The hypokalemic effect of insulin has been known since the early 20th century. The impact of insulin on plasma K ⁺ and plasma glucose is separable at multiple levels, suggesting independent mechanisms. For example, despite impaired glucose uptake, peripheral K ⁺ uptake is not impaired in humans with type 2 diabetes. Notably, the hypokalemic effect of insulin is not kidney dependent. Insulin and K ⁺ appear to form a feedback loop of sorts, in that increases in plasma K ⁺ have a marked stimulatory effect on insulin levels. Insulin-stimulated K ⁺ uptake, measured in rats using a “K ⁺ clamp” technique, is rapidly reduced by 2 days of K ⁺ depletion, before a modest drop in plasma K ⁺ , and in the absence of a change in plasma K ⁺ in rats subject to a lesser K ⁺ restriction for 14 days. Insulin-mediated K ⁺ uptake is thus modulated by the factors that serve to preserve plasma K ⁺ in the setting of K ⁺ deprivation (see also “Control of Potassium Secretion: The Effect of Potassium Intake” later). Inhibition of basal insulin secretion in normal subjects by somatostatin infusion increases serum K ⁺ by up to 0.5 mmol/L, in the absence of a change in urinary excretion, emphasizing the crucial role of circulating insulin in the regulation of plasma K ⁺ . Clinically, inhibition of insulin secretion by the somatostatin agonist octreotide can cause significant hyperkalemia in both anephric patients and patients with normal renal function.

Insulin stimulates the uptake of K ⁺ by several tissues, most prominently liver, skeletal muscle, cardiac muscle, and fat. It does so by activating several K ⁺ transport pathways, with particularly well-documented effects on the Na ⁺ /K ⁺ -ATPase. 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, it is clear that this is not the primary mechanism in most cell types. Insulin induces translocation of the Na ⁺ /K ⁺ -ATPase α-2 subunit to the plasma membrane of skeletal muscle cells, with a lesser effect on the α-1 subunit. This translocation is dependent on the activity of phosphoinositide-3 kinase (PI-3) kinase, which itself also binds to a proline-rich motif in the N-terminus of the α subunit. The activation of PI3-kinase by insulin thus induces phosphatase enzymes to dephosphorylate a specific serine residue adjacent to the PI3-kinase binding domain. Trafficking of Na ⁺ /K ⁺ -ATPase to the cell surface also appears to require the phosphorylation of an adjacent tyrosine residue, perhaps catalyzed by the tyrosine kinase activity of the insulin receptor itself. Finally, the “serum and glucocorticoid-induced 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. The hypokalemic effect of insulin plus glucose is blunted in SGK1 knockout mice, with a marked reduction in hepatic insulin-stimulated K ⁺ uptake.

The sympathetic nervous system plays a prominent role in regulating the balance between extracellular and intracellular K ⁺ . Again, as is the case for insulin, the effect of catecholamines on plasma K ⁺ has been known for some time ; however, a complicating issue is the differential effect of stimulating α- and β-adrenergic receptors. Uptake of K ⁺ by liver and muscle, with resultant hypokalemia, is stimulated via β ₂ receptors. The hypokalemic effect of catecholamines appears to be largely independent of changes in circulating insulin and has been reported in nephrectomized animals. The cellular mechanisms whereby catecholamines induce K ⁺ uptake in muscle include activation of the Na ⁺ /K ⁺ -ATPase, likely via increases in cyclic-AMP. 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. ^,

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

The association between changes in pH and plasma K ⁺ was observed some time ago. It has long been held that acute disturbances in acid-base equilibrium result in changes in serum K ⁺ , such that alkalemia shifts K ⁺ into cells, whereas acidemia is associated with K ⁺ release. ^, It is thought that this apparent K ⁺ -H ⁺ exchange and/or K ⁺ -HCO ₃ ^– cotransport serves to help maintain extracellular pH. Several different transport mechanisms together result in net exchange of K ⁺ with H ⁺ including functional coupling between Na ⁺ -H ⁺ exchangers with the Na ⁺ /K ⁺ -ATPase, coupling between Na ⁺ -2HCO ₃ ^– cotransport with the Na ⁺ /K ⁺ -ATPase, and coupling between Cl ^– -HCO ₃ ^– exchange and K ⁺ -Cl ^– cotransporters.

Rather limited data exist for the durable concept that a change of 0.1 unit in serum pH will result in 0.6 mmol/L change in serum K ⁺ in the opposite direction. However, despite the complexities of changes in K ⁺ homeostasis associated with various acid-base disorders, a few general observations can be made. The induction of metabolic acidosis by the infusion of mineral acids (NH ₄ ⁺ -Cl ^– or H ⁺ -Cl ^– ) consistently increases serum K ⁺ , whereas organic acidosis generally fails to increase serum K ⁺ . ^, Notably, a newer report failed to detect an increase in serum K ⁺ in normal human subjects with acute acidosis secondary to duodenal NH ₄ ⁺ -Cl ^– infusion, in which a modest acidosis was accompanied by an increase in circulating insulin. However, as noted by Adrogué and Madias, the concomitant infusion of 350 mL of D5W in these fasting subjects may have served to increase circulating insulin, thus blunting the potential hyperkalemic response to NH ₄ ⁺ -Cl ^– . Clinically, use of the oral phosphate binder sevelamer-hydrochloride in patients with end-stage renal disease (ESRD) is associated with acidosis, due to effective gastrointestinal absorption of H ⁺ -Cl ^– ; in hemodialysis patients, this acidosis has been associated with an increase in serum K ⁺ , which can be ameliorated by an increase in dialysis bicarbonate concentration. Of note, hyperkalemia is not an expected complication of sevelamer-carbonate, which has generally supplanted sevelamer-hydrochloride as a phosphate binder.

Metabolic alkalosis induced by sodium-bicarbonate infusion usually results in a modest reduction in serum K ⁺ . ^{, ,} Respiratory alkalosis reduces plasma K ⁺ , by a magnitude comparable with that of metabolic alkalosis. ^{, , ,} Finally, acute respiratory acidosis increases plasma K ⁺ ; the absolute increase is smaller than that induced by metabolic acidosis secondary to inorganic acids. ^{, ,} Again, however, some studies have failed to show a change in serum K ⁺ following acute respiratory acidosis. ^, The smaller increments in serum K ⁺ with respiratory acidosis are explained in part by the elevated serum HCO ₃ ^– levels in respiratory acidosis, which blunt pH effects on the Na ⁺ -2HCO ₃ ^– cotransporter, resulting in lesser apparent K ⁺ -H ⁺ exchange than in metabolic acidosis.

The proximal tubule and loop of Henle mediate the bulk of potassium reabsorption, such that a considerable fraction of filtered potassium is reabsorbed before entry into the superficial distal tubules, Renal potassium excretion is primarily determined by regulated secretion in the distal nephron, specifically within the connecting segment (CNT) and cortical collecting duct (CCD). The principal cells of the CNT and CCD play a dominant role in K ⁺ secretion; the relevant transport pathways are shown in Figs. 16.2 and 16.4 . Apical Na ⁺ entry via the amiloride-sensitive epithelial Na ⁺ channel (ENaC) results in the generation of a lumen-negative potential difference in the CNT and CCD, which drives passive K ⁺ exit through apical K ⁺ channels. A critical, clinically relevant consequence of this relationship is that K ⁺ secretion is dependent on delivery of adequate luminal Na ⁺ to the CNT and CCD ^, ; K ⁺ secretion by the CCD essentially ceases as luminal Na ⁺ drops below 8 mmol/L. Selective increases in thiazide-sensitive Na ⁺ -Cl ^– cotransport in the distal convoluted tubule (DCT), as seen in familial hyperkalemia with hypertension (FHHt, see “Hyperkalemia: Hereditary Tubular Defects and Potassium Excretion” later), reduce Na ⁺ delivery to principal cells in the downstream CNT and CCD, leading to hyperkalemia. Dietary Na ⁺ intake also influences K ⁺ excretion, such that excretion is enhanced by excess Na ⁺ intake and reduced by Na ⁺ restriction ( Fig. 16.5 ). ^, Basolateral exchange of Na ⁺ and K ⁺ is mediated by the Na ⁺ /K ⁺ -ATPase, providing the driving force for both Na ⁺ entry and K ⁺ exit at the apical membrane (see Figs. 16.2 and 16.4 ) .

K ⁺ secretory pathways in principal cells of the connecting segment (CNT) and cortical collecting duct (CCD).

The absorption of Na ⁺ via the amiloride-sensitive epithelial sodium channel (ENaC) generates a lumen-negative potential difference, which drives K ⁺ excretion through the apical secretory K ⁺ channel ROMK. Flow-dependent K ⁺ secretion is mediated by an apical voltage-gated, calcium-sensitive BK channel. Chloride-dependent, electroneutral K ⁺ secretion is likely mediated by a K ⁺ -Cl ^– cotransporter. Water transport in principal cells occurs via aquaporin-2 (Aqp-2) and aquaporins-3/4 (Aqp-3/4).

(A) Relationship between steady-state plasma K ⁺ and urinary K ⁺ excretion in the dog, as a function of dietary Na ⁺ intake (mmol/day).

Animals were adrenalectomized and replaced with aldosterone, and dietary K ⁺ and Na ⁺ content were varied as specified. (B) Relationship between steady-state plasma K ⁺ and urinary K ⁺ excretion as a function of circulating aldosterone. Animals were adrenalectomized and variably replaced with aldosterone, dietary K ⁺ content was varied.

A from Young DB, Jackson TE, Tipayamontri U, Scott RC. Effects of sodium intake on steady-state potassium excretion. Am J Physiol. 1984;246:F772–778. B from Young DB. Quantitative analysis of aldosterone’s role in potassium regulation. Am J Physiol. 1988;255:F811–822.

Under basal conditions of high Na ⁺ -Cl ^– and low K ⁺ intake, the bulk of aldosterone-stimulated Na ⁺ and K ⁺ transport occurs in the CNT, before the entry of tubular fluid into the CCD. The density of both Na ⁺ and K ⁺ channels is thus considerably greater in the CNT than in the CCD ^, ; the capacity of the CNT for Na ⁺ reabsorption may be as much as 10 times greater than that of the CCD. The recruitment of ENaC subunits in response to dietary Na ⁺ restriction begins in the CNT, with progressive recruitment of subunits to the apical membrane of the CCD at lower levels of dietary Na ⁺ . The activity of secretory K ⁺ channels in the CNT is also influenced by changes in dietary K ⁺⁷⁴ with axial extension distally ; again, this is consistent with progressive, axial recruitment of transport capacity for the absorption of Na ⁺ and secretion of K ⁺ along the distal nephron.

Electrophysiologic characterization has documented the presence of several subpopulations of apical K ⁺ channels in the CCD and CNT, most prominently a small-conductance (SK) 30 pS channel ^, and a large-conductance, Ca ²⁺ -activated 150 pS (BK) channel ^, (see Fig. 16.4 ). The SK channel is thought to mediate K ⁺ secretion under baseline conditions, hence its designation as the “secretory” K ⁺ channel. SK channel activity is mediated by the ROMK ( R enal O uter M edullary K ⁺ channel) protein, encoded by the Kcnj1 gene; targeted deletion of this gene in mice results in complete loss of SK activity within the CCD. Increased distal flow has a significant stimulatory effect on K ⁺ secretion, due in part to both enhanced delivery and absorption of Na ⁺ and to increased removal of secreted K ⁺ . ^, The apical Ca ²⁺ -activated BK channel plays a critical role in flow-dependent K ⁺ secretion by the CNT and CCD. BK channels have a heteromeric structure, with α-subunits that form the ion channel pore and modulatory β-subunits. The β1 subunits of BK channels are restricted to principal cells within the CNT, ^, whereas β4 subunits are detectable at the apical membranes of TAL, DCT, and intercalated cells. Flow-dependent K ⁺ secretion is reduced in mice with targeted deletion of the α1 and β1 subunits, ^{, ,} consistent with a dominant role for BK channels. The Ca ²⁺ -permeable TRPV4 channel increases intracellular Ca ²⁺ concentrations in response to tubular flow, resulting in the activation of BK channels. Additional work has demonstrated a critical role for the PIEZO1 mechanosensitive basolateral calcium-permeable channel in activating flow-dependent K ⁺ secretion.

In addition to apical K ⁺ channels, considerable evidence implicates apical K ⁺ -Cl ^– cotransport in distal K ⁺ secretion. ^{, ,} Pharmacologic studies of perfused tubules are consistent with K ⁺ -Cl ^– cotransport mediated by the KCC proteins, potentially mediated by KCC3a. A particularly provocative study underlines the importance of ENaC-independent K ⁺ excretion, be it mediated by apical K ⁺ -Cl ^– cotransport and/or by other mechanisms. Rats were infused with amiloride via osmotic minipumps, generating urinary concentrations considered sufficient to inhibit >98% of ENaC activity. Whereas amiloride almost abolished K ⁺ excretion in rats on a normal K ⁺ intake, acute and long-term high-K ⁺ diets led to an increasing fraction of K ⁺ excretion that was independent of ENaC activity (∼50% after 7–9 days on a high-K ⁺ diet).

In addition to secretion, the distal nephron is capable of considerable reabsorption of K ⁺ , particularly during restriction of dietary K ⁺ . ^{, , ,} This reabsorption is accomplished primarily by intercalated cells in the outer medullary collecting duct (OMCD), via the activity of apical H ⁺ /K ⁺ -ATPase pumps (see Fig. 16.2 ).

Aldosterone is well established as an important regulatory factor in K ⁺ excretion, and increases in plasma K ⁺ are an important stimulus for aldosterone secretion (see also “Regulation of Renal Renin and Adrenal Aldosterone” later). However, an important principle is that aldosterone plays a permissive, synergistic, but not essential role in K ⁺ homeostasis. This is reflected clinically in the frequent absence of hyperkalemia or hypokalemia in disorders associated with a deficiency or an overabundance of circulating aldosterone, respectively (see “Hyperaldosteronism” and “Hypoaldosteronism”). Regardless, 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 concentrations (see Fig. 16.5 ).

Aldosterone has no effect on the density of apical SK channels in the CCD or CNT; rather, the hormone induces a marked increase in the density of apical Na ⁺ channels, thus increasing the driving force for apical K ⁺ excretion. The apical amiloride-sensitive epithelial Na ⁺ channel (ENaC) is composed of three subunits, α-, β-, and γ-, that assemble together to synergistically traffic to the cell membrane and mediate Na ⁺ transport. Aldosterone activates ENaC channel complexes by multiple mechanisms. First, it induces transcription of the α-ENaC subunit, ^, increasing the availability for coassembly with the more abundant β and γ subunits. Second, aldosterone and dietary Na ⁺ -Cl ^– restriction stimulate a significant redistribution of ENaC subunits in the CNT and early CCD, from a largely cytoplasmic location during dietary Na ⁺ -Cl ^– excess to a purely apical distribution after aldosterone or Na ⁺ -Cl ^– restriction. ^{, ,} Third, aldosterone induces the expression of a serine-threonine kinase called SGK-1 (serum and glucocorticoid-induced kinase-1) ; coexpression of SGK-1 with ENaC subunits results in increased expression at the plasma membrane. SGK-1 modulates membrane expression of ENaC by interfering with regulated endocytosis of its channel subunits. Specifically, the kinase interferes with interactions between ENaC subunits and the ubiquitin-ligase Nedd4-2. The so-called “PPxY” domains in the C-termini of all three ENaC subunits bind to WW domains of Nedd4-2 ; these PPxY domains are deleted, truncated, or mutated in patients with Liddle syndrome (see “Liddle Syndrome” later), leading to a gain-of-function in channel activity. Nedd4-2 ubiquitinates ENaC subunits, thus inducing removal of channel subunits from the cell membrane followed by degradation in lysosomes and the proteasome. A PPxY domain in SGK-1 also binds to Nedd4-2, which is a phosphorylation substrate for the kinase; phosphorylation of Nedd4-2 by SGK-1 abrogates the inhibitory effect of this ubiquitin ligase on ENaC subunits ( Fig. 16.6 ). This signaling axis appears to be activated in a K+-dependent fashion by the upstream mTORC2 kinase.

Coordinated regulation of ENaC by the aldosterone-induced SGK kinase and the ubiquitin-ligase Nedd4-2.

Nedd4-2 binds via its WW domains to ENaC subunits via their “PPXY” domains (denoted PY here), ubiquitinating the channel subunits and targeting them for removal from the cell membrane and destruction in the proteasome. Aldosterone induces the SGK kinase, which phosphorylates and inactivates Nedd4-2, thus increasing surface expression of ENaC channels. Mutations that cause Liddle syndrome affect the interaction between ENaC and Nedd4-2.

From Snyder PM, Olson DR, Thomas BC. Serum and glucocorticoid-regulated kinase modulate Nedd4-2-mediated inhibition of the epithelial Na ⁺ channel. J Biol Chem. 2002;277:5–8.

Another mechanism whereby aldosterone activates ENaC involves proteolytic cleavage of the channel proteins by serine proteases. A “channel-activating protease” that increases channel activity of ENaC was initially identified in Xenopus laevis A6 cells. The mammalian ortholog, denoted CAP1 (channel-activating protease-1) or prostasin, is an aldosterone-induced protein in principal cells. Urinary excretion of CAP1 is increased in hyperaldosteronism, with a reduction after adrenalectomy. CAP1 is membrane associated, via a glycosylphosphatidylinositol (GPI) linkage ; mammalian principal cells also express two transmembrane proteases, denoted CAP2 and CAP3, with homology to CAP1. These and other proteases (furine, plasmin, etc.) activate ENaC by excising extracellular inhibitory domains from the α and γ subunits, increasing the open probability of channels at the plasma membrane. ^, This proteolytic cleavage of ENaC appears to activate the channel by removing the “self-inhibitory” effect of external Na ⁺ ; in the case of furin-mediated proteolysis of αENaC, this appears to involve the removal of an inhibitory domain from within the extracellular loop. Extracellular Na ⁺ appears to interact with a specific acidic cleft in the cleaved extracellular loop of α-ENaC, causing inhibition of the channel. Since SGK-1 increases channel expression at the cell surface, one would expect synergistic activation by coexpressed CAP1-3 and SGK; this is indeed the case. Therefore aldosterone activates ENaC by at least three separate synergistic mechanisms; induction of α-ENaC, induction of SGK-1 and repression of Nedd4-2, and induction of channel-activating proteases. Clinically, the inhibition of channel-activating proteases by the protease inhibitor nafamostat causes hyperkalemia, due to inhibition of ENaC activity. ^,

Changes in K ⁺ intake strongly modulate K ⁺ channel activity in the CNT and CCD (secretory capacity), in addition to H ⁺ /K ⁺ -ATPase activity in the OMCD (reabsorptive capacity). Increased dietary K ⁺ rapidly increases the activity of SK channels in the CCD and CNT, ^, along with a modest increase in Na ⁺ channel (ENaC) activity ; this is associated with an increase in apical expression of the ROMK channel protein. The increase in ENaC and SK channel density in the CCD occurs within hours of assuming a high-K ⁺ diet, with a minimal associated increase in circulating aldosterone. BK channels in the CNT and CCD are also activated by dietary K ⁺ loading. Trafficking of BK subunits is thus affected by dietary K ⁺ , with largely intracellular distribution of α-subunits in K ⁺ -restricted rats and prominent apical expression in K ⁺ -loaded rats. Again, aldosterone does not directly contribute to the regulation of BK channel activity or expression in response to a high-K ⁺ diet. However, aldosterone does participate in marked upregulation of the TRPV4 channel in response to a high-K ⁺ diet; Ca ²⁺ entry via TRPV4 increases intracellular Ca ²⁺ concentrations in response to tubular flow, thus activating BK channels. TRPV4 knockout mice demonstrate an impaired adaptation to a high-K ⁺ diet.

A complex, synergistic mix of signaling pathways regulates K ⁺ channel activity in response to changes in dietary K ⁺ . In particular, the WNK ( W ith N o L ysine) kinases play a critical role in modulating distal K ⁺ secretion. WNK1 and WNK4 were initially identified as the causative genes for FHHt (see also “Hyperkalemia: Hereditary Tubular Defects and Potassium Excretion” later). ROMK expression at the membrane of Xenopus oocytes is reduced by coexpression of WNK4; FHHt-associated mutations increase this effect, suggesting a direction inhibition of SK channels in FHHt. Transcription of the WNK1 gene generates several different isoforms; the predominant intrarenal WNK1 isoform is generated by a distal nephron transcriptional site that bypasses the N-terminal exons that encode the kinase domain, yielding a kinase-deficient “short” isoform (“WNK1-S”). Full-length WNK1 (WNK1-L) inhibits ROMK by inducing endocytosis of the channel protein; the shorter, kinase-deficient WNK1-S isoform inhibits this effect of WNK1-L, ^, and ROMK activity is impaired in WNK1-S knockout mice. The ratio of WNK1-S to WNK1-L transcripts is reduced by K ⁺ restriction (greater endocytosis of ROMK) ^, and increased by K ⁺ loading (reduced endocytosis of ROMK), ^, suggesting that this ratio between WNK1-S and WNK1-L functions as a molecular “switch” to regulate distal K ⁺ secretion. The BK channel is also regulated by the WNK kinases.

The membrane trafficking of ROMK is also modulated by tyrosine phosphorylation of the channel protein, such that tyrosine phosphorylation stimulates endocytosis and tyrosine dephosphorylation induces exocytosis. Intrarenal activity of the cytoplasmic tyrosine kinases, c-Src and c-Yes, is inversely related to dietary K ⁺ intake, with a decrease under high-K ⁺ conditions and a marked increase after several days of K ⁺ restriction. ^, Several studies have implicated the intrarenal generation of superoxide anions in the activation of cytoplasmic tyrosine kinases by K ⁺ depletion. Potential candidates for the upstream hormonal signals include angiotensin-II and growth factors such as IGF-1. In particular, angiotensin-II inhibits ROMK activity in K ⁺ -restricted rats, but not rats on a normal K ⁺ diet. This inhibition by angiotensin-II involves downstream activation of superoxide production and c-Src activity, such that the induction of angiotensin-II by low-K ⁺ diet appears to play a major role in reducing distal tubular K ⁺ secretion.

Under certain physiologic conditions associated with marked induction of aldosterone, such as dietary sodium restriction, Na ⁺ balance can be maintained without significant effects on K ⁺ excretion. Yet by activating ENaC and generating a more lumen-negative potential difference, increases in aldosterone should lead to an obligatory kaliuresis; how is this physiologic consequence avoided? The mechanisms that underlie this “aldosterone paradox,” the independent regulation of Na ⁺ and K ⁺ handling by the aldosterone-sensitive distal nephron has emerged. 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, ENaC-independent K ⁺ excretion within the distal nephron, and the differential regulation of various signaling pathways by aldosterone, angiotensin-II, and dietary K ^+132,133 (see also Chapter 6 ).

Electroneutral Na ⁺ -Cl ^– transport in the CCD and ENaC-independent K ⁺ secretion may play important roles in disconnecting Na ⁺ and K ⁺ transport within the distal nephron. Electroneutral, thiazide-sensitive, and amiloride-resistant Na ⁺ -Cl ^– transport within the CCD is mediated by the combined activity of the Na ⁺ -dependent Cl ^– -HCO ₃ ^– SLC4A8 Cl ^– -HCO ₃ ^– exchanger and the SLC26A4 Cl ^– -HCO ₃ ^– exchanger (see also Chapter 6 ). This transport mechanism is apparently responsible for up to 50% of Na ⁺ -Cl ^– transport in mineralocorticoid-stimulated rat CCD, ^, allowing for ENaC-independent, electroneutral Na ⁺ absorption that will not directly affect K ⁺ secretion. The converse effect emerges after dietary K ⁺ loading, which increases the fraction of ENaC-independent, amiloride-resistant K ⁺ excretion to ∼50%.

NCC, the thiazide-sensitive Na ⁺ -Cl ^– cotransporter in the DCT, plays a key role in K ⁺ homeostasis. Selective increases in DCT and NCC activity, as seen in FHHt, reduce Na ⁺ delivery to principal cells in the downstream CNT and CCD, leading to hyperkalemia. The DCT also clearly functions as a “potassium sensor,” directly responding to changes in circulating potassium. Reduction in potassium intake and/or hypokalemia thus leads to reduced basolateral [K ⁺ ] in the DCT; the subsequent hyperpolarization is dependent on basolateral Kir4.1-containing K ⁺ channels. Hyperpolarization leads to chloride exit, via basolateral CLC-NKB chloride channels, and a reduction in intracellular chloride; the reduction in intracellular chloride activates the WNK cascade, resulting in phosphorylation of NCC and activation of the transporter. Angiotensin-II also activates NCC via WNK-dependent activation of the SPAK kinase and phosphorylation of the transporter protein, ^, reducing delivery of Na ⁺ to the CNT and limiting K ⁺ secretion. In contrast, angiotensin-II inhibits ROMK activity via several mechanisms including downstream activation of c-src tyrosine kinases (see earlier). Whereas K ⁺ restriction induces renin and circulating angiotensin-II (see “Consequences of Hypokalemia”), increases in dietary K ⁺ are suppressive. ^, A high-K ⁺ diet also inactivates NCC due to the associated decrease in angiotensin-II, in addition to the increase in the ratio of WNK1-S to WNK1-L isoforms that occurs with increased K ⁺ intake ^{, ,} ; WNK1-S antagonizes the effect of WNK1-L on NCC, leading to inhibition of NCC in conditions with a relative excess of WNK1-S. Selective deletion of WNK1-S indicates that it plays a key role in the K+ switch pathway in the DCT. Nedd4-2 also negatively regulates NCC and WNK1, in addition to ENaC; mice with homozygous deletion of the Nedd4-2 gene develop severe hypokalemia during K ⁺ restriction, indicating a key role in renal adaptation.

Finally, within principal cells, increases in aldosterone induce the SGK1 kinase, which phosphorylates WNK4 and attenuates the effect of WNK4 on ROMK while activating ENaC. ^{, ,} However, when dietary K ⁺ intake is reduced, c-Src tyrosine kinase activity increases under the influence of increased angiotensin-II, causing inhibition of ROMK activity via tyrosine phosphorylation of the channel. ^, The increase in c-Src tyrosine kinase activity also abrogates the inhibitory effect of SGK1 on WNK4 ; Ssrc family tyrosine kinases also directly phosphorylate WNK4 and modulate its effects on ROMK. Again, angiotensin-II appears to mediate part of its inhibitory effect on ROMK through activation of c-Src, such that c-Src serves as an important component of the “switch” that regulates K ⁺ secretion in response to changes in dietary K ⁺ .

To summarize this important physiology, the differential effects of K ⁺ intake on angiotensin-II versus aldosterone appear to be critical in resolving the aldosterone paradox; 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 (see also Fig. 16.7 ). Under conditions of low-Na ⁺ intake but moderate K ⁺ intake, angiotensin-II and aldosterone are both strongly induced, leading to enhanced Na ⁺ -Cl ^– transport via NCC, increased ENaC activity, and decreased secretory K ⁺ channel activity. Although ENaC is activated, the relative inhibition of ROMK by the increased angiotensin-II prevents excessive kaliuresis. 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, leading to unopposed inhibition of ROMK by WN4. In addition, the aldosterone-dependent induction of electroneutral Na ⁺ -Cl ^– transport within the CCD increases Na ⁺ -Cl ^– reabsorption but blunts the effect on the lumen-negative potential, thus limiting kaliuresis. When dietary K ⁺ increases, circulating aldosterone is moderately induced but angiotensin-II is suppressed. This leads to inhibition of NCC and increased downstream delivery of Na ⁺ to principal cells in the CNT and CCD, where ENaC activity is increased and ROMK and BK channels are significantly activated. ENaC-independent K ⁺ secretion is also strongly induced by increased dietary K ⁺ intake, contributing significantly to the ability to excrete K ⁺ in the urine.

Integrated regulation of Na ⁺ -Cl ^– and K ⁺ transport in the DCT, CNT, and CCD.

Green arrowheads (activating pathways), red blunt end (inhibitory pathway). The left panel shows the pathway in the setting of a low-Na ⁺ diet, wherein Ang-II and SGK-1 signaling leads to phosphorylation of WNK4. This stimulates phosphorylation of SPAK, which in turn phosphorylates and activates thiazide-sensitive Na ⁺ -Cl ^– cotransport in the DCT via NCC. Stimulation of unknown receptors is hypothesized to cause phosphorylation of L-WNK1, which can also stimulate SPAK phosphorylation. L-WNK1 has other functions: 1. It blocks the NCC-inhibitory form of WNK4, thus activating NCC; and 2. It inhibits secretion of K ⁺ via ROMK channels. The right panel shows the pathway in the setting of high dietary K ⁺ intake, wherein aldosterone is stimulated and Ang-II is low. In the absence of sufficient Ang-II, AT1R cannot activate WNK4. This reduces SPAK activation and NCC phosphorylation. Dietary potassium loading also increases the level of KS-WNK1 isoform to suppress the activity of L-WNK1. In consequence, the inhibitory effect of WNK4 on NCC dominates, blocking traffic of NCC to the apical membrane and thereby reducing NCC activity. KS-WNK1 also blocks the effect of L-WNK1 on ROMK endocytosis, causing ROMK to increase at the apical membrane. The net effect is that K ⁺ secretion in the DCT and CNT/CCD is maximized, whereas NCC is suppressed. Aldosterone stimulation of ENaC (not shown) offsets the decreased Na ⁺ reabsorption by NCC, allowing robust potassium secretion without changes in sodium balance. The roles of WNK3, SGK1, and c-src cytoplasmic tyrosine kinases are not shown in the interest of clarity; see text for further details. NCC, NaCl cotransporter; ROMK, renal outer medullary K channel; SPAK, STE20/SPS1-related proline/alanine-rich kinase; WNK, With-No-K(lysine) kinase.

From Welling PA, Chang YP, Delpire E, Wade JB. Multigene kinase network, kidney transport, and salt in essential hypertension. Kidney Int. 2010;77:1063–1069.

Modulation of the renin-angiotensin-aldosterone (RAAS) axis has profound clinical effects on K ⁺ homeostasis. Although multiple tissues are capable of renin secretion, renin of renal origin has a dominant physiologic impact. Renin secretion by juxtaglomerular cells within the afferent arteriole is initiated in response to a signal from the macula densa, specifically a decrease in luminal chloride transported through the Na ⁺ -K ⁺ -2Cl ^– cotransporter (NKCC2) at the apical membrane of macula densa cells. In addition to this macula densa signal, decreased renal perfusion pressure and renal sympathetic tone stimulate renal renin secretion. The various inhibitors of renin release include angiotensin-II, endothelin, adenosine, atrial natriuretic peptide (ANP), TNF-α, and active vitamin D. The cGMP-dependent protein kinase type II (cGKII) tonically inhibits renin secretion, in that renin secretion in response to several stimuli is exaggerated in homozygous cGKII knockout mice. Activation of cGKII by ANP and/or nitric oxide has a marked inhibitory effect on the release of renin from juxtaglomerular cells. Local factors that stimulate renin release from juxtaglomerular cells include prostaglandins, adrenomedullin, catecholamines (β-1 receptors), and succinate (GPR91 receptor).

The relationship between renal renin release, the RAAS, and cyclooxygenase-2 (COX-2) is particularly complex. COX-2 is heavily expressed in the macula densa, with significant recruitment of COX-2 ⁽⁺⁾ cells seen with salt restriction or furosemide treatment. ^, Reduced intracellular chloride in macula densa cells appears to stimulate COX-2 expression via p38 MAP kinase, whereas both aldosterone and angiotensin-II reduce its expression. Prostaglandins derived from COX-2 in the macula densa play a dominant role in the stimulation of renal renin release by salt restriction, furosemide, renal artery occlusion, or angiotensin-converting enzyme (ACE) inhibition. ^, Specifically, COX-2–derived prostaglandins appear to play a role in tonic expression of renin in JG cells, via modulation of intracellular cyclic-AMP and calcium, rather than functioning in the acute regulation of renin release. Prostaglandins generated by the macula densa also participate in the recruitment during salt restriction of CD44 ⁺ mesenchymal stromal cells, which differerentiate into renin-producing cells.

Renin released from the kidney ultimately stimulates aldosterone release from the adrenal via angiotensin-II (AT-II). Hyperkalemia per se is also an independent and synergistic stimulus (see Fig. 16.8 ) for aldosterone release from the adrenal gland, ^, although dietary K ⁺ loading is less potent than dietary Na ⁺ -Cl ^– restriction in increasing circulating aldosterone. The resting membrane potential of adrenal glomerulosa cells is hyperpolarized, due to the activity of the “leak” K ⁺ channels TASK-1 and TASK-3; combined deletion of genes encoding these channels leads to baseline depolarization of adrenal glomerulosa cells and an increase in serum aldosterone that is resistant to dietary sodium loading. AT-II and K ⁺ both activate Ca ²⁺ entry in glomerulosa cells, via voltage-sensitive T-type Ca ²⁺ channels, ^, primarily Cav3.2. Elevations in extracellular K ⁺ thus depolarize glomerulosa cells and activate these Ca ²⁺ channels, which are independently and synergistically activated by AT-II. Calcium-dependent activation of calcium-calmodulin (CaM)-CaM-dependent protein kinase in turn activates the synthesis and release of aldosterone, via induction of aldosterone synthase. K ⁺ and AT-II also enhance transcription of the Cav3.2 Ca ²⁺ channel, by abrogating repression of this gene by the neuron restrictive silencing factor (NRS); this ultimately amplifies the induction of aldosterone synthase.

Synergistic effect of increased extracellular K ⁺ and angiotensin-II (ANG-II) in inducing aldosterone release from bovine adrenal glomerulosa cells.

Dose-response curves for ANG-II were performed at extracellular K ⁺ of 2 mmol/L (ο) and 5 mmol/L (•).

From Chen XL, Bayliss DA, Fern RJ, Barrett PQ. A role for T-type Ca ²⁺ channels in the synergistic control of aldosterone production by ANG II and K ⁺ . Am J Physiol. 1999;276:F674–683.

The role of adrenal K ⁺ sensing in aldosterone release has been dramatically underlined by the reports of both germline and somatic mutations, in aldosterone-producing adenomas, of transport proteins that control membrane excitability of adrenal zona glomerulosa cells (see also “Hyperaldosteronism” later). For example, somatic mutations in the adrenal K ⁺ channel, KCNJ5 (GIRK4), can be detected in ∼40% of aldosterone-producing adrenal adenomas ; these mutations endow the channel with a novel Na ⁺ conductance, leading to adrenal glomerulosa cell depolarization, Ca ²⁺ influx, and aldosterone release.

The adrenal release of aldosterone due to increased K ⁺ is dependent on an intact adrenal renin-angiotensin system, particularly during Na ⁺ restriction. ACE-inhibitors and angiotensin-receptor blockers (ARBs) thus completely abrogate the effect of high K ⁺ on salt-restricted adrenals. Direct, G-protein-dependent activation of the TASK-1 and/or TASK-3 K ⁺ channels by AT _1A or AT _1B receptors is thought to underlie the effect of AT-II on adrenal aldosterone release, with abrogation of this effect by ARBs or ACE-inhibitors. Other clinically relevant activators of adrenal aldosterone release include prostaglandins and catecholamines, via increases in cyclic-AMP. ^, Finally, ANP exerts a potent negative effect on aldosterone release induced by K ⁺ and other stimuli, at least in part by inhibiting early events in aldosterone synthesis. ANP is therefore capable of inhibiting both renal renin release and adrenal aldosterone release, functions that may be central to the pathophysiology of hyporeninemic hypoaldosteronism.

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

The expected values of the TTKG are largely based on historical data and are <3 to 4 in the presence of hypokalemia and >6 to 7 in the presence of hyperkalemia; the shifting opinions regarding the physiologically appropriate TTKG in hyperkalemia have been reviewed multiple times. Clearly, water absorption in the CCD and medullary collecting duct is an important determinant of the absolute K ⁺ concentration in the final urine; hence the use of a ratio of urine-to-plasma osmolality. Indeed, water absorption may in large part determine the TTKG, such that it far exceeds the limiting K ⁺ gradient. More recently, the originators of the TTKG have suggested that it fails to incorporate the putative effects of distal tubular urea reabsorption in K ⁺ excretion; however, neither urea transporter knockout mice nor rats treated with a urea transporter inhibitor demonstrate abnormalities in K ⁺ homeostasis. The TTKG continues to play an important role in clinical investigation of potassium homeostasis. The TTKG may be less useful in patients ingesting diets of changing K ⁺ and mineralocorticoid intake. There is, however, a linear relation between plasma aldosterone and the TTKG, suggesting that it provides a rough approximation of the ability to respond to aldosterone with kaliuresis. The response of the TTKG to mineralocorticoid administration, typically fludrocortisone, can thus be utilized in the diagnostic approach to hyperkalemia. In hypokalemic patients, a TTKG of <2 to 3 separates patients with redistributive hypokalemia from those with hypokalemia due to renal potassium wasting, who will have TTKG values that are >4.

An alternative to the TTKG in hypokalemic patients is the measurement of urine K ⁺ :creatinine ratio. The urine K ⁺ :creatinine ratio is usually <13 meq/g creatinine (1.5 meq/mmol creatinine) when hypokalemia is caused by poor dietary intake, transcellular potassium shifts, gastrointestinal losses, or previous use of diuretics. Higher values are indicative of ongoing renal potassium wasting. The utility of the K ⁺ :creatinine ratio was evaluated in a study of 43 patients with severe hypokalemia (ranging 1.5–2.6 mmol/L) associated with paralysis. The urine K ⁺ :creatinine ratio reliably distinguished between the 30 patients with hypokalemic periodic paralysis and the 13 patients with hypokalemia due mostly to renal potassium wasting. The K ⁺ :creatinine ratio was thus significantly lower in the patients with periodic paralysis (11 vs. 36 meq/g creatinine, 1.3 vs. 4.1 meq/mmol creatinine). The cutoff value was approximately 22 meq/g creatinine (2.5 meq/mmol).

The determination of urinary electrolytes for calculation of the TTKG or urine K ⁺ :creatinine ratio provides the opportunity for the measurement of urinary Na ⁺ , which will determine whether significant prerenal stimuli are limiting distal Na ⁺ delivery and thus K ⁺ excretion (see also Fig. 16.5 ). Urinary electrolytes also afford the opportunity to calculate the urinary anion gap, an indirect index of urinary NH ₄ ⁺ content and thus the ability to respond to acidemia.

Hypokalemia is a well-described risk factor for both ventricular and atrial arrhythmias. ^, For example, in patients undergoing cardiac surgery, a serum K ⁺ of < 3.5 mmol/L is a predictor of serious intraoperative arrhythmia, perioperative arrhythmia, and postoperative atrial fibrillation. Moderate hypokalemia does not, however, appear to increase the risk of serious arrhythmia during exercise stress testing. Electrocardiographic changes in hypokalemia include broad flat T-waves, ST depression, and QT prolongation; these are most marked when serum K ⁺ is <2.7 mmol/L. Hypokalemia, often accompanied by hypomagnesemia, is an important cause of the long QT syndrome (LQTS) and torsades de pointes, either alone or in combination with drug toxicity or with LQTS-associated mutations in cardiac K ⁺ and Na ⁺ channels. Hypokalemia accelerates the clathrin-dependent internalization and degradation of the cardiac HERG (human ether-a-go-go) K ⁺ channel protein. HERG encodes pore-forming subunits of the cardiac rapidly activating delayed rectifier K ⁺ channel (I _Kr ); I _Kr is largely responsible for potassium efflux during phases 2 and 3 of the cardiac action potential. Loss-of- function mutations in HERG reduce I _Kr and cause type II LQTS ; downregulation of HERG and I _Kr by hypokalemia provides an elegant explanation for the association with LQTS and torsades de pointes.

In accordance with the Nernst equation, the resting membrane potential is related to the ratio of the intracellular to the extracellular potassium concentration. In skeletal muscle, a reduction in plasma K ⁺ will increase this ratio and therefore hyperpolarize the cell membrane (i.e., make the resting potential more electronegative); this impairs the ability of the muscle to depolarize and contract, leading to weakness. However, in some human cardiac cells, particularly Purkinje fibers in the conducting system, hypokalemia results in a paradoxical depolarization ; this paradoxic depolarization plays an important role in the genesis of hypokalemic cardiac arrhythmias. ^, Resting membrane potential in excitable cells is determined mostly by a large family of “K2P1” K ⁺ channels, so-named due to the presence of two pore-forming (P) loop domains in each subunit. Hypokalemia causes K2P1 channels, which are normally selective for potassium, to suddenly transport sodium into cells, causing paradoxical depolarization. Notably, rodent cardiac cells respond to hypokalemia with a Nernst equation–predicted hyperpolarization and, unlike human cardiomyocytes, do not express the K2P1 channel TWIK-1; genetic manipulation indicates that TWIK-1 expression confers this paradoxic depolarization behavior on human and mouse cardiomyocytes.

An additional mechanism for hypokalemia-induced arrhythmia involves downregulation of cardiac Na ⁺ /K ⁺ -ATPase activity. ^, The resulting increase in intracellular Na ⁺ , which impedes removal of intracellular Ca ²⁺ by the Na ⁺ -Ca ²⁺ exchanger and other mechanisms, leads to intracellular calcium overload. The ensuing increase in calmodulin kinase-II activity reduces repolarization reserve by activating late Na ⁺ and Ca ²⁺ currents. This, in turn, predisposes the heart to early afterdepolarization-associated arrhythmias, such as torsades de pointes and polymorphic ventricular tachycardia.

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

Hypokalemia causes a host of structural and functional changes in the kidney. In humans, the renal pathology includes a relatively specific proximal tubular vacuolization, ^, interstitial nephritis, and renal cysts. Hypokalemic nephropathy can cause ESRD, mostly in patients with longstanding hypokalemia due to eating disorders and/or laxative abuse ; acute renal failure with proximal tubular vasculopathy has also been described. In animal models, hypokalemia increases susceptibility to acute renal failure induced by ischemia, gentamicin, and amphotericin. Potassium restriction in rats induces cortical AT-II and medullary endothelin-1 expression, with an ischemic pattern of renal injury. Hypokalemic nephropathy in rats is associated with progressive capillary loss, with reduced angiogenesis due to reduced VEGF expression.

The prominent functional changes in renal physiology that are induced by hypokalemia include Na ⁺ -Cl ^– retention, polyuria, phosphaturia, hypocitraturia, and increased ammoniagenesis. K ⁺ depletion in rats causes proximal tubular hyperabsorption of Na ⁺ -Cl ^– , in association with an upregulation of AT-II, AT ₁ receptor, and the α ₂ -adrenergic receptor in this nephron segment. NHE3, the dominant apical Na ⁺ entry site in the proximal tubule, is massively (>700%) upregulated in K ⁺ -deficient rats, which is consistent with the observed hyperabsorption of both Na ⁺ -Cl ^– and bicarbonate. Polyuria in hypokalemia is due to polydipsia and a vasopressin-resistant defect in urinary concentrating ability. This renal concentrating defect is multifactorial, with evidence for both a reduced hydroosmotic response to vasopressin in the collecting duct and decreased Na ⁺ -Cl ^– absorption by the TAL. K ⁺ restriction has been shown to result in a rapid, reversible decrease in the expression of aquaporin-2 in the collecting duct, beginning in the CCD and extending to the medullary collecting duct within the first 24 hours. Downregulation of aquaporin-2 and several other proteins in hypokalemic nephrogenic diabetes insipidus appears to occur via autophagy. ^, In the TAL, the marked reductions seen during K ⁺ restriction in both the apical K ⁺ channel ROMK and the apical Na ⁺ -K ⁺ -2Cl ^– cotransporter NKCC2 reduce Na ⁺ -Cl ^– absorption, and thus inhibit countercurrent multiplication and the driving force for water absorption by the collecting duct.

A large body of experimental and epidemiologic evidence implicates hypokalemia and/or reduced dietary K ⁺ in the genesis or worsening of hypertension, heart failure, and stroke. K ⁺ depletion in young rats induces hypertension, with a salt sensitivity that persists after K ⁺ levels are normalized; presumably, this salt sensitivity is due to the significant tubulointerstitial injury induced by K ⁺ restriction. Hypokalemia has also been linked to vascular calcification and arterial stiffness, via induction of autophagy and promotion of vascular smooth muscle calcification. Short-term K ⁺ restriction in healthy humans and patients with essential hypertension also induces Na ⁺ -Cl ^– retention and hypertension, and abundant epidemiologic data link dietary K ⁺ deficiency and/or hypokalemia with hypertension. ^, Correction of hypokalemia is particularly important in hypertensive patients treated with diuretics; blood pressure in this setting is improved with the establishment of normokalemia, and the cardiovascular benefits of diuretic agents are blunted by hypokalemia. ^, Hypokalemia reduces insulin secretion; this mechanism may play an important role in thiazide-associated diabetes. Finally, K ⁺ depletion may play important roles in the pathophysiology and progression of heart failure.

Hyperkalemia constitutes a medical emergency, primarily due to its effect on the heart. Hyperkalemia depolarizes cardiac myocytes, reducing the membrane potential from–90 mV to ∼–80 mV. This brings the membrane potential closer to the threshold for generation of an action potential; mild and/or rapid onset hyperkalemia will initially increase cardiac excitability since a lesser depolarizing stimulus is required to generate an action potential. Mild increases in extracellular K ⁺ also affect the repolarization phase of the cardiac action potential, via increases in I _Kr ; as discussed earlier (see “Consequences of Hypokalemia”), I _Kr is highly sensitive to changes in extracellular K ⁺ . This effect on repolarization is thought to underlie the “early” signs of hyperkalemia including ST-T segment depression, peaked T-waves, and Q-T interval shortening. Persistent and increasing depolarization inactivates cardiac sodium channels, thus reducing the rate of phase 0 of the action potential (V _max ); the decrease in V _max results in a reduction in myocardial conduction, with progressive prolongation of the P wave, PR interval, and QRS complex. Severe hyperkalemia results in loss of the P wave and a progressive widening of the QRS complex; fusion with T-waves causes a “sine-wave” sinoventricular rhythm.

Cardiac arrhythmias associated with hyperkalemia include sinus bradycardia, sinus arrest, slow idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, and asystole ^, ; a multitude of mechanisms are involved. The differential diagnosis and treatment of a wide-complex tachycardia in hyperkalemia can be particularly problematic; moreover, hyperkalemia potentiates the blocking effect of lidocaine on the cardiac Na ⁺ channel, such that use of this agent may precipitate asystole or ventricular fibrillation in this setting. Hyperkalemia can also cause a type I Brugada pattern in the electrocardiogram (ECG), with a pseudo-RBBB and persistent “coved” ST segment elevation in at least two precordial leads. This “hyperkalemic Brugada sign” occurs in critically ill patients with significant hyperkalemia (serum K ⁺ >7 mmol/L) and can be differentiated from genetic Brugada syndrome by an absence of P waves, marked QRS widening, and an abnormal QRS axis.

Classically, the electrocardiographic manifestations in hyperkalemia progress as shown in Table 16.2 . However, these changes are notoriously insensitive, such that only 55% of patients with serum K ⁺ >6.8 mmol/L in one case series manifested peaked T-waves. There is large interpatient variability in the absolute potassium level leading to ECG changes and cardiac toxicity of hyperkalemia. Relevant variables include the rapidity of the onset of hyperkalemia ^, and the presence or absence of concomitant hypocalcemia, acidemia, and/or hyponatremia. ^, Hemodialysis patients and patients with chronic renal failure in particular may not demonstrate electrocardiographic changes. 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. The ratio of precordial T-wave to R-wave amplitude (T:R ratio) may be a more specific sign of hyperkalemia than T-wave tenting.

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

In contrast to secondary hyperkalemic paralysis, HYPP is a primary myopathy. Patients with HYPP develop myopathic weakness during hyperkalemia induced by increased K ⁺ intake or rest after heavy exercise. The hyperkalemic trigger in HYPP serves to differentiate this syndrome from hypokalemic periodic paralysis (HOKP); a further distinguishing feature is the presence of myotonia in HYPP. Depolarization of skeletal muscle by hyperkalemia unmasks an inactivation defect in a tetrodotoxin-sensitive Na ⁺ channel in patients with HYPP, and autosomal dominant mutations in the SCN4A gene encoding this channel cause most forms of the disease. Mild muscle depolarization (5–10 mV) in HYPP results in a persistent inward Na ⁺ current through the mutant channel; the normal, allelic SCN4 channels quickly recover from inactivation and can then be reactivated, resulting in myotonia. When muscle depolarization is more marked (i.e., 20–30 mV), all of the Na ⁺ channels are inactivated, rendering the muscle inexcitable and causing weakness ( Fig. 16.9 ). Related disorders due to mutations within the large SCN4A channel protein include HOKP type II, paramyotonia congenita, and K ⁺ -aggravated myopathy. American Quarter Horses have historically had a high incidence (4.4%) of HYPP due to a mutation in equine SCN4A traced to the sire “Impressive,” but the horse industry has worked to eliminate it. Since 2007, a foal that tests positive for this genetic disease cannot be registered by the American Quarter Horse Association (see Fig. 16.9 ). Finally, loss-of-function mutations in the muscle-specific K ⁺ channel subunit “MinK-related peptide 2” (MiRP2) have also been shown to cause HYPP; MiRP2 and the associated Kv3.4 K ⁺ channel play a role in setting the resting membrane potential of skeletal muscle.

Hyperkalemic periodic paralysis (HYPP) due to mutations in the voltage-gated Na ⁺ channel of skeletal muscle.

(A) This disorder is particularly common in American Quarter Horses; an affected horse is shown during a paralytic attack, triggered by rest after heavy exercise

A, Courtesy Dr. Eric P. Hoffman. B, From Lehmann-Horn F, Jurkat-Rott K. Voltage-gated ion channels and hereditary disease. Physiol Rev . 1999;79:1317–1372.

Hyperkalemia has a significant effect on the ability to excrete acid urine due to interference with the urinary excretion of ammonium (NH ₄ ⁺ ). Potassium loading in humans results in modest reduction in urinary NH ₄ ⁺ excretion and an impaired response to acid loading. In rats, chronic potassium loading leads to hyperkalemia and metabolic acidosis due to a 40% reduction in urinary NH ₄ ⁺ excretion. Proximal tubular ammonia generation falls but without a significant effect on proximal tubular secretion of NH ₄ ⁺ . The TAL absorbs NH ₄ ⁺ from the tubular lumen, followed by countercurrent multiplication and ultimately excretion from the medullary interstitium ; hyperkalemia appears to inhibit renal acid excretion by competing with NH ₄ ⁺ for reabsorption by the TAL.

The NH ₄ ⁺ ion has the same ionic radius as K ⁺ and can be transported in lieu of K ⁺ by NKCC2, the apical Na ⁺ -K ⁺ /NH ₄ ⁺ -2Cl ^– cotransporter of the TAL; NH ₄ ⁺ exits the TAL via the basolateral Na ⁺ /H ⁺ exchanger NHE4. As is the case for other cations, countercurrent multiplication of NH ₄ ⁺ by the TAL greatly increases the concentration of NH ₄ ⁺ /NH ₃ available for secretion in the collecting duct. The NH ₄ ⁺ produced by the proximal tubule in response to acidosis is thus reabsorbed across the TAL, concentrated by countercurrent multiplication in the medullary interstitium, and secreted in the collecting duct. The capacity of the TAL to reabsorb NH ₄ ⁺ is increased during acidosis, due to an induction of NKCC2 and NHE4 expression. Hyperkalemia induces acidosis in rats by reducing the NH ₄ ⁺ between the vasa recta (surrogate for interstitial fluid) and collecting duct due to interference with absorption of NH ₄ ⁺ by the TAL.

More recently, in a mouse model for hyporeninemic hypoaldosteronism with prominent, treatable (by hydrochlorothiazide) hyperkalemic acidosis, hyperkalemia was correlated with reduced expression of ammonia-generating enzymes in the proximal tubule, combined with upregulation of the ammonia-recycling enzyme glutamine synthetase. Hyperkalemia did not affect expression of NKCC2 or NHE3. However, these mice demonstrated decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H ⁺ -ATPase in the inner stripe of the OMCD, further compromising urinary NH ₄ ⁺ excretion. These various changes in enzyme and transporter expression were reversed by correcting the hyperkalemia.

Clinically, patients with hyperkalemic acidosis due to hyporeninemic hypoaldosteronism demonstrate an increase in urinary NH ₄ ⁺ excretion in response to normalization of plasma K ⁺ with cation-exchange resins, ^, indicating a significant role for hyperkalemia in generation of the acidosis.

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

A substantial and growing body of evidence indicates a key role in K ⁺ homeostasis for NCC, the thiazide-sensitive Na ⁺ -Cl ^– cotransporter in the DCT, such that it is not surprising that thiazide treatment has such potent effects on serum K ⁺ . Selective increases in DCT and NCC activity, as seen in FHHt, reduce Na ⁺ delivery to principal cells in the downstream CNT and CCD, leading to hyperkalemia. The DCT also clearly functions as a “potassium sensor,” directly responding to changes in circulating potassium. A high-K ⁺ diet also inactivates NCC, whereas NCC is activated in hypokalemia.

Other drugs associated with hypokalemia due to kaliuresis include toxic levels of acetaminophen, which causes dose-dependent hypokalemia. High doses of penicillin-related antibiotics are another important cause of hypokalemia, increasing obligatory K ⁺ excretion by acting as nonreabsorbable anions in the distal nephron; in addition to penicillin, implicated antibiotics include nafcillin, dicloxacillin, ticarcillin, oxacillin, and carbenicillin. Increased distal delivery of other anions such as SO ₄ ^2– and HCO ₃ ^– also induces kaliuresis. The usual explanation is that K ⁺ excretion increases so as to balance the negative charge of these nonreabsorbable anions. However, increased delivery of such anions will also increase the electrochemical gradient for K ⁺ -Cl ^– exit via apical K ⁺ -Cl ^– cotransport or parallel K ⁺ -H ⁺ and Cl ^– -HCO ₃ ^– exchange ^{, ,} (see also “Potassium Transport in the Distal Nephron”). Drugs are also an important cause of Fanconi syndrome, which is often associated with significant hypokalemia (see “Renal Tubular Acidosis” later).

Several tubular toxins result in both K ⁺ and magnesium wasting. These include gentamicin, which can cause tubular toxicity with hypokalemia that can masquerade as Bartter syndrome (BS). Other drugs that can caused mixed magnesium and K ⁺ wasting include amphotericin, foscarnet, cisplatin, ^, and ifosfamide. One intriguing cause of hypomagnesemia and hypokalemia is cetuximab, a humanized monoclonal antibody specific for the receptor for epidermal growth factor (EGF) ; paracrine EGF stimulates magnesium transport via the apical TRPM6 cation channel in the DCT, with magnesium wasting and hypomagnesemia in patients treated with cetuximab. Aggressive replacement of magnesium is obligatory in the treatment of combined hypokalemia and hypomagnesemia since successful K ⁺ replacement depends on treatment of the hypomagnesemia (see “Hypomagnesemia”).

A handful of drugs lead to hypokalemia through inhibition of 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2), resulting in unopposed mineralocorticoid activity of circulating cortisol. The classic 11βHSD-2 inhibitor is licorice, through the active components glycyrrhetinic/glycyrrhizinic acid and carbenoxolone. More recently, the antifungals itraconazole and posaconazole have been shown to inhibit 11βHSD-2, with several reports of hypertension and hypokalemia in patients treated with these agents ^, (see “Syndromes of Apparent Mineralocorticoid Excess” later).

Finally, the antiandrogen drug abiraterone, which is used to treat prostate cancer, can also cause apparent mineralocorticoid excess (AME) with hypokalemia and hypertension. Abiraterone inhibits the CYP17A1 enzyme, 17-alpha hydroxylase; decreases cortisol; and increases plasma corticotropin (ACTH). Increased ACTH leads to the generation of excessive amounts of deoxycorticosterone, which has potent mineralocorticoid effects, causing hypokalemia and hypertension. This ACTH-dependent mineralocorticoid excess seen with abiraterone therapy can be minimized by coadministration of glucocorticoids, use of mineralocorticoid receptor (MR) antagonists, or salt restriction.

Increases in circulating aldosterone (hyperaldosteronism) may be primary or secondary. Increased levels of circulating renin in secondary forms of hyperaldosteronism lead to increased angiotensin-II (AT-II) and thus aldosterone and can be associated with hypokalemia; causes include renal artery stenosis, Page kidney (renal compression by a subcapsular mass or hematoma, with hyperreninemia), a paraneoplastic process, or renin-secreting renal tumors. The incidence of hypokalemia in renal artery stenosis is thought to be <20%. An unusual presentation of renal artery stenosis and renal ischemia is the “hyponatremic hypertensive syndrome,” in which concurrent hypokalemia may be profound.

Primary hyperaldosteronism (PA) may have a hereditary, genetic cause. Hypertension and hypokalemia, generally attributed to increases in circulating 11-deoxycorticosterone, are seen in patients with congenital adrenal hyperplasia due to defects in either steroid 11β-hydroxylase or steroid 17α-hydroxylase ; deficient 11β-hydroxylase results in virilization and other signs of androgen excess, whereas reduced sex steroids in 17α-hydroxylase deficiency result in hypogonadism.

The two major hereditary forms of isolated PA are denoted familial hyperaldosteronism type I (FH-I, also known as glucocorticoid-remediable hyperaldosteronism or GRA) and familial hyperaldosteronism type II (FH-II), in which aldosterone production is not repressible by exogenous glucocorticoids. Patients with FH-II are clinically indistinguishable from sporadic forms of PA due to bilateral adrenal hyperplasia; a gene has been localized to chromosome 7p22 by linkage analysis but has yet to be characterized. A third form of familial hyperaldosteronism (FH-III) was initially described in 2008, with hyporeninemia, hyperaldosteronism resistant to dexamethasone, and high levels of 18-oxocortisol and 18-hydroxycortisol. FH-III is due to somatic mutations in the adrenal K ⁺ channel KCNJ5, which endow the channel with a novel Na ⁺ conductance and activate adrenal glomerulosa proliferation and aldosterone release ; somatic mutations in KCNJ5 are also found in spontaneous adrenal adenomas (see later). More recently, a fourth form of familial hyperaldosteronism (FH-IV) has been described; it is caused by autosomal dominant gain-of-function mutations in the CACNA1H gene, which encodes the CaV3.2 calcium channel. ^, The CaV3.2 calcium channel protein is expressed in human adrenal glomerulosa cells, and the mutant channels demonstrate gain-of-function phenotypes, leading to increased induction of aldosterone synthase in cultured adrenal cells. The clinical characteristics of patients with FH-IV have not been fully described, but the index patients developed PA in childhood and one subject had a multiplex developmental disorder. ^,

Patients with FH-I/GRA are generally hypertensive, typically presenting at an early age; the severity of hypertension is, however, variable, such that some affected individuals are normotensive. Aldosterone levels are modestly elevated and regulated solely by ACTH. The diagnosis can be biochemically confirmed by a dexamethasone suppression test, with suppression of aldosterone to <4 ng/dL consistent with the diagnosis. Patients also have high levels of abnormal “hybrid” 18-hydroxylated steroids, generated by transformation of steroids typically formed in the zona fasciculata by aldosterone synthase, an enzyme that is normally expressed in the zona glomerulosa. FH-I has been shown to be caused by a chimeric gene duplication between the homologous 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, fusing the ACTH-responsive 11β-hydroxylase promoter to the coding region of aldosterone synthase; this chimeric gene is thus under the control of ACTH and expressed in a glucocorticoid-repressible fashion. Ectopic expression of the hybrid CYP11B1- CYP11B1 gene in the zona fasciculata has been reported in a single case where adrenal tissue became available for molecular analysis. Direct genetic testing for the hybrid CYP11B1-CYP11B2 has largely supplanted biochemical screening for FH-I; genetic testing for FH-I should be pursued in patients with PA and a family history of PA and/or strokes at a young age, or in young patients with PA (<20 years of age). For reasons unclear, patients with FH-I have a high frequency of hemorrhagic stroke due to cerebral aneurysms, roughly equivalent to the frequency in autosomal polycystic kidney disease.

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

Acquired causes of PA classically include aldosterone-producing adenomas (APA, 35% of cases), primary or unilateral adrenal hyperplasia (PAH, 2% of cases), idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia (60% of cases), and adrenal carcinoma (<1% of cases). A rare case involving paraneoplastic overexpression of aldosterone synthase in lymphoma has also been described.

The molecular characterization of adrenal adenomas with whole-genome sequencing and related techniques has been remarkably fruitful. In particular, acquired mutations in the adrenal K ⁺ channel KCNJ5 can be detected in ∼40% of aldosterone-producing adrenal adenomas. As in FH-III (see earlier), these somatic mutations endow the channel with a novel Na ⁺ conductance, leading to adrenal glomerulosa cell depolarization, Ca ²⁺ influx, and aldosterone release. Clinically, patients with adrenal KCNJ5 mutations have higher preoperative aldosterone level and higher lateralization index in adrenal vein sampling, without affecting the surgical response to adrenalectomy. Less frequently, somatic mutations in adrenal adenomas can be detected in the calcium channel CACNA1D or in a subunit (ATP2B3) of the Ca ²⁺ -ATPase pump, predicted to also lead to increased Ca ²⁺ influx and aldosterone release. Acquired mutations in the ATP1A α1 subunit of the Na ⁺ /K ⁺ -ATPase are, in turn, thought to generate chronic depolarization, leading also to exaggerated aldosterone release. A common consequence of the mutations in these “aldosterone-driver genes” is that they ultimately increase aldosterone production through increased expression of aldosterone synthase (CYP11B2).

More recently, other pathways separate from aldosterone signaling have been implicated in the genesis of APAs. Mutations in the CTNNB1 gene encoding β-catenin have also been described in APAs. ^, The mutations described appear to stabilize β-catenin, suggesting a role in WNT signaling, which has previously been implicated in adrenal development and adrenal adenomas.

Landmark studies with monoclonal antibodies to CYP11B2 (aldosterone synthase) and CYP11B1 (steroid 11β-hydroxylase, which catalyzes the terminal step in cortisol production) have recently provided a molecular definition of the zonation of human adrenal cortices. ^, Whereas CYP11B1 expression is uniformly expressed throughout the zona fasciculata, there is only sporadic expression of CYP11B2 in the zona glomerulosa of normal human adrenal glands. However, a subcortical population of nonneoplastic clusters of cells can also be detected; given the coexpression of other steroidogenic enzymes that are required for aldosterone synthesis, these CYP11B2+ clusters have been designated “aldosterone-producing cell clusters” (APCCs). ^{, ,} APCCs have also been demonstrated in adrenal tissues adjacent to APAs, suggesting that APCCs are a precursor to APA. ^, Consistent with this hypothesis, mutations in the known “aldosterone-driver genes” can be seen in ∼35% of APCCs in normal adrenal glands.

Immunochemical characterization of APAs also indicates expression of cortisol-producing enzymes CYP17A1 and CYP11B1, ^, providing a molecular explanation for the hypercortisolism associated with hyperaldosteronism. ^, In hyperaldosteronism due to both BAH and APAs, there is significant urinary excretion of cortisol and other glucocorticoid metabolites, exceeded only in patients with clinically overt Cushing syndrome. Glucocorticoid excretion in primary aldosteronism appears to correlate better with metabolic risk (type 2 diabetes, osteoporosis, metabolic syndrome) than does aldosterone excretion. To the extent that hypercortisolism isn’t affected by mineralocorticoid antagonists, these findings tend to underscore the preference for adrenalectomy in APAs. Increasing utilization of the plasma aldosterone (PAC)/plasma renin activity (PRA) ratio in hypertension clinics has led to reports of a much higher incidence of PA than previously appreciated, with incidence rates in hypertension ranging from zero to 72% ; however, the prevalence was 3.2% in a large, multicenter study of patients with mild to moderate hypertension without hypokalemia. It should be noted that new studies have revealed that there is a continuum in renin-independent hyperaldosteronism, among normotensive individuals with suppressed renin and inappropriately “normal” or high aldosterone levels, individuals with unrecognized but biochemically overt PA, and individuals with severe hypertensive PA. ^, The presumed pathophysiology behind this continuum of increasing autonomous aldosterone secretion is the age-dependent development of APCCs, the evident precursor to APAs. ^{, ,} Regardless, the PAC:PRA ratio is a screening tool, which classically must be confirmed by aldosterone suppression testing, measuring PAC or aldosterone secretion after loading with salt or intravenous saline. After controlling hypertension and hypokalemia (serum K ⁺ ≥4.0 mEqu/L), oral salt loading over 3 days is followed by measurement of 24-hour urine aldosterone, sodium, and creatinine excretion; the 24-hour sodium excretion should exceed 200 mmol/day for adequate suppression, and a urinary aldosterone of >33 nmol/day (12 micrograms/day) is consistent with PA. Alternatively, in the saline infusion test, recumbent patients are infused with 2 L of isotonic saline over 4 hours, followed by measurement of PAC. In patients without PA, the measured PAC after saline infusion should decrease to <139 pmol/L (5 ng/dL). The measured PAC in patients with PA usually does not suppress to <277 pmol/L (10 ng/dL); indeterminate values between 139 and 277 pmol/l (5–10 ng/dL) can be seen in patients with IHA. Patients with high probability features (hypokalemia, hypertension, high PAC:PRA ratio, abnormalities) may not necessarily require confirmatory testing, proceeding instead directly to imaging and adrenal venous sampling.

Since surgery can be curative in APA, adequate differentiation of APA from IHA is critical; this requires both adrenal imaging and adrenal venous sampling (see Fig. 16.10 ). Contemporary reports and recommendations have thus emphasized the continued importance of adrenal vein sampling in subtype differentiation. Laparoscopic adrenalectomy is increasingly the preferred surgical management in APA or PAH. Radiofrequency ablation appears to be an effective alternative in patients judged to be inappropriate for surgery. MR antagonists are indicated for medical therapy of PA, with carefully monitored use of glucocorticoid to suppress ACTH in some patients with FH-I/GRA.

Diagnostic algorithm in patients with primary hyperaldosteronism.

Adrenal adenoma (APA) must be distinguished from glucocorticoid remediable hyperaldosteronism (FH-I or GRA), primary or unilateral adrenal hyperplasia (PAH), and idiopathic hyperaldosteronism (IHA). This requires computed axial tomography (CT), adrenal venous sampling (AVS), and the relevant diagnostic biochemical and hormonal assays (see text).

From Young WF Jr. Adrenalectomy for primary aldosteronism. Ann Intern Med. 2003;138(2):157–159.

The true incidence of hypokalemia in patients with acquired forms of PA remains difficult to evaluate, due to a variety of factors. First, historically, patients have only been screened for hyperaldosteronism when hypokalemia is present, so even recent case series from clinics with such a referral pattern may suffer from a selection bias; other series have concentrated on hypertensive patients, also a selection bias. Second, the incidence of hypokalemia is higher in adrenal adenomas than in IHA, likely due to higher average levels of aldosterone. Third, since increased kaliuresis in hyperaldosteronism can be induced by dietary Na ⁺ -Cl ^– loading or diuretics, dietary factors and/or medications may play a role in the incidence of hypokalemia at presentation. Fourth, as noted earlier, there is a continuum in renin-independent hyperaldosteronism, among normotensive individuals with suppressed renin and inappropriately “normal” or high aldosterone levels, individuals with unrecognized but biochemically overt PA, and individuals with severe hypertensive PA. ^, Regardless, it is clear that hypokalemia is not a universal feature of PA; this is perhaps not unexpected, since aldosterone does not appear to affect the hypokalemic response of H ⁺ /K ⁺ -ATPase, the major reabsorptive pathway for K ⁺ in the distal nephron. A related issue is whether PA is underdiagnosed when hypokalemia is used as a criterion for further investigation.

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

The syndromes of “apparent mineralocorticoid excess” (AME) have a self-explanatory label. In the classic form of AME, recessive loss-of-function mutations in the 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2) gene cause a defect in the peripheral conversion of cortisol to the inactive glucocorticoid cortisone; the resulting increase in the half-life of cortisol is associated with a marked decrease in synthesis, such that plasma levels of cortisol are normal and patients are not Cushingoid. The 11βHSD-2 protein is expressed in epithelial cells that are targets for aldosterone; in the kidney, these include cells of the DCT, connecting segment (CNT), and CCD. Since the MR has equivalent affinity for aldosterone and cortisol, generation of cortisone by 11βHSD-2 serves to protect mineralocorticoid-responsive cells from illicit activation by cortisol. In patients with AME, the unregulated mineralocorticoid effect of glucocorticoids results in hypertension, hypokalemia, and metabolic alkalosis, with suppressed PRA and aldosterone. Biochemical diagnosis entails measuring the urinary-free cortisol to urinary-free cortisone ratio on a 24-hour urine collection. Biochemical studies of mutant enzymes usually indicate a complete loss of function; lesser enzymatic defects in patients with AME are associated with altered ratios of urinary cortisone/cortisol metabolites, lesser impairment in the peripheral conversion of cortisol to cortisone, and/or older age at presentation.

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

Pharmacologic inhibition of 11βHSD-2 is also associated with hypokalemia and AME. The most infamous offender is licorice, in its multiple guises (licorice root, tea, candies, herbal remedies, etc.). The early observations that licorice required small amounts of cortisol to exert its kaliuretic effect, in the Addisonian absence of endogenous glucocorticoid, presaged the observations that its active ingredients (glycyrrhentinic/glycyrrhizinic acid and carbenoxolone) inhibit 11βHSD-2 and related enzymes. Licorice intake remains considerable in European countries, particularly Iceland, Netherlands, and Scandinavia ; Pontefract cakes, eaten both as sweets and as a laxative, are a continued source of licorice in the United Kingdom, whereas it is an ingredient in several popular sweeteners and preservatives in Malaysia. Glycyrrhizinic acid is also a component of Chinese herbal remedies, prescribed for disorders such as for allergic rhinitis. Pharmacologic inhibition of 11βHSD-2 has also been tested in patients with ESRD, as a novel mechanism to control hyperkalemia (see “Management of Hyperkalemia”). Carbenoxolone is in turn used in some countries in the management of peptic ulcer disease. More recently, the antifungals itraconazole and posaconazole have been shown to inhibit 11βHSD-2, ³³³ with several reports of hypertension and hypokalemia in patients treated with these agents. ^,

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

Liddle syndrome constitutes an autosomal dominant gain-in-function of ENaC, the amiloride-sensitive Na ⁺ channel of the CNT and CCD. Patients manifest severe hypertension with hypokalemia, unresponsive to spironolactone yet sensitive to triamterene and amiloride. Liddle syndrome could therefore also be classified as a syndrome of AME. Both hypertension and hypokalemia are variable aspects of the Liddle phenotype; consistent features include a blunted aldosterone response to ACTH and reduced urinary aldosterone excretion. ^, The differential diagnosis for Liddle syndrome, as a cause of hereditary hypertension with hypokalemia and suppressed aldosterone, includes AME due to deficient 11βHSD-2; however, whereas the Liddle syndrome phenotype is resistant to blockade of the MR with spironolactone and sensitive to amiloride, AME patients are sensitive to both drugs. Commercial genetic testing for both syndromes is available in the United States.

The vast majority of mutations target the C-terminus of either the β- or γ-ENaC subunit, with a small minority of mutations in α-ENaC. ENaC channels containing Liddle syndrome mutations are constitutively overexpressed at the cell membrane ^, ; unlike wild-type ENaC channels, they are not sensitive to inhibition by intracellular Na ⁺ , an important regulator of endogenous channel activity in the CCD. The mechanism whereby mutations in the C-terminus of ENaC subunits lead to this channel phenotype are discussed earlier in this chapter (see Fig. 16.6 and “Control of Potassium Secretion: Aldosterone” earlier). In addition to effects on interaction with Nedd4-2-dependent retrieval from the plasma membrane, Liddle-associated mutations increase proteolytic cleavage of ENaC at the cell membrane ; aldosterone-induced “channel-activating proteases” activate ENaC channels at the plasma membrane. This important result provides a mechanistic explanation for the longstanding observation that Liddle-associated mutations in ENaC appear to have a dual activating effect, on both the open probability of the channel (i.e., on channel activity) and expression at the cell membrane.

Given the overlapping and synergistic mechanisms that regulate ENaC activity, it stands to reason that mutations in ENaC that give rise to Liddle syndrome might do so by a variety of means. Indeed, mutation of a residue within the extracellular domain of γ-ENaC, versus the usual C-terminal site of mutations in Liddle syndrome, increases open probability of the channel without changing surface expression; the patient with this mutation has a typical Liddle syndrome phenotype. More recently, a missense mutation in the extracellular domain of α-ENaC has also been described in a Liddle kindred, increasing open probability of the channel without increasing susceptibility to activation by proteases. Extensive searches for more common mutations and polymorphisms in ENaC subunits that correlate with blood pressure in the general population have essentially been negative, despite characterization of specific gain-of-function variants. However, there are a handful of genetic studies that correlate specific variants in ENaC subunits with biochemical evidence of greater in vivo activity of the channel (i.e., a suppressed PRA and aldosterone and/or increased ratios of urinary K ⁺ : aldosterone/PRA). ^,

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

Early studies in BS suggested that these patients had a defect in the function of the TAL. Many of the clinical features are mimicked by the administration of loop diuretics, to which at least a subset of patients with antenatal BS do not respond. The apical Na ⁺ -K ⁺ -2Cl ^– cotransporter (NKCC2, SLC12A1) of the mammalian TAL (see Fig. 16.2 ) was thus an early candidate gene. In 1996, disease-associated mutations were found in the human NKCC2 gene in four kindreds with antenatal BS ; in the genetic classification of BS, these patients are considered to have BS type I. Although the functional consequences of disease-associated NKCC2 mutations have not been comprehensively studied, the first and subsequent reports include patients with frameshift mutations and premature stop codons that predict the absence of a functional NKCC2 protein.

BS is a genetically heterogeneous disease. Given the role of apical K ⁺ permeability in the TAL, encoded at least in part by ROMK, ^, this K ⁺ channel was another early candidate gene. K ⁺ recycling via the Na ⁺ -K ⁺ -2Cl ^– cotransporter and apical K ⁺ channels generates a lumen-positive potential difference in the TAL, which drives the paracellular transport of Na ⁺ and other cations (see also Fig. 16.2 ). Multiple disease-associated mutations in ROMK have been reported in patients with BS type II, most of whom exhibit the antenatal phenotype. ^, Finally, mutations in BS type III have been reported in the chloride channel CLC-NKB, which is expressed at the basolateral membrane of at least the TAL and DCT. In a significant fraction of patients with BS the NKCC2, ROMK, and CLC-NKB genes are not involved. For example, a subset of patients with associated sensorineural deafness exhibit linkage to chromosome 1p31 ; the gene for this syndrome, denoted Barttin, is an obligatory subunit for the CLC-NKB chloride channel. The occurrence of deafness in these patients suggests that Barttin functions in the regulation or function of Cl ^– channels in the inner ear. Notably, the CLC-NKB gene is immediately adjacent that for another epithelial Cl ^– channel, denoted CLC-NKA; digenic inactivation was described in two siblings with deafness and BS, suggesting that CLC-NKA plays an important role in Barttin-dependent Cl ^– transport in the inner ear.

Patients with activating mutations in the calcium-sensing receptor (CaSR) have been described with autosomal dominant hypocalcemia and hypokalemic alkalosis. ^, The CaSR is heavily expressed at the basolateral membrane of the TAL, where it is thought to play an important inhibitory role in regulating the transcellular transport of both Na ⁺ -Cl ^– and Ca ²⁺ . For example, activation of the basolateral CaSR in the TAL is known to reduce apical K ⁺ channel activity, which would induce a Bartter-like syndrome (see Fig. 16.2 ). Coexpression of NKCC2 with a BS gain-of-function mutant in the CaSR reveals reduced phosphorylation and reduced activity of NKCC2, dependent on the generation of inhibitory arachidonic acid-derived metabolites known to inhibit TAL function. Genetic activation of the CaSR by these mutations is also expected to increase urinary Ca ²⁺ excretion, by inhibiting generation of the lumen-positive potential difference that drives paracellular Ca ²⁺ transport in the TAL. In addition, the “set-point” of the CaSR response to Ca ²⁺ in the parathyroid is shifted to the left, inhibiting PTH secretion by this gland. No doubt the positional cloning of other BS genes will have a considerable impact on mechanistic understanding of the TAL.

Despite the reasonable correlation between the disease gene involved and the associated subtype of familial alkalosis, there is significant phenotypic overlap and phenotypic variability in hereditary hypokalemic alkalosis. For example, patients with mutations in CLC-NKB most frequently (44.5%) exhibit classic BS but can present with a more severe antenatal phenotype (29.5%), or even with a phenotype similar to Gitelman syndrome (26.0%). ^{, ,} With respect to BS due to mutations in NKCC2, a number of patients have been described with variant presentations, including an absence of hypokalemia. Two brothers were described with a late onset of mild BS; these patients were found to be compound heterozygotes for a mutant form of NKCC2 that exhibits partial function, with a loss-of-function mutation on the other NKCC2 allele. Further genetic heterogeneity has also emerged, with the description of patients with hypokalemic alkalosis due to mutations in claudin 10, which presumably disrupt paracellular cation transport by the TAL. Notably, the genetic heterogeneity in BS, GS, and related disorders is arguably not a major clinical issue in contemporary clinical practice; most commercial genetic analysis of patients with hereditary, hypokalemic alkalosis now involves testing an extensive panel of relevant genes, rather than testing single genes.

BS type II is particularly relevant to K ⁺ homeostasis, given that ROMK is the SK secretory channel of the CNT and CCD (see “Potassium Secretion in the Distal Nephron”). Patients with BS type II typically have slightly higher serum K ⁺ than the other genetic forms of BS ^, ; patients with severe (9.0 mmol/L), transient, neonatal hyperkalemia have also been described. It is likely that this reflects a transient, developmental deficit in the other K ⁺ channels involved in distal K ⁺ secretion, including the apical maxi-K channel responsible for flow-dependent K ⁺ secretion in the distal nephron. ^, Distal K ⁺ secretion in ROMK knockout mice is primarily mediated by maxi-K/BK channel activity, such that developmental deficits in this channel would indeed lead to hyperkalemia in BS type II. The mammalian TAL has two major apical K ⁺ conductances, the 30 pS channel corresponding to ROMK and a 70 pS channel ; both are thought to play a role in transepithelial salt transport by the TAL. ROMK is evidently a subunit of the 70 pS channel, given the absence of this conductance in TAL segments of ROMK knockout mice. More recently, a distinctive form of BS has emerged due to X-linked mutations in the MAGED2 gene. These kindreds are characterized by polyhydramnios with prematurity and a severe but transient form of antenatal BS. MAGE-D2 affects the expression and function of NKCC2 and NCC.

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

A major advance in the understanding of hereditary alkaloses was the realization that a subset of patients exhibits marked hypocalciuria, rather than the hypercalciuria typically seen in BS; patients in this hypocalciuric subset are universally hypomagnesemic. Such patients are now clinically classified as suffering from Gitelman syndrome. Although PRA may be increased, renal prostaglandin excretion is not elevated in these hypocalciuric patients, another distinguishing feature between Bartter and Gitelman syndromes. Gitelman syndrome is a milder disorder than BS; however, patients do report significant morbidity, mostly related to muscular symptoms and fatigue. ^, The QT interval is frequently prolonged in Gitelman syndrome, suggesting an increased risk of cardiac arrhythmia ; however, a more exhaustive cardiac evaluation of a large group of patients failed to detect significant abnormalities of cardiac structure or rhythm. Presyncope and/or ventricular tachycardia has been observed in at least two patients with Gitelman syndrome, ^, one with concomitant LQTS due to a mutation in the cardiac KCNQ1 K ⁺ channel.

The hypocalciuria detected in Gitelman syndrome is an expected consequence of inactivating the thiazide-sensitive Na ⁺ -Cl ^– cotransporter NCC (SLC12A2), and loss-of-function mutations in the human gene have been reported ; many of these mutations lead to a defect in cellular trafficking when introduced into the human NCC protein. Gitelman syndrome is genetically homogeneous, except for patients with mutations in CLC-NKB and an overlapping phenotype. ^{, , ,} More recently, loss-of-function mutations in the KCNJ10 encoding the basolateral Kir 4.1 K ⁺ channel in the DCT have been implicated in a related syndrome of hypokalemic metabolic alkalosis with hypomagnesemia, accompanied by seizures, sensorineural deafness, ataxia, and mental retardation (SeSAME or EAST syndrome). ^, In Kir 4.1-deficient, KCNJ10 knockout mice, the loss of basolateral K ⁺ conductance reduces basolateral Cl ^– conductance, leading to reduced expression of SPAK kinase and reduced apical NCC expression. Notably, the genetic heterogeneity in Gitelman syndrome and related disorders is arguably not a major clinical issue in contemporary clinical practice; most commercial genetic analysis of patients with hereditary, hypokalemic alkalosis now involves testing an extensive panel of relevant genes, rather than testing for mutations in single candidate genes.

The NCC protein has been localized to the apical membrane of epithelial cells in the DCT and connecting segment. A mouse strain with targeted deletion of the Slc12a2 gene encoding NCC exhibits hypocalciuria and hypomagnesemia, with a mild alkalosis and marked increase in circulating aldosterone. These knockout mice exhibit marked morphologic defects in the early DCT, with both a reduction in absolute number of DCT cells and changes in ultrastructural appearance. That Gitelman syndrome is a disorder of cellular development and/or cellular apoptosis should perhaps not be a surprise, given the observation that thiazide treatment promotes marked apoptosis of this nephron segment. This cellular deficit leads to downregulation of the DCT magnesium channel TRPM6, resulting in the magnesium wasting and hypomagnesemia seen in Gitelman syndrome. The downstream CNT tubules are hypertrophied in NCC-deficient mice, reminiscent of the hypertrophic DCT and CNT segments seen in furosemide-treated animals. These CNT cells also exhibit an increased expression of ENaC at their apical membranes versus littermate controls ; this is likely due to activation of SGK1-dependent trafficking of ENaC by the increase in circulating aldosterone (see “Control of Potassium Secretion: Aldosterone” earlier).

Hypokalemia does not occur in NCC null mice on standard rodent diet, but emerges on a K ⁺ -restricted diet; plasma K ⁺ of these mice is ∼1 mM lower than K ⁺ -restricted littermate controls. Several mechanisms account for the hypokalemia seen in GS and NCC–/– mice. The distal delivery of both Na ⁺ and fluid is decreased in NCC null mice, at least on a normal diet; however, the increased circulating aldosterone and CNT hypertrophy likely compensate, leading to increased kaliuresis. As discussed earlier for thiazides, decreased luminal Ca ²⁺ in NCC-deficiency may augment baseline ENaC activity, further exacerbating the kaliuresis. Of particular interest, NCC-deficient mice develop considerable polydipsia and polyuria on a K ⁺ -restricted diet ; this is reminiscent perhaps of the polydipsia that has been implicated in thiazide-associated hyponatremia.

Hypocalciuria in Gitelman syndrome is not accompanied by changes in plasma calcium, phosphate, vitamin D, or PTH, suggesting a direct effect on renal calcium transport. The late DCT is morphologically intact in NCC-deficient mice, with preserved expression of the epithelial calcium channel (TRPV5) and the basolateral Na ⁺ -Ca ²⁺ exchanger. Furthermore, the hypocalciuric effect of thiazides persists in mice deficient in TRPV5, arguing against the putative effects of this drug on distal Ca ²⁺ absorption. Rather, several lines of evidence argue that the hypocalciuria of Gitelman syndrome and thiazide treatment is due to increased absorption of Na ⁺ by the proximal tubule, ^, with secondary increases in proximal Ca ²⁺ absorption. An interesting association has repeatedly been described between chondrocalcinosis, the abnormal deposition of calcium pyrophosphate dihydrate (CPPD) in joint cartilage, and Gitelman syndrome. Patients have also been reported with ocular choroidal calcification.

Treatment of Gitelman syndrome encompasses liberalization of salt intake and lifelong supplementation with oral magnesium and potassium. Reasonable targets for serum potassium and serum magnesium are 3.0 mEq/L and 0.6 mmol/L (1.46 mg/dL). Organic anion salts of magnesium are preferred over magnesium chloride/hydroxide/oxide. Patients with refractory hypokalemia may require treatment with potassium-sparing diuretics, RAAS inhibitors, and/or nonsteroidal inflammatory drugs.

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

Renal tubular acidosis (RTA) and related tubular defects can be associated with hypokalemia. Proximal RTA is characterized by a reduction in proximal bicarbonate absorption, with a reduced plasma bicarbonate concentration. Isolated proximal RTA is quite rare; genetic causes include loss-of-function by mutations in the basolateral Na ⁺ -bicarbonate transporter. More commonly, proximal RTA occurs in the context of multiple proximal tubular transport defects, encompassing the Fanconi syndrome (FS). The cardinal features of FS include hyperaminoaciduria, glycosuria with a normal plasma glucose concentration, and phosphate wasting; associated defects include the proximal RTA, hypouricemia, hypercalciuria, hypokalemia, salt wasting, and increased excretion of low-molecular-weight proteins. FS is most commonly drug associated; important contemporary causes include aristolochic acid, ifosfamide, and the acyclic nucleoside phosphonates (tenofivir, cidofovir, and adefovir). Before treatment with bicarbonate, patients with a proximal RTA will typically demonstrate mild hypokalemia, due primarily to baseline hyperaldosteronism ; patients have, however, been described with profound hypokalemia on presentation, before treatment. Regardless, treatment with oral sodium bicarbonate will markedly increase distal tubular Na ⁺ and HCO ₃ ^– delivery, causing a marked increase in renal potassium wasting. Patients will often require mixed base replacement with oral citrate and bicarbonate, in addition to aggressive K ⁺ -Cl ^– supplementation.

Hypokalemia is also associated with distal RTA, the so-called “type I” RTA. Hypokalemic distal RTA is most commonly due to a “secretory” defect, with reduced H ⁺ -ATPase activity and decreased ability to acidify the urine. For example, hereditary defects in subunits of the H ⁺ -ATPase are associated with profound hypokalemia, in addition to acidosis and hypercalciuria. Pathophysiology of the associated hypokalemia is multifactorial, due to the loss of electrogenic H ⁺ secretion (with enhanced K ⁺ secretion to maintain electroneutrality in the distal nephron), loss of H ⁺ /K ⁺ -ATPase activity, and increases in aldosterone. ^, Notably, in hereditary distal RTA, hypokalemia is more common in those with H ⁺ -ATPase defects than in patients with mutations in the basolateral Cl ^– -HCO ₃ ^– exchanger. Sjögren syndrome is perhaps the most common cause of hypokalemic distal RTA in adults; the associated hypokalemia can be truly profound, often resulting in marked weakness and respiratory arrest.

Magnesium deficiency results in refractory hypokalemia, particularly if the plasma Mg ²⁺ is <0.5 mmol/L ²⁴⁸ ; hypomagnesemic patients are thus refractory to K ⁺ replacement in the absence of Mg ²⁺ repletion. ^, Magnesium deficiency is also a common concomitant of hypokalemia, in part because associated tubular disorders (e.g., aminoglycoside nephrotoxicity) may cause both kaliuresis and magnesium wasting. Plasma Mg ²⁺ levels must thus be checked on a routine basis in hypokalemia. ^,

Several mechanisms appear to contribute to the effect of magnesium depletion on plasma K ⁺ . Magnesium depletion has inhibitory effects on muscle Na ⁺ /K ⁺ -ATPase activity, resulting in significant efflux from muscle and a secondary kaliuresis. Distal K ⁺ secretion also appears to be enhanced, due to a reduction in the normal physiologic inward rectification of ROMK secretory K ⁺ channels, with a subsequent increase in outward conductance. ROMK and other KIR channels are inward-rectifying (i.e., K ⁺ flows inward more readily than outward); even though outward conductance is usually less than inward conductance, K ⁺ efflux predominates in the CNT and CCD since the membrane potential is more positive than the equilibrium potential for K ⁺ . Intracellular Mg ²⁺ plays a key role in inward rectification, binding, and blocking the pore of the channel from the cytoplasmic side. The hypomagnesemia-associated reduction in cytoplasmic Mg ²⁺ in principal cells reduces inward rectification of ROMK, increasing outward conductance and increasing K ⁺ secretion; this has been confirmed in vivo. Finally, it has been suggested that the repletion of intracellular K ⁺ is impaired in hypomagnesemia, even in normokalemic patients. Decreased intracellular Mg ²⁺ enhances K ⁺ efflux from the cytoplasm of cardiac and perhaps skeletal myocytes, likely due to reduced intracellular blockade of inward-rectifying K ⁺ channels (increased efflux) and inhibition of the Na ⁺ /K ⁺ -ATPase (decreased influx); plasma K ⁺ levels thus remain normal at the expense of intracellular K ⁺ . ^{, ,} This phenomenon is particularly important in patients with cardiac disease taking both diuretics and digoxin. In such patients, hypokalemia and arrhythmias will respond to correction of magnesium deficiency and potassium supplementation. ^,

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 “Control of Potassium Excretion: Aldosterone”). Aldosterone release from the adrenal may be reduced by hyporeninemic hypoaldosteronism and its multiple causes, by medications, or due to isolated deficiency of ACTH. The isolated loss in pituitary secretion of ACTH leads to a deficit in circulating cortisol; variable defects in other pituitary hormones are likely secondary to this reduction in cortisol. Concomitant hyporeninemic hypoaldosteronism is frequent ; however, hyperkalemia is perhaps less common in secondary hypoaldosteronism than in Addison disease.

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

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

Isolated deficits in aldosterone synthesis with hyperreninemia are caused by loss-of-function mutations in aldosterone synthase, although genetic heterogeneity has been reported. Patients typically present in childhood with volume depletion and hyperkalemia. Much like pseudohypoaldosteronism due to loss-of-function mutations in the MR (see later), patients tend to become asymptomatic in adulthood. Acquired hyperreninemic hypoaldosteronism has been described in critical illness, type II diabetes, amyloidosis due to familial Mediterranean fever, and after metastasis of carcinoma to the adrenal gland. Finally, aldosterone synthesis is selectively reduced by heparin, with a 7% incidence of hyperkalemia associated with heparin therapy. Both unfractionated and low-molecular-weight ^, heparin can cause hyperkalemia. Hyperkalemia due to prophylactic subcutaneous unfractionated heparin (5000 units twice daily) has also been reported. Heparin reduces the adrenal aldosterone response to both angiotensin-II and hyperkalemia, resulting in hyperreninemic hypoaldosteronism. Histologic findings in experimental animals include a marked diminution in size of the zona glomerulosa and an attenuated hyperplastic response to salt depletion.

Most primary adrenal insufficiency is due to autoimmunity in either Addison disease or the context of a polyglandular endocrinopathy. Adrenal insufficiency can be seen following adrenalectomy for primary hyperaldosteronism, with 14% developing postoperative hyperkalemia and 5% developing long-term insufficiency requiring fludrocortisone. The antiphospholipid syndrome may also cause bilateral adrenal hemorrhage and adrenal insufficiency. Another renal syndrome in which there should be a high index of suspicion for adrenal insufficiency is renal amyloidosis. Finally, HIV is a particularly important infectious cause of adrenal insufficiency. The most common cause of adrenalitis in HIV disease is cytomegalovirus; however, a long list of infectious, degenerative, and infiltrative processes may involve the adrenal glands in these patients. Although the adrenal involvement in HIV is usually subclinical, adrenal insufficiency may be precipitated by stress, drugs such as ketoconazole that inhibit steroidogenesis, or the acute withdrawal of steroid agents such as megesterol.

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

Hyporeninemic hypoaldosteronism is a common predisposing factor in several large, overlapping subsets of hyperkalemic patients: diabetic patients, the elderly, ^{, ,} and patients with renal insufficiency. Hyporeninemic hypoaldosteronism has also been described in systemic lupus erythematosus (SLE), ^, multiple myeloma, and acute glomerulonephritis. Classically, patients should have suppressed PRA and aldosterone, which cannot be activated by typical maneuvers such as furosemide or sodium restriction. Approximately 50% have an associated acidosis, with reduced renal excretion of NH ₄ ⁺ , a positive urinary anion gap, and urine pH <5.5. ^, Although the generation of this acidosis is clearly multifactorial, strong clinical ^{, ,} and experimental evidence suggests that hyperkalemia per se is the dominant factor, due to competitive inhibition of NH ₄ ⁺ transport in the TAL and reduced distal excretion of NH ₄ ⁺ (see also “Consequences of Hyperkalemia” earlier).

Several factors account for the reduced PRA in diabetic patients with hyporeninemic hypoaldosteronism. First, many patients have an associated autonomic neuropathy, with impaired release of renin during orthostatic challenges. Failure to respond to isoproterenol with an increase in PRA, despite an adequate cardiovascular response, suggests a postreceptor defect in the ability of the juxtaglomerular apparatus to respond to β-adrenergic stimuli (see also “Regulation of Renal Renin” earlier). Second, the conversion of prorenin to active renin is impaired in some diabetic patients, despite adequate release of prorenin in response to furosemide ; this suggests a defect in the normal processing of prorenin. Third, as is the case with perhaps all patients with hyporeninemic hypoaldosteronism (see later), many diabetic patients appear to be volume expanded, with subsequent suppression of PRA.

The most attractive, unifying hypothesis for the suppression of PRA in hyporeninemic hypoaldosteronism is that primary volume expansion increases circulating ANP, which then exerts a negative effect on both renal renin release and adrenal aldosterone release (see also “Regulation of Renal Renin and Adrenal Aldosterone”). There is evidence that these patients are volume expanded, and many will respond to either Na ⁺ -Cl ^– restriction or to furosemide with an increased PRA (i.e., renin is physiologically rather than pathologically suppressed), ^{, ,} Patients with hyporeninemic hypoaldosteronism due to a diversity of underlying causes have elevated ANP levels, ^{, , , ,} which is also an indicator of their underlying volume expansion. Patients who respond to furosemide with an increase in PRA exhibit a concomitant decrease in ANP. Furthermore, the infusion of exogenous ANP can suppress the adrenal aldosterone response to both hyperkalemia and dietary Na ⁺ -Cl ^– depletion.

Unlike hyporeninemic hypoaldosteronism, hyperkalemic distal RTA is associated with a normal or increased aldosterone and/or PRA. Urine pH in these patients is >5.5, and they are unable to increase acid or K ⁺ excretion in response to furosemide, Na ⁺ -SO ₄ ^2– or fludrocortisone. Classic causes include SLE, sickle cell anemia, ^, and amyloidosis.

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

The recessive form of PHA-I is caused by various combinations of mutations in all three subunits of ENaC, resulting in impairment in its channel activity. Patients with this syndrome present with severe neonatal salt wasting, hypotension, and hyperkalemia; in contrast to the autosomal dominant form of PHA-I, the syndrome does not improve in adulthood. One unexpected result in the physiologic characterization of ENaC was that mice with a targeted deletion of the α-ENaC subunit were found to die within 40 hours of birth due to pulmonary edema. Patients with recessive PHA-I may have pulmonary symptoms, which can occasionally be severe ; however, it appears that, unlike in ENaC-deficient mice, the modest residual activity associated with heteromeric PHA-I channels is generally sufficient to mediate pulmonary Na ⁺ and fluid clearance in humans with loss-of-function mutations in ENaC.

Pseudohypoaldosteronism type II (PHA-II) (also known as Gordon syndrome and more recently as FHHt [Familial Hyperkalemia with Hypertension]) is in every respect the “mirror image” of Gitelman syndrome; the clinical phenotype includes hypertension, hyperkalemia, hyperchloremic metabolic acidosis, suppressed PRA and aldosterone, hypercalciuria, and reduced bone density. FHHt behaves like a gain-of-function in the thiazide-sensitive Na ⁺ -Cl ^– cotransporter NCC, and treatment with thiazides typically results in resolution of the entire clinical picture. FHHt is an extreme form of hyporeninemic hypoaldosteronism due to volume expansion; aggressive salt restriction decreases ANP levels and increases PRA, with resolution of the hypertension, hyperkalemia, and metabolic acidosis.

FHHt is an autosomal dominant syndrome, with four genetic loci. In an initial landmark paper, mutations in two related serine-threonine kinases were detected in various kindreds with FHHT. The catalytic sites of these kinases lack specific catalytic lysines conserved in other kinases, hence the designation “WNK” ( W ith N o L ysine). Whereas FHHT mutations in WNK4 affect the C-terminus of the coding sequence, large intronic deletions in the WNK1 gene result in increased expression. Both kinases are expressed within the distal nephron, in both DCT and CCD cells; whereas WNK1 localizes to the cytoplasm and basolateral membrane, WNK4 protein is found at the apical tight junctions. WNK-dependent phosphorylation and activation of the downstream SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) kinases leads to phosphorylation of a cluster of N-terminal threonines in NCC, resulting in an activation of Na ⁺ -Cl ^– cotransport (see also Fig. 16.6 ). However, coexpression of WNK4 with NCC reveals additional inhibitory influence of the kinase on NCC, effects which are blocked by FHHt-associated point mutations in the kinase. In particular, the inhibitory effects of WNK4 appear to dominate in mouse models with overexpression of wild-type versus FHHt mutant WNK4. Mutations in the Cullin 3 and kelch-like 3 (KLHL3) genes also cause FHHt; the proteins encoded by these genes are part of a ubiquitin- ligase complex that regulates the WNK1 and WNK4 kinase proteins. Autosomal dominant mutations in both Cullin 3 and KLHL3 act through dominant negative effects. ^,

A key insight from the mechanistic study 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, leading to hyperkalemia. This and other effects of the WNK pathways on distal K ⁺ secretion are discussed earlier in this chapter (see “Control of Potassium Secretion: the Effect of Potassium Intake”).

Hyperkalemia is a well-recognized complication of nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclo-oxygenases. NSAIDs cause hyperkalemia by a variety of mechanisms, as would be predicted from the relevant physiology. By decreasing glomerular filtration rate and increasing sodium retention, they decrease distal delivery of Na ⁺ and reduce distal flow rate. Moreover, the flow-activated apical maxi-K channel in the CNT and CCD is activated by prostaglandins, so NSAIDs will reduce its activity and the flow-dependent component of K ⁺ excretion. ^, NSAIDs are also a classic cause of hyporeninemic hypoaldosteronism. ^, The administration of indomethacin to normal volunteers thus attenuates furosemide-induced increases in PRA. ^, Finally, NSAIDs would not cause hyperkalemia with such regularity if they did not also blunt the adrenal response to hyperkalemia, which is at least partially dependent on prostaglandins acting through prostaglandin EP2 receptors and cyclic-AMP.

The physiology reviewed earlier in this chapter (see “Regulation of Renal Renin and Adrenal Aldosterone”) would suggest that COX-2 inhibitors are equally likely to cause hyperkalemia. Indeed, COX-2 inhibitors can clearly cause sodium retention and a decrease in glomerular filtration rate, ^, suggesting NSAID-like effects on renal pathophysiology. COX-2–derived prostaglandins stimulate renal renin release, and COX-2 inhibitors reduce PRA in both dogs and humans. Salt restriction potentiates the hyperkalemia seen in dogs treated with COX-2 inhibitors, such that hypovolemic patients may be particularly prone to hyperkalemia in this setting. The COX-2 inhibitor, celecoxib, and the nonselective NSAID ibuprofen have equivalent negative effects on K ⁺ excretion after a defined oral load. Not surprisingly, hyperkalemia and acute kidney injury are associated with COX-2 inhibitors. ^{, ,} Where the data have been reported, circulating PRA and/or aldosterone have been reduced in hyperkalemia associated with COX-2 inhibitors. ^,

Both cyclosporine (CsA) and tacrolimus cause hyperkalemia; the risk of sustained hyperkalemia may be higher in renal transplant patients treated with tacrolimus than in those treated with CsA. CsA is perhaps the most versatile of all drugs in the variety of mechanisms whereby it causes hyperkalemia. It causes hyporeninemic hypoaldosteronism due in part to its inhibitory effect on COX-2 expression in the macula densa. CsA inhibits apical SK secretory K ⁺ channels in the distal nephron, in addition to basolateral Na ⁺ -K ⁺ -ATPase. Finally, CsA causes redistribution of K ⁺ and hyperkalemia, particularly when used in combination with β-blockers. A provocative but preliminary report has linked acute hyperkalemia secondary to CsA to indirect activation of K _ATP channels (see also earlier).

Inhibition of apical ENaC activity in the distal nephron by amiloride and other K ⁺ -sparing diuretics predictably results in hyperkalemia. Amiloride is structurally similar to the antibiotics trimethoprim (TMP) and pentamidine, which can also inhibit ENaC. Trimethoprim thus inhibits Na ⁺ reabsorption and K ⁺ secretion in perfused CCDs. Both TMP/SMX (Bactrim) and pentamidine were reported to cause hyperkalemia during high-dose treatment of Pneumocystis pneumonia in HIV patients, ^, who are otherwise predisposed to hyperkalemia. However, this side effect is not restricted to high-dose intravenous therapy; in a study of hospitalized patients treated with standard doses of trimethoprim, significant hyperkalemia occurred in >50%, with severe hyperkalemia (>5.5 mmol/L) in 21%. Risk factors for hyperkalemia due to normal-dose TMP include renal insufficiency, hyporeninemic hypoaldosteronism, and concomitant use of ACE-inhibitors and ARBs. This is not a trivial association, in that TMP/SMX administration increases the risk of sudden death in patients treated with ACE-inhibitors, angiotensin-receptor blockers, or spironolactone.

Whereas TMP and pentamidine directly inhibit ENaC, a novel, indirect mechanism for ENaC inhibition-associated hyperkalemia has also been reported. ^, Aldosterone induces expression of the membrane associated proteases CAP1-3 (see “Control of Potassium Excretion: Aldosterone”). Nafamostat, a protease inhibitor widely used in Japan for pancreatitis and other indications, is known to cause hyperkalemia ; indirect evidence suggests that the mechanism involves inhibition of amiloride-sensitive Na ⁺ channels in the CCD. It has been evaluated as a treatment for COVID-19, with hyperkalemia reported in trials. Treatment of rats with nafamostat was shown to reduce the urinary excretion of CAP1/prostasin, in contrast to the reported effect of aldosterone. Thus inhibition of the protease activity of CAP1 by nafamostat appears to abrogate its activating effect on ENaC (see Fig. 16.13 ) and may reduce expression of the protein in the CCD.

Pharmacologic inhibition of the epithelial Na ⁺ channel ENaC.

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

Hyperkalemia is a predictable and common effect of ACE inhibition, direct renin inhibition, and antagonism of the mineralocorticoid and angiotensin receptors (see also Fig. 16.14 ). The oral contraceptive agent Yasmin-28 and related products contain the progestin drospirenone, which inhibits the MR and can potentially cause hyperkalemia in susceptible patients. As with many other causes of hyperkalemia, that induced by pharmacologic targeting of the RAAS axis depends on concomitant inhibition of the adrenal aldosterone release by hyperkalemia; the adrenal release of aldosterone due to increased K ⁺ is clearly dependent on an intact adrenal renal-angiotensin system, such that this response is abrogated by systemic ACE inhibitors and ARBs (see “Regulation of Renal Renin and Adrenal Aldosterone Release”). Dual treatment with lisinopril and spironolactone in subjects with CKD is also associated with a reduction in extrarenal potassium disposition, given that reduced K ⁺ excretion alone does not explain the substantial increase in serum K ⁺ after a defined oral potassium load. Similarly, the addition of spironolactone to losartan in treatment of diabetic nephropathy causes a significant increase in serum K ⁺ without significant change in urinary K ⁺ excretion. ACE inhibitors and ARBs have the additional potential to cause acute renal failure and acute hyperkalemia in patients with an angiotensin-dependent GFR; the renin inhibitor aliskiren has also been reported to cause acute renal failure with acute hyperkalemia, albeit in conjunction with spironolactone.

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

RAAS inhibitors are an increasingly important cause of hyperkalemia, given the indications to combine spironolactone with ACE inhibitors and/or ARBs in renal and cardiac disease, in addition to the emergence of MR antagonists with perhaps a greater potential for hyperkalemia. Hyperkalemia can occur within a week of starting angiotensin-receptor blockade. Heart failure, diabetes, and CKD increase the risk of hyperkalemia from these agents. ^{, ,} The prevalence of hyperkalemia associated with the combined use of MR antagonists and ACE inhibitors/ARBs appears to be much higher in clinical practice (∼10%) than what has been reported in large clinical trials, in part due to the use of higher than recommended doses. Notably, Juurlink and colleagues studied the correlation between the rate of spironolactone prescription for Canadian patients with heart failure on ACE inhibitors, following the publication of The Randomized Aldactone Evaluation Study (RALES), with hyperkalemia and associated morbidity. This provocative study found an abrupt increase in the rate of prescription for spironolactone after release of RALES, with a temporal correlation to increases in the rate of admissions with hyperkalemia ; the association remained statistically significant for admissions where hyperkalemia was the primary diagnosis. However, a study from the United Kingdom found a similar increase in spironolactone use after the publication of RALES, but without an increase in hyperkalemia or hyperkalemia-associated admissions to hospital. It should also be emphasized that the development of hyperkalemia, or for that matter the presence of predisposing factors for hyperkalemia, does not appear to mitigate the mortality benefits of eplerenone in heart failure.

More recently, a new mineralocorticoid, finerenone, has emerged for clinical use, with greater selectivity and potency than spironolactone and eplerenone, combined with a shorter half-life. Given the results of the FIDELIO and FIGARO trials, finerenone has emerged as a key “pillar” in management of diabetic kidney disease. Although head-to-head comparison with spironolactone is lacking, comparative post-hoc analysis has indicated a lesser risk of hyperkalemia from finerenone when compared with spironolactone. Another key advance is the availability of SGLT2 inhibitors, which clearly reduce the risk of serious hyperkalemia in type 2 diabetes without increasing the risk of hypokalemia.

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

• Estimate glomerular filtration rate using MDRD and/or related equations.

• Inquire about diet and dietary supplements (e.g., salt substitutes and licorice) and prescribe a low-potassium diet, preferably with the assistance of a nutritionist.

• Inquire about medications, particularly those that can interfere with renal K ⁺ excretion (e.g., NSAIDS, COX-2 inhibitors, and K ⁺ -sparing diuretics) and, if appropriate, discontinue these agents.

• Continue or initiate loop or thiazide-like diuretics, if otherwise appropriate (hypertension, edema).

• Correct acidosis with sodium bicarbonate.

• Initiate treatment with a low dose of only one of the agents (i.e., of ACE-inhibitors, ARB, or MR antagonists).

• Check serum K ⁺ 3 to 5 days after initiation of the therapy and each dose increment, at most within 1 week, followed by another measurement 1 week later.

• If the serum K ⁺ is >5.6, ACE inhibitors, ARBs, and/or MR blockers should be stopped and the patient should be treated for hyperkalemia.

• If serum K ⁺ is increased but <5.6 mmol/L, reduce the dose and reassess the possible contributing factors. If the patient is on a combination of ACE inhibitors, ARBs, and/or MR blockers, all but one should be stopped and potassium rechecked.

• If therapy with ACE inhibitors, ARBs, and/or MR blockers is considered particularly critical for management of the patient, consider coadministration of a K ⁺ binder such as sodium zirconium cyclosilicate (SZC).

• A combination of a MR blocker and either an ACE inhibitor or an ARB should be used with extreme caution in patients with stage IV or V of CKD (eGFR <30). If otherwise indicated in a diabetic patient, preference should be given to finerenone if available.

• The dose of spironolactone in combination with ACE inhibitors or ARBs should be no more than 25 mg/day. For diabetics, consider utilizing finerenone in preference to spironolactone.

• Consider therapy with an SGLT2 inhibitor in hyperkalemic patients, if otherwise indicated.