ill patients. Kunin AS. 465. Ferraccioli GF. et al.238:608-610. Spurious hyperkalaemia due to EDTA contamination: common and not always easy to identify. 2000. 463. Medicine (Baltimore). 437. 2001.277:478-480. Crit Care Med. Graber M. Einhorn LM. Lin JJ. Karlmark B. Carlson RW. 2001. and low plasma renin. 413. Sevastos N.43:436-443. Katoh T. Rastergar A.39:641-648. Moe OW. 441. Dietary potassium and stroke-associated mortality. Rastegar A. Post TW. Baz EM. Kahn T. Noni juice (Morinda citrifolia): hidden potential for hyperkalemia? Am J Kidney Dis. et al.12:383386. 452. Smith HM. Pseudohyperkalemia due to pneumatic tube transport in a leukemic patient.21:115-124. et al. Hyperkalemia caused by penicillin. 2002. et al.60:339-354. Am J Kidney Dis. 464.24:864-865. Hamm LL. Villamil MF.36:1049-1053. Hirota K. 436. 1989. Feig PU. 1972. Pseudohyperkalemia in patients with increased cellular components of blood. 1975. 1985. Semin Dial. 1970. Baum M. Henney RP. 425. Clin Pharmacol Ther.35:310-312. 1942. Glucose-induced hyperkalemia in diabetic subjects. Giebisch G. Toto RD.316:235-240. 2005. 2002. Ford C. O’Connor N. 467. Pediatrics. Goldfarb DS.42:214-216. Oliver Jr TK. Ann Intern Med. Theophylline toxicity and the β-adrenergic system. Comparison of surgery and prolonged spironolactone therapy in patients with hypertension. Diabetes. observational study. Postgrad Med J. et al. 2005.113:1350-1357.46:746-748. Keith NM. Rose BD. Sterns RH. 1993.45:601-603. et al.
et al. 534. et al. Isolated hypoaldosteronism in adults. 500. McCauley J. Selective hypoaldosteronism with hyperreninemia in a diabetic patient. Lindenfeld S. Raja R. 1977. Coluzzi F. South Med J. Fishman LM. 488. Franco R. 495. Am J Med. N Engl J Med. Koren-Michowitz M. Oelkers W. Oh MS. Impaired K+ regulation contributes to exercise limitation in end-stage renal failure.17:191-195. Prevalence and possible origin. 2004. Jabr RI. Arch Intern Med. Van Gaal LF. 1997. 2002. Spontaneous puberty in 46. 482.86:1008-1012. Early onset of hyperkalemia in patients treated with low molecular weight heparin: a prospective study. Achermann JC.30:31-59:vi. et al. 1977. Nguyen HV. Renin-aldosterone system can respond to furosemide in patients with hyperkalemic hyporeninism. 1988. Heparin-induced aldosterone suppression and hyperkalemia. Adrenal function in the human immunodeficiency virus–infected patient. Singer I. Intensive Care Med. J Am Soc Nephrol. Am J Kidney Dis. 2000. et al. 516. Arch Intern Med. Fukuyama J. Kayes-Wandover KM. Collazos J.299:164-169. 510. and phenotypic expression in adults. 2003. Hyperkalemia in diabetic ketoacidosis. Mactier RA. et al.87:3248-3254. J Clin Endocrinol Metab. Stockigt JR. et al. Semiz S. et al. Q J Med. Milionis HJ. Australas J Ageing. A mechanism for hyporeninemic hypoaldosteronism in chronic renal disease. Molecular physiology of the thiazide-sensitive sodiumchloride cotransporter. J Clin Invest.17:1429-1436. Falana B. 1999.15:113-114.90:538-541. Human hypertension caused by mutations in WNK kinases. Kruer JJ. Magnus Nzerue C. DuBose Jr TD. International Congenital Lipoid Adrenal Hyperplasia Consortium. 538. Platau E. Kidney Int. 1996. J Clin Endocrinol Metab. 1975.82:1624-1632. Adrenal insufficiency. Bui T. Effect of selective aldosterone deficiency on acidification in nephron segments of the rat inner medulla. 1992. Adrenal dysfunction in patients with renal amyloid. 477. Biglieri EG. Report of 10 cases and review of literature. Isolated corticotropin deficiency in adults. Extrarenal potassium homeostasis with maximal exercise in end-stage renal disease. 486.90:783-785. and severe adrenal failure. 1995. Jameson JL. Shannon C. 1992.19:307-309. et al. Black H. N Engl J Med. Paradoxical glucose-induced hyperkalemia. Gordon RD. 522. hypercalciuria. 527.86:268-271. N Engl J Med. 533. Hung DZ. et al. Pseudohypoaldosteronism type II: marked sensitivity to thiazides. et al. 491. Mol Cell Endocrinol. 512. Clark BA. Functional expression of a pseudohypoaldosteronism type I mutated epithelial Na+ channel lacking the pore-forming region of its alpha subunit. Amelioration of type 4 renal tubular acidosis in chronic renal failure with furosemide. 2002. 2001. 507. Hyperkalemia in end-stage renal disease: mechanisms and management. Fulop M. Mower MM. 2004. 1999.13:299-302.17:343-346. Am J Kidney Dis. Fuhrman TM. Metabolism. Am J Nephrol. Endocrinol Metab Clin North Am.99:1265-1271. Kidney Int. 1986. J Clin Endocrinol Metab. 528.72:188-192. Wilson AJ. 509. 2003. Sugawara T. Shapiro R. Schindler RE. Am J Hypertens. 537. J Clin Invest. Autosomal dominant pseudohypoaldosteronism type 1: mechanisms. J Clin Invest. Pediatr Res. Fray JC. Brown RS. et al. Fujieda K. 525.43:e31-e35. 1998. 2003. et al. 530. et al. Sangkabutra T. Akcay A.59:744-750. Anesthesiology.288:40-43. 513. 1990. 506. Tunny TJ. 1993. 1999. Am J Med. et al. 493. Dimos G. Refractory hyperkalaemia associated with use of ε-aminocaproic acid during coronary bypass in a dialysis patient.87:1019-1025. Lancet. Phenotypic spectrum of mutations in DAX-1 and SF-1. 523.78:660-663. XX subjects with congenital lipoid adrenal hyperplasia. 480. Circ Res.63:283-290. Prognostic implications of hyperkalemia in toad toxin intoxication. Ann Intern Med. complete 46. Hassan ZU. . J Clin Endocrinol Metab. Danby P. 524. Itsarayoungyuen K. 1977. Mayo J. Tajima T. J Clin Anesth. et al. Perazella MA. Science. 496. DuBose TD. 492. King JA. Am J Med Sci. Thapa S. Tan SY. et al. 1980.15:15571561. 532.335:1206-1212. Yamamoto T. Taylor HC. 518. Martyn JA. A renin-deficiency syndrome. Cohen RA. Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity.91:237-241. Oster JR. 1997. et al. 2001. Role of atrial natriuretic factor in changes in the responsiveness of aldosterone to angiotensin II secondary to sodium loading and depletion in man. Speiser PW. Baltazar RF. 490.335:1870-1878. Diabetic ketoacidosis–induced hyperkalemia. 2000. et al. 526. et al. Isolated adrenal mineralocorticoid deficiency due to amyloidosis associated with familial Mediterranean fever. Clapp LH. 485. 504.23:1157-1166. Meeks JJ.104:967-974. et al. N Engl J Med. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. Amelioration of metabolic acidosis with fludrocortisone therapy in hyporeninemic hypoaldosteronism. Am J Kidney Dis. 1990.162:10951098.6:1134-1142. Bekaert JL.33:782-785. Hum Exp Toxicol. Acute fluoride poisoning leading to fatal hyperkalemia. et al.148:397-401. 2006. et al. Reider R. Kayes-Wandover KM. 2002.16:296299. Schambelan M. Blumenfeld JD. Caflisch CR. normomagnesemia. Clin Exp Pharmacol Physiol. Electrolyte changes during craniotomy caused by administration of hypertonic mannitol. 1995. Kidney Int. Am J Physiol. drug-related potassium-channel syndrome by glibenclamide. Molecular basis of adrenal insufficiency. Sebastian A. 520. 1990. Kidney Int. 502. 511. Indomethacin-induced prostaglandin inhibition with hyperkalemia.51:591-602. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. Espinosa G. Hyperkalemia induced by indomethacin and naproxen and reversed by fludrocortisone. 503. DeFronzo RA. et al. 2002. and low bone mineral density. J Clin Endocrinol Metab. et al. 2002. Acute hyperkalemia associated with intravenous ε-aminocaproic acid therapy. Toad venom poisoning: resemblance to digoxin toxicity and therapeutic implications.185:17-25. 2006. Congenital hyperreninemic hypoaldosteronism unlinked to the aldosterone synthase (CYP11B2) gene. et al. et al. 481. 531. et al. Sirken G. Ann Intern Med. et al. 1990. Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients. Garces J. 2001.297:576-583.57:62R-69R. DeFronzo RA. 1972. 1998. Geller DS. 1996. Succinylcholine-induced hyperkalemia in patients with renal failure: an old question revisited.89:e14. 2000. J Am Soc Nephrol.86:5379-5382. Hyperkalemia in the elderly. Severe hyperkalaemia in association with diabetic ketoacidosis in a patient presenting with severe generalized muscle weakness. Khanna R. 2005. 2003. Heart. Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights.43:983-999. J Pediatr Endocrinol Metab. 535. Pseudohypoaldosteronism type 1 and respiratory distress syndrome. Type 1 aldosterone synthase deficiency presenting in a middle-aged man. Combined aldosterone-insulin deficiency. Gowda RM. 1979. Pathophysiology of low renin syndromes: sites of renal renin secretory impairment and prorenin overexpression. Agmon D. et al. Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms. Hu WH. 489. Hiort O. 487.12:451-459. Reversal of life-threatening. et al. Richtsfeld M. Impaired renal tubular potassium secretion in sickle cell disease. 2009. Elisaf MS.18:421-427. Medicine (Baltimore). Ann Intern Med. Singer I.263:F116-F126.293:1107-1112. 1982. Bonny O. Mayan H. Am J Med. et al. 2005. Curr Opin Nephrol Hypertens.132:229-235. Taufield PA. Contrast-induced translocational hyponatremia and hyperkalemia in advanced kidney disease. 505. 2007. 501. 2001. Lush DJ. et al. 508. Ko B. Tuchelt H. 498. Biochemical correction in the syndrome of hypertension and hyperkalaemia by severe dietary salt restriction suggests renin-aldosterone suppression critical in pathophysiology. 1996. 519. 1988. Green J. 529. 479. De Leeuw IH.7:1223-1227. Goldfarb S. 494. Sebastian A. Arch Intern Med. 1984. 521. Khan IA. Brull SJ. Nephrol Dial Transplant. O’Brien A.365:1873-1875. Mechanisms of hyperkalemia in systemic lupus erythematosus.49:742-747.12:416-418. Fujieda K. 2005. 478.82:106-118. Chan R. Biswas P. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. 1979. et al. 2009. Allon M. Batlle D.28:97. Nephrol Dial Transplant.287:573-578.18:198-200. Schambelan M. Wilson FH. Martinez E. et al. Schambelan M. J Lab Clin Med. Chest. Ling BN. Lee FO. 517. Eicosanoids modulate apical Ca2+dependent K+ channels in cultured rabbit principal cells.17:1150-1151. Arruda JA. evidence for neonatal lethality. Labetalol-induced hyperkalemia in renal transplant recipients. Michelis MF. et al. et al. 536.98:575-586. Singer M. Bose HS. 1974. Webster CL.686 Section II Disorders of Body Fluid Volume and Composition 476. Morimoto S. Intractable life-threatening hyperkalaemia in a diabetic patient.22:347-351. 1990.104:158-169. Pharmacoepidemiol Drug Saf. Nephrol Dial Transplant. Harris KP. Strauss 3rd JF. Klemm SA. Hoover RS. Yavuz T. Subcutaneous unfractionated heparininduced hyperkalaemia in an elderly patient. et al.79:57-65. A reversible cause of hyporeninemic hypoaldosteronism. 499. Calcium modulation of vascular smooth muscle ATP-sensitive K(+) channels: role of protein phosphatase-2B. 515. Williams B. Am J Med Sci. Liu AA. 483. J Am Soc Nephrol. Chi HT. 1988. 514.76:915-922. Jackson E. Clin Sci (Lond). 484.12:534. Eaton DC. β-Adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. 2001. 497. Strunk B. Nzerue CM. Anesth Analg.152:1705-1712. 1979. Hasegawa K.81:799-801.90:310-316. Ovarian steroidogenesis is spared to some extent despite inactivating mutations in the steroidogenic acute regulatory protein (StAR) gene. XY sex reversal. Impaired renal tubular potassium secretion in systemic lupus erythematosus.
Semin Dial. 596.45:174-176.127:430-436. Spironolactone use and renal toxicity: population based longitudinal analysis. Schwarz KC. N Engl J Med. 1995. 561.119:296-301. Pergola PE. 543. N Engl J Med. Frenette L. Nath KA.328:703-706. et al. 1989. Rowe JW. in patients with left ventricular dysfunction after myocardial infarction.19:266-272. et al. In: Basow DS. Nephron Physiol. et al. Montoliu J. Alonso AB. 564. Severe acidosis and hyperpotassemia treated with sodium bicarbonate infusion. 2009. 578. 1976. 576. Gross P. 550. Hoff HE. N Engl J Med. Am J Physiol.Chapter 17 Disorders of Potassium Balance 539. Am J Med. 2000. 1982. N Engl J Med. 1988. Eplerenone.41:369-374. Plasma ionic calcium levels following injection of chloride.78:677-682. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Eaton DC. A randomized. Management of emergencies. Pistrosch F. Giebisch G.92(suppl 1):33-40. 2010. Kidney Int. et al. Am J Kidney Dis. Allon M. Subcutaneous terbutaline use in CKD to reduce potassium concentrations. 597. Waltham. 1936. Perazella MA. 1966. 2002.145:505-508.246:E174E180. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. 2009. Shaw S. Mechanisms of impaired potassium handling with dual renin-angiotensin-aldosterone blockade in chronic kidney disease. Treatment and prevention of hyperkalemia in end-stage renal disease. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. 2002.109:307-314. N Engl J Med. 2004. Tan SY. Raskin P.20:2641-2650. 569. 573.147:713-717. Miyata Y. eds. 551. et al. Wahren J. 1993. 589. Cases A. 585. et al.35:572-573. The additive effects of calcium and digitalis. Am J Cardiol.85:507-512. 580. Philadelphia: Lippincott Williams & Wilkins. Maggiorini M. et al. 565. et al. 1996. Alappan R. 687 568. 2004. 555.351:2448-2450:[author reply. Hyperkalaemia with cyclooxygenase-2 inhibition and hypoaldosteronism. 570. 544. Brown M. 546. Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure. 588.348:1309-1321. 1999. Cohen DL. 577.13:279-280. Nephrol Dial Transplant. Effect of trimethoprimsulfamethoxazole on Na+ and K+ transport properties in the rabbit cortical collecting duct perfused in vitro. Wei L. Treatment of hyperkalaemia in renal failure: salbutamol v. et al. Jones J.4:228-232. 2003. Hyperkalemia. Miner Electrolyte Metab. Tsuruoka S. et al. controlled trial. J Intensive Care Med. Kidney Int. J Am Soc Nephrol. nonselective cyclooxygenase inhibition on dynamic renal potassium excretion: a randomized trial. 595. 2000:1647-1700. 1999. Arch Intern Med. 1987. Fahey T. Roberts C. 552. Schneider HG. Emerg Med J. Ann Intern Med. 1991. 598. 549. Pharmacoepidemiol Drug Saf.12:1254-1255.19:92-93. Tomos P. et al. 545. et al. 556. 2005. et al. Johnson ES.71:609-613. 574. a selective aldosterone blocker.53:754-760. 2010. The kidney: physiology and pathophysiology. 2010. Cyclooxygenase-2 inhibition and renal physiology. Potassium homeostasis and renin-angiotensinaldosterone system inhibitors.32:2225-2226. 579. Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients. Salbutamol metered-dose inhaler with spacer for hyperkalemia: how fast? How safe? Chest. Preston RA. 560. Richardson R. Calcium salts in management of hyperkalaemia. Insulin-mediated potassium uptake is normal in uremic and healthy subjects. 1984. Caldicott D. Palmer BF. et al. 1993. Ann Intern Med. Blumberg A. 558. Adams-Huet B. 2009. Best evidence topic report.19:444-450. et al. De Wolf A. Effect of hypertonic versus isotonic sodium bicarbonate on plasma potassium concentration in patients with end-stage renal disease. Managing hyperkalemia caused by inhibitors of the reninangiotensin-aldosterone system.19:215-220. Trimethoprim-sulfamethoxazole–induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study. Kidney Int. 2000. Preston RA. Terrovitou C. Goldfarb DS. Perazella MA. 2010. White RD. Oishi M. Davey M. Liou HH. 2010. et al. Hyperkalemia after the publication of RALES. J Am Soc Nephrol. insulin. 542. et al. 557. et al. Therapeutic approach to hyperkalemia. Sutherland DE. 562. Ann Intern Med.45:1040-1045. Schlessinger F. vol 2. .118:1643-1650. Climacteric. Ferrari P. Blumberg A. Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients. 2006. 590. Insulin decreases the serum potassium concentration during the anhepatic stage of liver transplantation. 2002. J Thorac Cardiovasc Surg. Alvestrand A.10(suppl 1):11-18. 548. Lubash GD.115:617-622. Hypokalemic effects of intravenous infusion or nebulization of salbutamol in patients with chronic renal failure: comparative study. 1989. Severe hyperkalaemia after cotrimoxazole administration in a patient with hyporeninaemic hypoaldosteronism. Ling BN. 2004. 547. DeFronzo R. et al. ed. Revert L. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Smith PK. Juurlink DN. Bantle JP. Transplant Proc. Ruilope LM.341:709-717. Am J Kidney Dis. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). et al. Factors affecting the toxicity of potassium.89:10D-17D. Acute renal failure and hyperkalaemia associated with cyclooxygenase-2 inhibitors. Perazella MA. 586. 1999. Cyclosporine A suppresses cyclooxygenase-2 expression in the rat kidney.23:266-271. N Engl J Med. Montoliu J. et al. Emmett M. In: Seldin DW. Preferred therapy of hyperkalemia in renal insufficiency: survey of nephrology training-program directors. 2008. Pitt B. Hocherl K. Cyclosporin A inhibits apical secretory K+ channels in rabbit cortical collecting tubule principal cells. J Clin Endocrinol Metab. UpToDate. Bakris G.351:543-551. 2005.17:297-302. Kang Y. 1939. Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS. Iqbal Z. Allon M. Pitt B. BMJ. Mount DB. Townsend RR. 593. 1977. Afshartous D. Ann Intern Med. 1985. Anesthesiology. Is there added value to adding ARB to ACE inhibitors in the management of CKD? J Am Soc Nephrol. Mulhern JG. Clin J Am Soc Nephrol. 1993. Am J Med. et al. 2000.22:366-367. Lam Q. Clinical disorders of hyperkalemia. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensinconverting enzyme inhibition in diabetic nephropathy.102:51-60. Oster JR. Nephrol Dial Transplant. Rodriguez R.38:869-872. Weidmann P. 1990. Venzin RM. 559. Greenwood C. A mechanism for pentamidine-induced hyperkalemia: inhibition of distal nephron sodium transport. Mengle HAK. Am J Physiol. Clin Pharmacol Ther. 572. 1993. Kim HJ. Vitzthum H. Pitt B. 584. Ling BN. O’Shea MH. Choi MJ. Potassium homeostasis during hyperinsulinemia: effect of insulin level. Buller GK. Rolfe M. Goldsmith RS. Clin Nephrol. Pei Y. Levinsky NG. Evans KJ. Ostovar H. Mehdi UF. et al. 540. 599. 2004. Wright FS. Greenberg A. Drospirenone and its antialdosterone properties. et al. 2005. Han SW. VI. Lens XM.124:316-320. Antoniou T. Am J Kidney Dis. Mannella P. 2000. MA. Circulation. Copkney C. Nephrol Dial Transplant. Drug-induced hyperkalemia: old culprits and new offenders. Swan SK. 575.351:585-592.242:E373E377. 567. Gutierrez R. 2004. Nephron. Aliskiren-associated acute renal failure with hyperkalemia. et al. Circulation.122:103-106. Nephrol Dial Transplant. Minaker KL. et al. and age. Muto S. Randomized Aldactone Evaluation Study Investigators. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities. 2002. et al. Mandelberg A.22:314-319. 2009. et al. 1959. 571. Perazella MA. UpToDate. 594. 1992. Weidmann P. 583.13:2427-2436.43:1197-1209. Genazzani AR. Hypertension.20:272-290. Harris Jr RC. Cronin D. Am J Physiol. 1993.106:1151-1153. Renal mechanism of trimethoprim-induced hyperkalemia.44:974984. 600. 587. 2008. N Engl J Med.274:1076-1077. 582. 1993. Arch Intern Med. Conn Med. 554. 592. Mulrow PJ. Emerg Med J. Kidney Int.19:2163-2166.5:531-548. Elisaf M.20:16661668. Cohen BD. and gluceptate salts of calcium. Arch Intern Med. et al. Effects of selective vs. JAMA. Velazquez H. Mueller BA. Sowinski KM. Non-dialytic treatment of acute hyperkalemia in the dialysis patient. 541. Struthers AD. Intern Med J. Treatment and prevention of hyperkalemia. Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure. Braden GL. Hyperkalemia: a review. Simoncini T. Predicting the risk of hyperkalemia in patients with chronic kidney disease starting lisinopril. 1997.170:1045-1049. 1994. 2007. 2004. 553. 2005. Bower JO. Higgins R. Winkler AW. gluconate. 581. et al. Approach to hyperkalemic end-stage renal disease patients in the emergency department. Nephrol Dial Transplant. Cohen CD. Friedman EA. 3rd ed. 591. 563. Lens XM. Potassium-lowering effect of albuterol for hyperkalemia in renal failure.340:c1768. Nebulised levalbuterol or albuterol for lowering serum potassium. A case of hyperkalemic distal renal tubular acidosis secondary to tacrolimus in living donor liver transplantation. Dreher F.63:131-136. Inhibition of the renin-aldosterone response to furosemide by indomethacin.133:1-9.19:1149-1153. 566.320:60-61. et al. 2448-2450]. Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin.71:326-328. N Engl J Med. beta-blockade. Kleyman TR. Extrarenal effect of cyclosporine A on potassium homeostasis in renal transplant recipients. Hyperkalaemia: again.84:208-211. Weir MR. Smith D.
et al. et al. 1998.312:1289-1290.108:752-760. 1950. 1986. Allon M. Hwang ER.50:2063-2069. Ng YY. 658. New insights into diuretic use in patients with chronic renal disease. Michelson EL. 1996. 2003.59:S33-S35. Controversial issues in the treatment of hyperkalaemia.52:2813-2815. Effect of dialysate sodium concentration on interdialytic increase of potassium.21:733-735.38:26-29. Elkinton JR. 639. Sutton JM. Asano Y. Maesaka JK. Surgery. J Crit Care.16:5-7. Reduction of serum calcium by sodium sulfonated polystyrene resin. Gerstman BB. Gales BJ. 1996. Roser HW. Effect of albuterol treatment on subsequent dialytic potassium removal. Am J Surg Pathol. Evans BM. 2006. et al. Burns. Wilcox CS. Berne TV. Reversal of trimethoprim-induced antikaliuresis. Kirkman R. 2001. Am J Kidney Dis. The faster potassium-lowering effect of high dialysate bicarbonate concentrations in chronic haemodialysis patients. 619. DeFronzo RA. Control of hyperkalemia with fludrocortisone in a patient with systemic lupus erythematosus. Hyperkalaemic cardiac arrest successfully treated with peritoneal dialysis. Burry L.3:333-337. Sherman RA. 1994. Redaelli B. Santoro A. Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease. Effect of a new model of hemodialysis potassium removal on the control of ventricular arrhythmias. Huber A.47:809-814. 610. Management of hyperkalemia with cation-exchange resin. Kidney Int. Bernholc AS. Yoon SH. 640. et al. et al. A randomized controlled trial of fludrocortisone for the treatment of hyperkalemia in hemodialysis patients. Williams TE. Milne MD. 1989. 1985. Dangers of resonium A in the treatment of hyperkalemia in renal failure. Papadimitriou M. 627. et al.50:609-617. 1992. Flinn RB. 648. 642. 653. Chung JH. Jackson MA. Hamilton SR. 2010. 1936. Acute decreases in serum potassium augment blood pressure. 635. Am J Kidney Dis.33:179-183. et al. 2000. Nephrol Dial Transplant. 1961. 2002. Gastroenterology. 628. Agarwal R. Rombola G.6:284-288. 643. 629. endoscopic. Fludrocortisone for the treatment of heparin-induced hyperkalemia. 1980. Kidney Int. 1997. Brown S. Sherman DS. Bernstein P. 618. Furuya R. Linakis JG. 2001. Pathophysiology of potassium absorption and secretion by the human intestine. Management of severe hyperkalemia without hemodialysis: case report and literature review.36:212-218. Int J Artif Organs. Lancet. Colonic necrosis and perforation following oral sodium polystyrene sulfonate (Resonium A/Kayexalate) in a burn patient. Gruy-Kapral C. 644.18:2215-2218. 2007. Chou SY. Chisholm GD.28:508-514. Kaisar MO. Nephrol Dial Transplant. Hypercalcaemia from calcium ion-exchange resin in patients on regular haemodialysis. Nephron. Ogden DA. Ellis KJ. Gales MA. 2005. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. Am J Kidney Dis. Shaw AB. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol. Kamel KS. 606. Upper gastrointestinal tract injury in patients receiving Kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical. Fish DN. acid-base and potassium changes. 2009. Effect of fludrocortisone acetate on reducing serum potassium levels in patients with end-stage renal disease undergoing haemodialysis.220:547-552.20:591-597. 607. 2006. 630. Nootens J. Chu G. Ann Pharmacother. et al. Kumagai H. 1997. Zehnder C. McGowan CE. 622. et al. Am J Surg Pathol. Lodwick R. 614. et al. Dreyling KW. De Ferrari ME. 1968. Am J Kidney Dis. et al.53:201-207. Hou S. Schambelan M. 1997. 1995. 656. Am J Nephrol. Amelioration of hyperchloremic acidosis with furosemide therapy in patients with chronic renal insufficiency and type 4 renal tubular acidosis. J Formos Med Assoc. Sebastian A.11:2337-2343. et al.12:1629-1634. Lancet. Tsuruta H. 1961. Fordtran JS.1:1470. et al. et al. Sodium polystyrene sulfonate treatment for lithium toxicity: effects on serum potassium concentrations.26:607-613. Cardiac arrhythmias on hemodialysis in chronic renal failure patients. A study of incidence and contributory factors.264:111-115.265:791-795. Amaya F. 2008. 604. 1995. The effect of potassium on the excitability and resting metabolism of frog’s muscle. 641. Caramelo C. 1996. 603. Hemodialysate composition and intradialytic metabolic. et al. Mead AW. relationship with dialytic potassium removal and total body potassium. Plasma potassium in patients with terminal renal failure during and after haemodialysis. 626.101:267-272. Safety and efficacy of low-potassium dialysate. Variability in potassium removal by hemodialysis. N Engl J Med. Bhagavan BS. 1987.19:697-699. Allon M. 633. Suki WN.102: 493-497.28:189-190. 1996. Zehnder C. et al. 615. Berlyne GM. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol. 650. Cardiac arrhythmias in hemodialysis patients. Am J Med Sci. Merrill JP. Kidney Int. Gingell JC. Rectally administered sodium polystyrene sulfonate. 2002. Ward RA. Brueggemeyer CD. Simulation of potassium extraction by continuous haemodiafiltration. 647. Dolson GM. 616. Wizemann V.32:129-135. Abraham SC. Rojas M.688 Section II Disorders of Body Fluid Volume and Composition 601. 1994.2:948-950. Dialysis-induced cardiac arrhythmias: fact or fiction? Importance of preexisting cardiac disease in the induction of arrhythmias during renal replacement therapy.4:287-300.39:356-360. 659. Am J Nephrol. Reiser IW.23:1415-1421. et al. Blumberg A. Hemodial Int. Am J Physiol. Kidney Int. Hyperkalaemia after cyclosporin therapy. et al. Lapinsky SE. 1953. J Am Soc Nephrol. Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion. Janabi K. et al. 605. 2002. Cheng ES. Ion-exchange resins in the treatment of anuria. et al. 1984. et al. Imbriano LJ.20:159-161. 637.107:548-571. Colussi G. Rashid A. Morrison G. 2000. Effect of acetate-free biofiltration with a potassiumprofiled dialysate on the control of cardiac arrhythmias in patients at risk: a pilot study.86:162-170. 624. Nephron. Cardiac arrhythmias and electrolyte changes during haemodialysis. Mechanism and prevention of cardiac arrhythmias in chronic hemodialysis patients. Effect of bicarbonate administration on plasma potassium in dialysis patients: interactions with insulin and albuterol. Bernardo MV. 2003. 1984. Dyer ME. et al. et al.37:180-185. et al. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. 1990. . Nephrol Dial Transplant. Stringer KM. Sterns RH. 1984. Newton JL. Wei C. 634. Shanklin N. Allon M. Acad Emerg Med. 617. Kim DM.1:167-169. J Am Soc Nephrol. 611. et al. 638. Fukui M. Traba ML.264:115-119. Investigations into the mechanisms of hyperkalemia following renal transplantation. et al. Baron AD.34:606-610. et al. Kidney Int. 2002. Lee LA. Tabei K. Semin Dial. 625.13:798-805. De Nicola L. Monzu B. Petersen KC.16:78-84. Pegg SP. et al. Treatment of potassium retention in uremia with cation exchange resin: preliminary report. et al. Nephron. 655. et al. 621. et al. Emmett M. 612. J Am Soc Nephrol.21:316-321. 1995.21:60-69. et al. 1994. Use of diuretics in chronic renal failure. Scherr L. 602. Potassium-lowering effect of mineralocorticoid therapy in patients undergoing hemodialysis. et al. Wathen RL. Hemodynamic actions of insulin. Heguilen RM.17:811-819. Nephrol Dial Transplant. 609. 1989. Am J Health Syst Pharm. McElroy PA.30:198-201. 645. Nephrol Dial Transplant. Intestinal necrosis associated with postoperative orally administered sodium polystyrene sulfonate in sorbitol. Jones NC. Saha S. 651. Treating interdialytic hyperkalemia with fludrocortisone. Nephron.22:3273-3276. Anaesth Intensive Care. Nephron. Kramer W. 2008. 1995. Funke T.12:108-113. 613. et al. Gastroenterology. Afzalpurkar R.89:399-402. Medical and dialytic management of hyperkalemia in hemodialysis patients.9:1924-1930. and histopathologic findings. Platt R. Shanklin N.13:137-143. 652. 623. 1977. Squires RD. 1984. Low-potassium and glucosefree dialysis maintains urea but enhances potassium removal. J Physiol (Lond).68:148. N Engl J Med. Durham JH. Kidney Int Suppl. Brown MI. 1996. 631. Lillemoe KD. Am J Kidney Dis. Welzant WR. Sakao T. 1996. Effect of potassium-chelating resins on phosphorus absorption. BMJ. 657. Lancet. Kyriakidis M. Nephrol Dial Transplant. 608. 649. 1987. Kass CL.267:E187E202. Lancet. 1966.11:357-365.25:637-644. South Med J. Kimura K. Nephron. Chronic hemodialysis: high risk patients for arrhythmias? Nephron. 646. Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in sorbitol. Silberman H.7:318-322. Cardiac arrhythmias in chronic renal failure? Holter monitoring during dialysis and everyday activity at home.26:321-326. 632. 1992. Clin Nephrol. Solandt DY. et al. Weber H. Carvalhana V.92:576-581. Ramirez G. Gutzwiller JP. Hutchinson SG. Munoz RI. Schollmeyer P. Nephrol Dial Transplant. 620. 1984. Am J Kidney Dis. 654. Clark JK. 1990. et al. Patients with complex arrhythmias during and after haemodialysis suffer from different regimens of potassium removal. 636. Wanner C.
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