Potassium and Its Discontents: New Insight, New Treatments : Journal of the American Society of Nephrology

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Potassium and Its Discontents

New Insight, New Treatments

Ellison, David H.*,†; Terker, Andrew S.*; Gamba, Gerardo

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Journal of the American Society of Nephrology 27(4):p 981-989, April 2016. | DOI: 10.1681/ASN.2015070751
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Disorders of plasma potassium concentration can be rapidly fatal. This fact evokes concern among clinicians and often militates for treatment, even when the indication may not be strong. Although immediate treatment for severe hyperkalemia is clearly effective, such treatment typically does not reduce the total body potassium burden. Thus, definitive treatment usually requires the removal of potassium from the body, most commonly in the urine. When this cannot be achieved or is inadequate, which often occurs in patients with late-stage CKD, clinicians often turn to sodium polystyrene sulfonate (SPS). Although this binding resin has been in use for many years, its efficacy has been questioned,1 and its risks have clearly been shown.2 These issues have caused some to argue against the routine use of SPS, whereas others suggest that we are damned if we do but also, damned if we do not.3

Recently, two new oral agents for the removal of potassium from the body have been studied in clinical trials. The characteristics of these agents will be discussed below, but their development has occurred in parallel with, but independent of substantial strides in understanding how total body potassium homeostasis is maintained. Although these insights hold the potential to drive more physiologic approaches to potassium disorders, this goal remains unmet. Because hyperkalemia is the most common potassium disorder in patients with CKD and because there are new approaches for treating hyperkalemia, the focus of this review will be on normal potassium homeostasis and hyperkalemia.

Gastrointestinal Absorption and Plasma Concentrations

Individuals consuming a Western diet typically ingest approximately 50–100 mEq (2–4 g) potassium daily.46 Approximately 10% is excreted in the stool, and therefore, the vast majority of ingested potassium is eliminated in the urine to maintain steady state. Within the body, the bulk of potassium is inside of cells, so that extracellular fluid contains only 50–80 mEq (4 mEq/L×14 L=56 mEq). Because dietary intake varies widely, it is not surprising that elaborate physiologic control systems adjust renal potassium excretion to meet physiologic needs.

A single meal may contain more potassium than is present in the plasma, and therefore, it might be expected that a high-K+ meal might raise plasma [K+] (brackets indicate concentration) substantially; however, plasma [K+] is buffered by both renal and extrarenal mechanisms. Thus, large and potentially harmful swings in plasma [K+] typically do not occur during the day. Because urinary K+ excretion increases rapidly after a meal, some have postulated that there is an undefined gut sensor, which enhances K+ excretion.7 This effect, however, is most apparent when K+ is ingested with food,8 suggesting that it may involve well recognized metabolic factors, such as insulin. It should also be appreciated that plasma [K+] does increase substantially after a potassium-rich meal (Figure 1). In humans, a high-K+ meal increased plasma [K+] from 0.4 to 0.7 mEq/L, raising plasma aldosterone.9 Furthermore, steady–state plasma [K+] concentrations are strongly modulated by chronic dietary intake, because increasing K+ intake from 75 to 400 mEq/L for 3 weeks increased plasma [K+] by 0.47 mEq/L and increased plasma aldosterone concentration.9 The role of such changes in plasma [K+] in modulating renal excretion will be addressed below.

Figure 1:
Changes in urinary K+ excretion associate with changes in plasma K+ concentration. Effect of a meal on plasma K+ concentration, plasma aldosterone concentration, and urinary K+ excretion in humans. The studies were conducted in six healthy volunteers who consumed a normal (25 mmol) and high (100 mmol) meal. Note the close correlation between rise in plasma K+, rise in aldosterone, and rise in urinary K+ excretion. Modified from Rabelink et al. 9, with permission.

Two additional sources of variation in plasma K+ concentrations are circadian and interindividual. Normal plasma K+ concentrations are between 3.5 and 4.5 mEq/L. Although it is often stated that plasma K+ is tightly regulated,7 plasma K+ concentration is one of the plasma constituents with the highest circadian variation10 (Figure 2); in fact, this rhythm is one of the most persistent when diurnal variations in activity, posture, and dietary intake are eliminated.11 There may also be inherited interindividual differences in plasma [K+]; it has been recognized recently that plasma [Na+] has a strong heritable component,12 and it would be surprising if similar factors do not exist for [K+].

Figure 2:
Plasma K+ concentration varies throughout the day. Plasma measurements were conducted in 24 normal men under standardized conditions, with meals indicated by black bars. The whiskers indicate the lowest and highest results, and the central box spans the 25th to 75th percentiles. Reprinted from Sennels et al. 10, with permission.

Renal K+ Handling

Mechanisms of renal K+ excretion are well established and reviewed extensively.13,14 Potassium is freely filtered, but owing to its primarily intracellular distribution, rates of filtration do not typically determine rates of excretion. In fact, >80%–90% of filtered K+ is reabsorbed along the proximal tubule and loop of Henle, so that only 10% of filtered K+ is delivered to the distal tubule and collecting duct (CD), even as dietary intake varies. This means that the vast majority of excreted K+ is derived from secretion along the distal nephron.

Studies during the early micropuncture era found that K+ secretion along the superficial distal tubule, comprising the distal convoluted tubule (DCT) and connecting tubule (CNT), accounted for nearly all K+ excretion. However, when in vitro microperfusion became popular, it was easier to use cortical CDs to perfuse; because these segments expressed all components of the K+ secretory system and responded to aldosterone, it became common to assign K+ secretory primacy to this nephron segment. Molecular insights and reanalysis of extant data, however, made it clear that the late DCT (the DCT2) and CNT play the dominant roles in K+ secretion15; it seems that the CD plays an important role primarily when the organism is stressed or aldosterone levels are very high.

Like plasma [K+] (Figure 2), urinary K+ excretion exhibits substantial circadian variation. In humans, the ratio of peak-to-minimum K+ excretion is approximately 5:1.16 Although it might be thought that this relates entirely to dietary intake patterns or plasma [K+], this rhythm is maintained, even when diurnal variations in activity, posture, and dietary intake are perturbed, providing evidence that it is related to central clock mechanisms.16 This type of response has been termed predictive in contrast to reactive,17 in that it primes the system in anticipation of the need to excrete K+.

Mechanisms of K+ Secretion

Given the central importance of the distal tubule to K+ homeostasis, it is not surprising that this segment of the nephron expresses a broad array of transport and regulatory proteins, which enables fine excretory control. A key component of the K+ secretory pathway is the Na+ channel (epithelial sodium channel [ENaC]) (Figure 3). This channel is expressed along the latter part of the DCT (the DCT2),18 the site at which substantial K+ secretion begins.19 ENaC activity depolarizes the luminal membrane of cells, thereby increasing the driving force favoring K+ movement from peritubular space to lumen. ENaC activity is strongly enhanced by aldosterone, which increases K+ secretion secondarily.

Figure 3:
Dietary K+ affects NaCl and K+ transport differently, via aldosterone and plasma K+ concentration. On a high-K+ diet, high–plasma K+ concentration inhibits NCC, although it stimulates aldosterone. Aldosterone stimulates ENaC (and ROMK), enhancing K+ secretion. On a low-K+ diet, NCC is stimulated by low plasma [K+], but aldosterone levels are low. Thus, Na+ and Cl are retained, raising BP.

The inwardly rectifying K+ channel renal outer medullary K+ (ROMK) is expressed along the entire distal nephron from the thick ascending limb (TAL) through the CDs.20 Its role of mediating regulated K+ secretion, however, only begins at the transition from the DCT1 to the DCT2, the site at which ENaC first appears.18 In the DCT2 and more distal segments, ROMK traffics to the apical membrane in response to dietary K+ loading,20,21 confirming its important role in regulating K+ balance. Although this mechanism of K+ secretion is very important, the observation that people, or mice, that lack functional ROMK lose rather than gain K+22,23 led to the recognition of other mechanisms for K+ secretion along the distal nephron.

Maxi-K channel (BK) also plays an important role in K+ secretion. This channel differs from ROMK, however, in several ways.24 First, although expressed along the distal nephron, it is primarily located at the apical membrane of intercalated cells. Second, unlike ROMK, it needs to be activated to be open. An important activator of BK is luminal flow, but recently, it has become clear that this channel also plays an important role in aldosterone–regulated K+ secretion. Thus, the increase in urinary K+ excretion in response to a low–salt, high–potassium diet is attenuated in mice lacking BK channels compared with wild-type mice.25 This provides evidence that K+ secretion by BK channels is affected by ENaC activity.

Another transport protein that plays a key role in K+ secretion is the thiazide–sensitive NaCl cotransporter (NCC; gene symbol SLC12A3). Its key role in K+ excretion was not fully appreciated until Gitelman syndrome, which presents with unrelenting K+ wasting, was found to be caused by mutations in SLC12A3.26 Gradually, it has become clear that the unique role of NCC is the result of its specific site of expression and its unique mechanisms of regulation.

NCC expression defines the DCT, which is interposed between the TAL and the CNT. The proximal portion of the DCT (DCT1) expresses NCC27 but not electrogenic Na+ or K+ channels at its apical membrane18,28 (although ROMK can be found in the DCT immunohistochemically,20 it does not seem to contribute to apical K+ conductance28). This means that the transepithelial voltage of the DCT is near zero.29 Thus, the proximal part of the DCT (the DCT1), which reabsorbs NaCl in an electroneutral manner, acts as an insulator, separating the TAL, with its lumen–positive transepithelial voltage, from the CNT, with its lumen–negative transepithelial voltage, driving K+ secretion.

NCC activity is exquisitely sensitive to extracellular [K+], which might seem unexpected given that NCC does not transport K+ and the DCT1 secretes little K+.19 In this case, it was the molecular solution to familial hyperkalemic hypertension (also called pseudohypoaldosteronism type 2 or Gordon syndrome) that began to unravel this puzzle.3032 Familial hyperkalemic hypertension is a rare monogenic hypertensive disease accompanied by hyperkalemia. The phenotype appears as if the Na+-retaining effects of aldosterone are intact, but the kaliuretic effects are not. The molecular solution showed that mutations in WNK kinases or their regulatory proteins cause the disease, in large part by activating NCC33,34; this indicated that NCC plays a key role in determining whether aldosterone (and ENaC) enhances K+ secretion.

Although the reports describing WNK effects have often seemed contradictory and confusing, recently, a consensus view has begun to emerge, which has proven clarifying.35,36 WNK kinases phosphorylate intermediary kinases, SPAK and OxSR1, which can phosphorylate and activate NCC and other cation chloride cotransporters. WNKs also form hetero- or homodimers through their carboxy-terminal tails.37,38 All four WNKs can activate NCC in vitro, but the nature of their effects in vivo depends on both their sites of expression and modifying properties. It has recently become clear that WNKs are inhibited by chloride.39 In fact, WNK4, which is most highly expressed in the DCT, is uniquely chloride sensitive.40

A recent model suggests that plasma [K+] signals to NCC by altering intracellular [Cl] in the DCT.41,42 It turns out that DCT cells are exceptionally sensitive to changes in plasma [K+]. Thus, when plasma [K+] is high, cell [Cl] is high, WNKs are turned off, and NCC is suppressed (Figure 3). This occurs, although plasma aldosterone concentrations, which are thought to stimulate NCC in other conditions,43 rise during hyperkalemia (see above).4448 When plasma [K+] is low, the opposite occurs.41,44 These effects can occur very rapidly, such as when K+ is administered by gavage45 or intravenously47; the rapid decrease in abundance of the phosphorylated form of NCC suggests that high plasma [K+] leads to rapid NCC dephosphorylation. These effects, however, do not occur in isolation. Instead, the same high–[K+] signal also enhances aldosterone secretion by adrenal zona glomerulosa cells.49 Aldosterone activates ENaC in the CNT (and CD). Thus, switching from a low- to a high-K+ diet switches NCC off and ENaC on. Because less of the delivered Na+ load will be reabsorbed by NCC, more will be delivered into the K+ secretory segments, segments primed to secrete K+ through the effects of aldosterone. Although this model is attractive, however, several important details remain to be confirmed.

All states of high-aldosterone activity, however, are not characterized by K+ wasting. This seems to reflect, in part, NCC activation by angiotensin II. Low-salt diet increases and high-salt diet decreases NCC activity.50 Captopril infusion induces retrieval of NCC from the DCT apical membrane,51 and angiotensin II induces activation of NCC in the absence of adrenal glands,52 an effect that is prevented by losartan. The effect of angiotensin II on NCC is a WNK4- and SPAK-dependent process. In vitro and in vivo experiments revealed that SPAK and NCC are not activated by angiotensin II in the absence of WNK4.53,54 Additionally, angiotensin II through protein kinase C induces phosphorylation of KLHL3, preventing the ubiquitylation and thus, destruction of WNK4.55

Angiotensin II may also play a role in transport along the CD. Angiotensin II has been reported to stimulate the activity and translocation of ENaC to the apical membrane through an aldosterone-independent mechanism,56,57 although it has also been reported that deletion of AT1a receptors along the CD does not reduce ENaC abundance.58 Because angiotensin II may also reduce ROMK activity,59,60 it might be predicted to stimulate sodium reabsorption in the CD but not K+ secretion, which would be appropriate in states of volume depletion. In other situations, however, angiotensin II has been proposed to increase K+ excretion. Todkar et al.61 suggested that angiotensin enhanced potassium secretion in mice lacking aldosterone.

In addition, during salt depletion, angiotensin II may induce dephosphorylation of the mineralocorticoid receptor in the intercalated cells of the CD, allowing aldosterone to interact with its receptor and thus, increasing Cl reabsorption by pendrin combined with H+-ATPase.62 The H+-ATPase activation should depolarize the transepithelial voltage and attenuate K+ secretion. In addition, extracellular fluid volume depletion may activate an electroneutral sodium chloride uptake pathway that is dependent on sodium–dependent chloride bicarbonate exchange in parallel with pendrin.63 Thus, the combination of increased activity of NCC, ENaC, and pendrin together with inhibition of ROMK by angiotensin II maximize salt reabsorption while inhibiting K+ secretion in the distal nephron.

Effects of K+ Intake on BP

A natriuretic effect of K+ in humans was reported nearly 80 years ago,64 and BP-lowering effects of K+ supplementation and raising effects of K+ deficit were later reported.6568 However, dietary K+ has typically received less attention than salt, perhaps because the traditional body fluid model for BP control assigns primacy to Na+.69 It is now clear from large population studies that dietary K+ intake associates inversely with BP.70,71 Although mechanisms involving the sympathetic nervous system, the vasculature, and circulating factors, such as endogenous ouabain, may all play roles in the beneficial effects of high-K+ intake, natriuresis is rarely cited as essential.72,73

Because high-K+ intake will switch off NCC, this would be expected to contribute to the ensuing natriuresis. We recently reported that the ability of low-K+ intake to increase arterial pressure is absent in mice lacking NCC.41 These experiments, conducted during concomitant high–salt intake, suggest that NCC and the DCT play essential roles in the beneficial effects of dietary K+ loading.


Two chronic disease processes are responsible for a substantial proportion of hyperkalemic episodes: heart failure and CKD. In these settings, the use of renin-angiotensin-aldosterone system (RAAS) blocking drugs typically contributes.74 In individuals with heart failure, low renal blood flow and GFR, poor distal Na+ delivery, and the use of drugs that block the RAAS impair K+ excretion.75,76 In the setting of CKD, these same factors are often involved, although low GFR itself is often more obvious.77 Because drugs that block the RAAS are among the most effective for treating individuals with both heart failure and CKD and because these drugs contribute substantially to the increased risk for hyperkalemia, RAAS inhibitors often play a role.78 This has generated interest within the cardiovascular community in finding ways to achieve the benefits of RAAS blockade, while reducing its potassium retaining effects.

CKD is another major risk factor for hyperkalemia. In a large study of individuals who had been hospitalized, the adjusted rate of potassium ≥5.5 was 7.67 per 100 patient months for individuals with CKD (eGFR<60 ml/min per 1.73 m2) versus 2.3 for those without.79 In a much smaller study80 of a low-clearance clinic, the prevalence of K≥5.5 mM was 31.5%, with GFR being the most important factor associated with hyperkalemia.

Treatment of Hyperkalemia

As noted above, there are many strategies for treating hyperkalemia both acutely and chronically; most of these have been in routine use for many years.81 When treatment is urgent, treatment is first aimed at cell membrane stabilization with intravenous calcium. Although this approach is effective, its duration of action is <60 minutes, making additional treatments necessary. The typical secondary treatments are insulin and glucose or in rare situations, inhaled β-agonists. These shift potassium into cells, with durations of action of ≤6 hours. Definitive treatment must, however, remove K+ from the body. When kidney function permits, loop diuretics combined with intravenous saline (depending on the effective arterial blood volume) are the first line of treatment. Dialysis is typically used for individuals with inadequate kidney function. However, frequently, physicians turn to oral K+ binding resins to achieve K+ removal; today, this is almost always SPS (Kayexalate and others). Calcium polystyrene sulfonate is much less commonly used. Sterns et al.1 estimated that the typical community hospital dispenses 2000 doses of SPS per year. SPS was approved by the Food and Drug Administration (FDA) in 1958, well before today’s rigorous standards for efficacy were established, and some have questioned whether it is, in fact, efficacious.1 This issue of efficacy, however, has been complicated by increasing concerns about safety.

SPS can be constipating, and therefore, it has commonly been administered with sorbitol to induce osmotic diarrhea. Case reports, however, noted that SPS, often combined with sorbitol, could induce intestinal necrosis in patients, which was frequently fatal. In 2009, the FDA placed a Black Box warning on the use of SPS with sorbitol on the basis of this information. More recently, however, a comprehensive review found a substantial number of patients with intestinal necrosis that occurred with SPS without sorbitol.2 Harel et al.2 urge caution in the use of SPS, but others have argued that the common clinical use and the infrequency of complications suggest that SPS is usually well tolerated and effective.3,82

The concerns about safety and efficacy have prompted interest in developing new agents to treat hyperkalemia. Two have recently been evaluated in prospective trials and seem to be effective. The first is sodium zirconium cyclosilicate (ZS-9), an oral, inorganic, nonsystemic cation exchanger, which was designed to preferentially entrap monovalent cations in the gastrointestinal tract. ZS-9 has a microporous framework structure and exhibits >25-fold selectivity for potassium over Ca2+ or Mg2+.83 Unlike SPS, ZS-9 does not swell within the gastrointestinal tract.

ZS-9 has been evaluated in several recent trials (Figure 4). In one,84 753 individuals with moderate hyperkalemia (5–6.5 mEq/L) were randomized to placebo or one of several doses of ZS-9. There was a significant dose–dependent reduction of plasma [K+] at 48 hours that ranged from 0.46 to 0.73 mEq/L at doses from 2.5 to 10 g per dose. During a maintenance phase of the study, ZS-9 was also more effective than placebo at preventing plasma [K+] from rising.

Figure 4:
ZS-9 and SPS lower plasma K+ concentration. ZS-9 versus placebo indicates results of ZS-9 extracted from Figure 1.84 ZS-9 (10 g) is drawn from data in Kosiborod et al. 86. Effects of SPS and SPS + sorbitol are from Gruy-Kapral et al. 92. Note that the data are not necessarily comparable but shown for illustration. Modified from Kosiborod et al. 86 and Gruy-Kapral et al. 92, with permission.

In another study involving the same group,85 253 individuals with plasma [K+] ≥5.1 mmol/L were given 10 g ZS-9 three times daily for 48 hours in an initial open–label phase. At 24 hours, the decrease in [K+] was 0.7 mmol/L, and at 48 hours, it was 1.1 mmol/L, both values significantly different from zero. Those who achieved normokalemia at the end of this phase were then randomized to placebo or different doses of ZS-9 for days 8–28. There was a significant dose–dependent relation between dose and plasma [K+] at the end of this period, with a difference of 0.7 mmol/L at the highest dose (15 g three times per day). Dose-dependent edema was the major observed side effect, occurring in 14% of patients taking a high dose of ZS-9 versus only 2% treated with placebo.85

In a follow-up letter to the editor, the same group culled from the initial results 45 patients whose plasma [K+] was ≥6.0 mmol/L. For individuals who received 10 g, the plasma [K+] had declined by 0.4 mmol/L at 1 hour, 0.6 mmol/L at 2 hours, and 0.7 mmol/L at 4 hours. By 4 hours, 80% of individuals had plasma [K+] values ≤6.0.86

Patiromer is a second new agent recently investigated. Patiromer consists of the polymer anion (the active moiety patiromer) and a calcium-sorbitol counterion complex. It is a nonabsorbed cation exchange polymer that binds K+ in the lumen of the gastrointestinal tract and like ZS-9, does not swell appreciably in liquids. During the development of patiromer, calcium fluoride was identified as a degradation product, and efforts were undertaken to develop a more stable compound, resulting in a calcium-sorbitol counterion complex. Because serum fluoride did not rise substantially when patients were treated for ≤1 year, investigators have concluded that fluoride toxicity is not a concern. Unlike in SPS, sorbitol is not added as a laxative but at very small amounts to stabilize the complex.

In a trial,87 243 patients with stage 3 or 4 CKD who were receiving RAAS blockade and whose plasma [K+] was between 5.1 and 6.5 were enrolled. In an initial phase, all patients received patiromer at a dose that depended on enrollment plasma [K+]. At the end of 4 weeks, those who achieved target [K+] values were randomized to continue patiromer or receive placebo. During the subsequent 4 weeks, the mean [K+] declined by 1 mmol/L. As in the trial with ZS-9, plasma [K+] increased more when patients were randomized to placebo than to active treatment. Several side effects have been noted with patiromer, most notably hypomagnesemia (in 8.6% of patients in one study88); this led to the administration of magnesium supplements to some subjects. Because hypomagnesemia may be associated with cardiac arrhythmias,89 this may be concern in patients with disordered plasma [K+]. A variety of gastrointestinal side effects were also noted.

As noted by editorialists,90,91 these studies show efficacy of the new agents in lowering plasma [K+] when monitored over time. In maintenance studies, they were clearly superior to placebo in attenuating a rise. Unfortunately, in neither study was the active drug compared with SPS, and therefore, we are left without comparative effectiveness information. Furthermore, although the drugs were generally well tolerated, the incidence and effect of the noted side effects will need further study. Furthermore, because the incidence of intestinal necrosis with SPS is low,2 a comparison of safety profiles will require monitoring of many more patients receiving the agents. Thus, the role of these agents in either intermediate-term treatment of hyperkalemia or maintenance therapy awaits further trials. These agents are expected to be evaluated by the FDA during the next year, a process that will involve careful consideration of their efficacy and toxicity.


The intake of K+ is increasingly appreciated as an important determinant of human health, and higher K+ intake is associated with lower BP and mortality in the population as a whole. Although many factors may contribute, it seems clear that important effects of K+ involve kidney salt transport. Potassium acts directly on DCT cells, where it inhibits NCC activity. Because K+ also stimulates aldosterone secretion, this means that high-K+ diets elicit a natriuresis by turning off NCC but turning on ENaC. Because ENaC cannot fully compensate for the Na+ rejected by the DCT, natriuresis ensues. Although high-K+ intake is healthful for most, individuals with CKD and heart failure, especially when treated with RAAS inhibitors, are at risk for hyperkalemia, a potentially deadly complication. Here, physicians have long relied on SPS to treat hyperkalemia that is unresponsive to simpler approaches. Two new nonabsorbable agents have recently shown efficacy in treating hyperkalemia. It is hoped that their role in standard of care will be defined by studies comparing them directly with more traditional approaches.



Work in the authors’ laboratories has been supported by National Institutes of Health Grants 2R01DK051496-15A1 and 5T32DK067864-10 to D.H.E. and Department of Veterans Affairs Grant 1I0BX002228-01A1 to D.H.E. A.S.T. was supported by American Heart Association Predoctoral Fellowship Award 3PRE14090030 and National Institute of Diabetes and Digestive and Kidney Diseases Grant 5T32DK067864-08.

Published online ahead of print. Publication date available at www.jasn.org.


1. Sterns RH, Rojas M, Bernstein P, Chennupati S: Ion-exchange resins for the treatment of hyperkalemia: Are they safe and effective? J Am Soc Nephrol 21: 733–735, 2010
2. Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM: Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: A systematic review. Am J Med 126: 264.e9–264.e24, 2013
3. Watson M, Abbott KC, Yuan CM: Damned if you do, damned if you don’t: Potassium binding resins in hyperkalemia. Clin J Am Soc Nephrol 5: 1723–1726, 2010
4. Cogswell ME, Zhang Z, Carriquiry AL, Gunn JP, Kuklina EV, Saydah SH, Yang Q, Moshfegh AJ: Sodium and potassium intakes among US adults: NHANES 2003-2008. Am J Clin Nutr 96: 647–657, 2012
5. Mente A, O’Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, Morrison H, Li W, Wang X, Di C, Mony P, Devanath A, Rosengren A, Oguz A, Zatonska K, Yusufali AH, Lopez-Jaramillo P, Avezum A, Ismail N, Lanas F, Puoane T, Diaz R, Kelishadi R, Iqbal R, Yusuf R, Chifamba J, Khatib R, Teo K, Yusuf SPURE Investigators: Association of urinary sodium and potassium excretion with blood pressure. N Engl J Med 371: 601–611, 2014
6. Weiner ID, Wingo CS: Hyperkalemia: A potential silent killer. J Am Soc Nephrol 9: 1535–1543, 1998
7. Gumz ML, Rabinowitz L, Wingo CS: An integrated view of potassium homeostasis. N Engl J Med 373: 60–72, 2015
8. Lee FN, Oh G, McDonough AA, Youn JH: Evidence for gut factor in K+ homeostasis. Am J Physiol Renal Physiol 293: F541–F547, 2007
9. Rabelink TJ, Koomans HA, Hené RJ, Dorhout Mees EJ: Early and late adjustment to potassium loading in humans. Kidney Int 38: 942–947, 1990
10. Sennels HP, Jørgensen HL, Goetze JP, Fahrenkrug J: Rhythmic 24-hour variations of frequently used clinical biochemical parameters in healthy young males--the Bispebjerg study of diurnal variations. Scand J Clin Lab Invest 72: 287–295, 2012
11. Moore Ede MC, Brennan MF, Ball MR: Circadian variation of intercompartmental potassium fluxes in man. J Appl Physiol 38: 163–170, 1975
12. Wilmot B, Voruganti VS, Chang YP, Fu Y, Chen Z, Taylor HA, Wilson JG, Gipson T, Shah VO, Umans JG, Flessner MF, Hitzemann R, Shuldiner AR, Comuzzie AG, McWeeney S, Zager PG, Maccluer JW, Cole SA, Cohen DM: Heritability of serum sodium concentration: Evidence for sex- and ethnic-specific effects. Physiol Genomics 44: 220–228, 2012
13. Welling PA: Regulation of renal potassium secretion: Molecular mechanisms. Semin Nephrol 33: 215–228, 2013
14. Palmer BF: Regulation of potassium homeostasis. Clin J Am Soc Nephrol 10: 1050–1060, 2015
15. Meneton P, Loffing J, Warnock DG: Sodium and potassium handling by the aldosterone-sensitive distal nephron: The pivotal role of the distal and connecting tubule. Am J Physiol Renal Physiol 287: F593–F601, 2004
16. Gumz ML, Rabinowitz L: Role of circadian rhythms in potassium homeostasis. Semin Nephrol 33: 229–236, 2013
17. Moore-Ede MC: Physiology of the circadian timing system: Predictive versus reactive homeostasis. Am J Physiol 250: R737–R752, 1986
18. Loffing J, Pietri L, Aregger F, Bloch-Faure M, Ziegler U, Meneton P, Rossier BC, Kaissling B: Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets. Am J Physiol Renal Physiol 279: F252–F258, 2000
19. Velázquez H, Ellison DH, Wright FS: Chloride-dependent potassium secretion in early and late renal distal tubules. Am J Physiol 253: F555–F562, 1987
20. Wade JB, Fang L, Coleman RA, Liu J, Grimm PR, Wang T, Welling PA: Differential regulation of ROMK (Kir1.1) in distal nephron segments by dietary potassium. Am J Physiol Renal Physiol 300: F1385–F1393, 2011
21. Frindt G, Palmer LG: Effects of dietary K on cell-surface expression of renal ion channels and transporters. Am J Physiol Renal Physiol 299: F890–F897, 2010
22. Wagner CA, Loffing-Cueni D, Yan Q, Schulz N, Fakitsas P, Carrel M, Wang T, Verrey F, Geibel JP, Giebisch G, Hebert SC, Loffing J: Mouse model of type II Bartter’s syndrome. II. Altered expression of renal sodium- and water-transporting proteins. Am J Physiol Renal Physiol 294: F1373–F1380, 2008
23. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP: Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14: 152–156, 1996
24. Sansom SC, Welling PA: Two channels for one job. Kidney Int 72: 529–530, 2007
25. Cornelius RJ, Wen D, Li H, Yuan Y, Wang-France J, Warner PC, Sansom SC: Low Na, high K diet and the role of aldosterone in BK-mediated K excretion. PLoS One 10: e0115515, 2015
26. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP: Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 12: 24–30, 1996
27. Obermüller N, Bernstein P, Velázquez H, Reilly R, Moser D, Ellison DH, Bachmann S: Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney. Am J Physiol 269: F900–F910, 1995
28. Zhang C, Wang L, Zhang J, Su XT, Lin DH, Scholl UI, Giebisch G, Lifton RP, Wang WH: KCNJ10 determines the expression of the apical Na-Cl cotransporter (NCC) in the early distal convoluted tubule (DCT1). Proc Natl Acad Sci U S A 111: 11864–11869, 2014
29. Wright FS: Increasing magnitude of electrical potential along the renal distal tubule. Am J Physiol 220: 624–638, 1971
30. Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP: Human hypertension caused by mutations in WNK kinases. Science 293: 1107–1112, 2001
31. Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M, Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre XInternational Consortium for Blood Pressure (ICBP): KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet 44: 456–460, 2012
32. Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Välimäki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP: Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482: 98–102, 2012
33. Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann KE, Toka HR, Nelson-Williams C, Ellison DH, Flavell R, Booth CJ, Lu Y, Geller DS, Lifton RP: Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nat Genet 38: 1124–1132, 2006
34. Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin SH, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S: Molecular pathogenesis of pseudohypoaldosteronism type II: Generation and analysis of a Wnk4(D561A/+) knockin mouse model. Cell Metab 5: 331–344, 2007
35. Chávez-Canales M, Zhang C, Soukaseum C, Moreno E, Pacheco-Alvarez D, Vidal-Petiot E, Castañeda-Bueno M, Vázquez N, Rojas-Vega L, Meermeier NP, Rogers S, Jeunemaitre X, Yang C-L, Ellison DH, Gamba G, Hadchouel J: WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension 64: 1047–1053, 2014
36. Huang CL, Cheng CJ: A unifying mechanism for WNK kinase regulation of sodium-chloride cotransporter. Pflugers Arch 467: 2235–2241, 2015
37. Thastrup JO, Rafiqi FH, Vitari AC, Pozo-Guisado E, Deak M, Mehellou Y, Alessi DR: SPAK/OSR1 regulate NKCC1 and WNK activity: Analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation. Biochem J 441: 325–337, 2012
38. Yang C-L, Zhu X, Ellison DH: The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest 117: 3403–3411, 2007
39. Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ: Chloride sensing by WNK1 involves inhibition of autophosphorylation. Sci Signal 7: ra41, 2014
40. Terker AS, Zhang C, Erspamer KJ, Gamba G, Yang CL, Ellison DH: Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis [published online ahead of print September 30, 2015]. Kidney Int doi:
41. Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, Siler DA, Park HJ, Fu Y, Cohen DM, Weinstein AM, Wang WH, Yang CL, Ellison DH: Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab 21: 39–50, 2015
42. Bazua-Valenti S, Chavez-Canales M, Rojas-Vega L, Gonzalez-Rodriguez X, Vazquez N, Rodriguez-Gama A, Argaiz ER, Melo Z, Plata C, Ellison DH, Garcia-Valdes J, Hadchouel J, Gamba G: The effect of WNK4 on the Na+-Cl- cotransporter is modulated by intracellular chloride. J Am Soc Nephrol 26: 1781–1786, 2015
43. Subramanya AR, Ellison DH: Distal convoluted tubule. Clin J Am Soc Nephrol 9: 2147–2163, 2014
44. van der Lubbe N, Moes AD, Rosenbaek LL, Schoep S, Meima ME, Danser AH, Fenton RA, Zietse R, Hoorn EJ: K+-induced natriuresis is preserved during Na+ depletion and accompanied by inhibition of the Na+-Cl- cotransporter. Am J Physiol Renal Physiol 305: F1177–F1188, 2013
45. Sorensen MV, Grossmann S, Roesinger M, Gresko N, Todkar AP, Barmettler G, Ziegler U, Odermatt A, Loffing-Cueni D, Loffing J: Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice. Kidney Int 83: 811–824, 2013
46. Vitzthum H, Seniuk A, Schulte LH, Müller ML, Hetz H, Ehmke H: Functional coupling of renal K+ and Na+ handling causes high blood pressure in Na+ replete mice. J Physiol 592: 1139–1157, 2014
47. Rengarajan S, Lee DH, Oh YT, Delpire E, Youn JH, McDonough AA: Increasing plasma [K+] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis. Am J Physiol Renal Physiol 306: F1059–F1068, 2014
48. Vallon V, Schroth J, Lang F, Kuhl D, Uchida S: Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1. Am J Physiol Renal Physiol 297: F704–F712, 2009
49. Gomez-Sanchez CE: Channels and pumps in aldosterone-producing adenomas. J Clin Endocrinol Metab 99: 1152–1156, 2014
50. Chiga M, Rai T, Yang SS, Ohta A, Takizawa T, Sasaki S, Uchida S: Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney Int 74: 1403–1409, 2008
51. Sandberg MB, Riquier AD, Pihakaski-Maunsbach K, McDonough AA, Maunsbach AB: ANG II provokes acute trafficking of distal tubule Na+-Cl(-) cotransporter to apical membrane. Am J Physiol Renal Physiol 293: F662–F669, 2007
52. van der Lubbe N, Lim CH, Fenton RA, Meima ME, Jan Danser AH, Zietse R, Hoorn EJ: Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone. Kidney Int 79: 66–76, 2011
53. San-Cristobal P, Pacheco-Alvarez D, Richardson C, Ring AM, Vazquez N, Rafiqi FH, Chari D, Kahle KT, Leng Q, Bobadilla NA, Hebert SC, Alessi DR, Lifton RP, Gamba G: Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc Natl Acad Sci U S A 106: 4384–4389, 2009
54. Castañeda-Bueno M, Cervantes-Pérez LG, Vázquez N, Uribe N, Kantesaria S, Morla L, Bobadilla NA, Doucet A, Alessi DR, Gamba G: Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process. Proc Natl Acad Sci U S A 109: 7929–7934, 2012
55. Shibata S, Zhang J, Puthumana J, Stone KL, Lifton RP: Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A 110: 7838–7843, 2013
56. Mamenko M, Zaika O, Ilatovskaya DV, Staruschenko A, Pochynyuk O: Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone. J Biol Chem 287: 660–671, 2012
57. Sun P, Yue P, Wang WH: Angiotensin II stimulates epithelial sodium channels in the cortical collecting duct of the rat kidney. Am J Physiol Renal Physiol 302: F679–F687, 2012
58. Stegbauer J, Gurley SB, Sparks MA, Woznowski M, Kohan DE, Yan M, Lehrich RW, Coffman TM: AT1 receptors in the collecting duct directly modulate the concentration of urine. J Am Soc Nephrol 22: 2237–2246, 2011
59. Wei Y, Zavilowitz B, Satlin LM, Wang WH: Angiotensin II inhibits the ROMK-like small conductance K channel in renal cortical collecting duct during dietary potassium restriction. J Biol Chem 282: 6455–6462, 2007
60. Yue P, Sun P, Lin DH, Pan C, Xing W, Wang W: Angiotensin II diminishes the effect of SGK1 on the WNK4-mediated inhibition of ROMK1 channels. Kidney Int 79: 423–431, 2011
61. Todkar A, Picard N, Loffing-Cueni D, Sorensen MV, Mihailova M, Nesterov V, Makhanova N, Korbmacher C, Wagner CA, Loffing J: Mechanisms of renal control of potassium homeostasis in complete aldosterone deficiency. J Am Soc Nephrol 26: 425–438, 2015
62. Shibata S, Rinehart J, Zhang J, Moeckel G, Castañeda-Bueno M, Stiegler AL, Boggon TJ, Gamba G, Lifton RP: Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia. Cell Metab 18: 660–671, 2013
63. Leviel F, Hübner CA, Houillier P, Morla L, El Moghrabi S, Brideau G, Hassan H, Parker MD, Kurth I, Kougioumtzes A, Sinning A, Pech V, Riemondy KA, Miller RL, Hummler E, Shull GE, Aronson PS, Doucet A, Wall SM, Chambrey R, Eladari D: The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice. J Clin Invest 120: 1627–1635, 2010
64. Keith NM, Binger MW: Diuretic action of potassium salts. JAMA 105: 1584–1591, 1935
65. Aburto NJ, Hanson S, Gutierrez H, Hooper L, Elliott P, Cappuccio FP: Effect of increased potassium intake on cardiovascular risk factors and disease: Systematic review and meta-analyses. BMJ 346: f1378, 2013
66. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, Yan H, Lee SF, Mony P, Devanath A, Rosengren A, Lopez-Jaramillo P, Diaz R, Avezum A, Lanas F, Yusoff K, Iqbal R, Ilow R, Mohammadifard N, Gulec S, Yusufali AH, Kruger L, Yusuf R, Chifamba J, Kabali C, Dagenais G, Lear SA, Teo K, Yusuf SPURE Investigators: Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med 371: 612–623, 2014
67. Krishna GG, Kapoor SC: Potassium depletion exacerbates essential hypertension. Ann Intern Med 115: 77–83, 1991
68. Krishna GG, Kapoor SC: Potassium supplementation ameliorates mineralocorticoid-induced sodium retention. Kidney Int 43: 1097–1103, 1993
69. Adrogué HJ, Madias NE: Sodium surfeit and potassium deficit: Keys to the pathogenesis of hypertension. J Am Soc Hypertens 8: 203–213, 2014
70. Montasser ME, Shimmin LC, Gu D, Chen J, Gu C, Kelly TN, Jaquish CE, Rice T, Rao DC, Cao J, Chen J, Liu DP, Whelton P, He J, Hixson JE: Blood pressure response to potassium supplementation is associated with genetic variation in endothelin 1 and interactions with E selectin in rural Chinese. J Hypertens 28: 748–755, 2010
71. Zhang Z, Cogswell ME, Gillespie C, Fang J, Loustalot F, Dai S, Carriquiry AL, Kuklina EV, Hong Y, Merritt R, Yang Q: Association between usual sodium and potassium intake and blood pressure and hypertension among U.S. adults: NHANES 2005-2010. PLoS One 8: e75289, 2013
72. He FJ, Marciniak M, Carney C, Markandu ND, Anand V, Fraser WD, Dalton RN, Kaski JC, MacGregor GA: Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives. Hypertension 55: 681–688, 2010
73. Adrogué HJ, Madias NE: Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 356: 1966–1978, 2007
74. Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, Weir MR, Fink JC: The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 169: 1156–1162, 2009
75. Vardeny O, Claggett B, Anand I, Rossignol P, Desai AS, Zannad F, Pitt B, Solomon SDRandomized Aldactone Evaluation Study (RALES) Investigators: Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail 7: 573–579, 2014
76. Desai AS: Hyperkalemia in patients with heart failure: Incidence, prevalence, and management. Curr Heart Fail Rep 6: 272–280, 2009
77. Lazich I, Bakris GL: Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. Semin Nephrol 34: 333–339, 2014
78. Palmer BF: Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 351: 585–592, 2004
79. Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, Weir MR, Fink JC: The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 169(12): 1156–1162, 2009
80. Sarafidis PA, Blacklock R, Wood E, Rumjon A, Simmonds S, Fletcher-Rogers J, Ariyanayagam R, Al-Yassin A, Sharpe C, Vinen K: Prevalence and factors associated with hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc Nephrol 7: 1234–1241, 2012
81. Kovesdy CP: Management of hyperkalemia: An update for the internist [published online ahead of print June 18, 2015]. Am J Med doi:
82. Watson MA, Baker TP, Nguyen A, Sebastianelli ME, Stewart HL, Oliver DK, Abbott KC, Yuan CM: Association of prescription of oral sodium polystyrene sulfonate with sorbitol in an inpatient setting with colonic necrosis: A retrospective cohort study. Am J Kidney Dis 60: 409–416, 2012
83. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS: Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One 9: e114686, 2014
84. Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola P, Singh B: Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 372: 222–231, 2015
85. Kosiborod M, Rasmussen HS, Lavin P, Qunibi WY, Spinowitz B, Packham D, Roger SD, Yang A, Lerma E, Singh B: Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: The HARMONIZE randomized clinical trial. JAMA 312: 2223–2233, 2014
86. Kosiborod M, Peacock WF, Packham DK: Sodium zirconium cyclosilicate for urgent therapy of severe hyperkalemia. N Engl J Med 372: 1577–1578, 2015
87. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ-Schmidt H, Berman L, Pitt BOPAL-HK Investigators: Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 372: 211–221, 2015
88. Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, Stasiv Y, Zawadzki R, Berman L, Bushinsky DAAMETHYST-DN Investigators: Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: The AMETHYST-DN Randomized Clinical Trial. JAMA 314: 151–161, 2015
89. Agus MS, Agus ZS: Cardiovascular actions of magnesium. Crit Care Clin 17: 175–186, 2001
90. Winkelmayer WC: Treatment of hyperkalemia: From "hyper K+" strikeout to home run? JAMA 314: 129–130, 2015
91. Ingelfinger JR: A new era for the treatment of hyperkalemia? N Engl J Med 372: 275–277, 2015
92. Gruy-Kapral C, Emmett M, Santa Ana CA, Porter JL, Fordtran JS, Fine KD: Effect of single dose resin-cathartic therapy on serum potassium concentration in patients with end-stage renal disease. J Am Soc Nephrol 9: 1924–1930, 1998

ion transport; K channels; ion channel

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