Potassium Derangements: A Pathophysiological Review, Diagnostic Approach, and Clinical Management

Abstract

Potassium is an essential cation critical in fluid and electrolyte balance, acid–base regulation, and neuromuscular functions. The normal serum potassium is kept within a narrow range of 3.5–5.2 meq/L while the intracellular concentration is approximately 140–150 meq/L. The total body potassium is about 45–55 mmol/kg; thus, a 70 kg male has an estimated ~136 g and 60 kg female has ~117 g of potassium. In total, 98% of the total body potassium is intracellular. Skeletal muscle contains ~80% of body potassium stores. The ratio of intracellular to extracellular potassium concentration (Ki/Ke) maintained by Na+/K+ ATPase determines the resting membrane potential. Disturbances of potassium homeostasis lead to hypo- and hyperkalemia, which if severe, can be life-threatening. Prompt diagnosis and management of these problems are important.

1. Introduction

1.1 Cellular shift of potassium

The body maintains potassium (K) homeostasis by two key mechanisms: transcellular shift and renal K reabsorption/excretion [1, 2, 3, 4, 5, 6, 7]. The transcellular shift acts immediately within minutes to hours in response to K disturbances in the extracellular fluid. This is also called internal K balance. Cellular shifting is extremely important in the body’s defense against K disturbances in the extracellular space. Without transcellular redistribution, even small disturbances in K balance could lead to life-threatening potassium derrangements.

Important internal K regulators are catecholamines, insulin, thyroid hormone, tonicity, mineral acidosis, and various medications [8, 9, 10]. Insulin binds to cellular receptors, leading to increased activity of glucose transporter (GLUT4) and Na⁺/ K⁺ ATPase, while catecholamines (via beta2 adrenergic receptors) also upregulate Na⁺/ K⁺ ATPase. This in turn causes uptake of K into cells. Alpha-adrenergic receptor stimulation shifts K into the extracellular space; however, under physiological conditions, this effect is less significant. Theophylline and caffeine exert the same effect by increasing the activity of Na⁺/ K⁺ ATPase via inhibition of cellular phosphodiesterase and degradation of cyclic adenosine monophosphate (cAMP). There are some important blockers of cellular K channels that prohibit exit of K from cells, causing severe life-threatening hypokalemia. Examples of these entities include: chloroquine, verapamil, barium, and cesium [11, 12, 13, 14, 15, 16]. Rapidly dividing cells with high metabolic activity, as seen during initiation of therapy for megaloblastic anemia, could cause large K shifts into cells and consequently hypokalemia [16]. Extracellular mineral acidosis downregulates Na⁺/H⁺ exchanger 7 [7, 9]. This downregulates the activity of Na⁺/K⁺ ATPase and ultimately K released out of cells. Metabolic alkalosis has the opposite effect with K shifting intracellularly. Finally, changes in plasma osmolality also lead to cellular K shifts.

1.2 Periodic paralysis

Periodic paralysis (PP) includes a group of rare neuromuscular disorders characterized by episodic paralysis. It includes three main phenotypes: hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and thyrotoxic periodic paralysis. Both genetic and acquired forms of the disorder have been described. The genetic form is usually caused by mutations in the calcium channel (CACNA1S, 60%), sodium channel (SCN4A, 20%), and less commonly inward rectifying potassium channels (KCNJ2, KCNJ18) [17, 18, 19, 20]. The genetic mutations alone would not cause K to shift, but instead sensitize skeletal muscle to changes in serum K [21]. In hypokalemic PP symptoms are triggered after there is a drop in K due to cellular shifting such as a carbohydrate rich meal, exercise, or K losses. In hyperkalemic PP symptoms are usually triggered after K-rich food or severe exercise. Acquired thyrotoxic periodic paralysis is more prevalent in Asian populations from China, Taiwan, Japan, and Philippines. Patients are generally young males with a history of recurrent partial or complete paralysis, with a tendency to affect lower limbs more than upper limbs. The episodes may also be precipitated by exercise or carbohydrate-rich meals. The condition is triggered by transcellular K shift in response to an enhanced catecholamine action mediated by thyroxine [22].

1.3 Renal handling of potassium

Potassium is freely filtered across the glomerular membrane (Figure 1). Approximately 90% of K is reabsorbed by the early part of the tubule and less than 10% reaches the distal nephron. The bulk of the reabsorption takes place in the proximal convoluted tubule (PCT), which accounts for ~65–70% of the filtered K, followed by the thick ascending limb (TAL), which accounts for ~25%. The more distal nephron reabsorbs or secretes K based on the body requirements, thus playing a critical role in maintaining K balance [23, 24].

Figure 1.

Schematic representation of renal tubular handling of potassium. Urinary potassium is excreted after filtration, reabsorption, and secretion along the tubules. Over 90% of reabsorption of potassium takes place in the PCT and TAL, whereas DCT, cortical and medullary CD have capacity for variable reabsorption and secretion. PCT proximal convoluted tubule, TAL thick ascending limb, DCT distal convoluted tubule, CD collecting duct.

In the PCT, the Na⁺/ K⁺ ATPase drives the active sodium reabsorption. This causes net inward fluid movement, including passive reabsorption of K with water due to solvent drag. In the ascending limb of the loop of Henle, the main channels are apical sodium/potassium/chloride co-transporter (NKCC2), apical renal outer medullary potassium channel (ROMK), and basolateral Na⁺/ K⁺ ATPase. The reabsorption of K takes place via NKCC2 [25]. The distal nephron consists of early distal convoluted tubule (DCT1), late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). DCT1 contains apical Na⁺ Cl⁻ cotransporter channel (NCC), basolateral Na⁺/ K⁺ ATPase, and basolateral heteromeric K⁺ channel (Kir 4.1/ 5.1), among others. DCT2 is a transition between DCT1 and CNT with epithelial sodium channel (ENaC) expressions. NCC is regulated by two proteins from the serine/threonine kinase family called with-no-lysine (WNK) 1 and 4 [26], which in turn are regulated by Kir 4.1/ 5.1. Loss of function mutation in Kir 4.1/ 5.1 depolarizes DCT, inactivates NCC, and results in salt wasting. This will modify ENaC action downstream and affect K secretion [27]. Recent studies indicate that Kir 4.1/5.1 can sense dietary K changes. A high K diet can inhibit Kir 4.1/ 5.1, whereas a low K diet activates it [28]. As such, Kir 4.1/ 5.1 plays an important role in K homeostasis via sensing K intake and modulating NCC and ENaC activities [29, 30]. In the collecting duct (CD), there are two types of cells—principal cells and intercalated cells (alpha and beta). The main channels involved are basolateral Na⁺/K⁺ ATPase, apical ENaC, ROMK, and Maxi-K (flow dependent) channels. Aldosterone binds to its mineralocorticoid receptor (MR) and stimulates ENaC expression [31]. The net result is enhanced Na reabsorption that causes luminal electronegativity and drives K excretion via ROMK channel. The increased urine flow in this nephron segment can also enhance K loss via Maxi-K.

1.4 Aldosterone paradox

Aldosterone paradox [32] refers to the ability of aldosterone to stimulate reabsorption of sodium without excessive secretion of K in the setting of volume depletion and its ability to stimulate K excretion without sodium retention during hyperkalemia and euvolemia. Volume depletion leads to an activation of the renin angiotensin aldosterone system (RAAS) and a drop in glomerular filtration rate (GFR). The reduced urinary flow and Na delivery will limit the amount of K secretion. Furthermore, angiotensin II (AT II) can directly inhibit ROMK activity when there is a K deficit [33]. In hyperkalemia, distal delivery of sodium and urine volume is preserved due to the lack of AT II stimulation, allowing sufficient K secretion stimulated by the increase in aldosterone [34]. As a result, excessive fluid retention is not present.

1.5 Adaptation to hyperkalemia

Due to the renal adaptive responses, normal extracellular K levels are usually maintained even when there is a significant fall in GFR [35]. Hyperkalemia only develops when there is a severe defect in the distal nephron. This is due to “Potassium Adaptation” from changes in the remaining intact distal nephron, where it undergoes an adaptive increase in expressions of ROMK, ENaC, and Na⁺/K⁺ ATPases in order to maintain body K homeostasis. This change is in part due to higher aldosterone levels and will achieve a new steady state. However, it should be noted this steady state in chronic kidney disease (CKD) is delicate and can be easily disrupted again with an increased K intake or use of RAAS inhibitors [36].

Under normal circumstances, the gastrointestinal tract, responsible for 5–10% of K excretion, plays a minimal role in K balance. However, it can adapt in times of K derangement by increasing K excretion in cases of advancing CKD. Studies indicate at cellular level, this is due to increased expression of Na⁺/K⁺ATPase and the apical colonic BK channels 41 [37, 38]. This gastrointestinal adaptation plays an instrumental role in maintaining K homeostasis in end stage renal disease (ESRD) patients [39, 40].

1.6 Renal circadian rhythm

The kidneys play a major role in regulating K balance, excreting ~90% of the dietary K load [41, 42]. The renal K excretion follows a circadian rhythm regulated by central (suprachiasmatic nucleus) and peripheral (renal cells) biological clocks [43]. Full details of this control mechanism are still poorly defined and are beyond the scope of this chapter. Suffice to say that even with destruction of suprachiasmatic nucleus, the kidneys are able to maintain a circadian excretion of K. Elegant studies have demonstrated that maximum kaliuresis occurs at noon, reaches a nadir at midnight, and rhythm is maintained with a high K diet as well [44].

1.7 Pseudo-hyper and hypokalemia

Pseudohyperkalemia is defined as an elevation of serum K by more than 0.3 meq/L over the plasma K [45]. Pseudohyperkalemia can result from either mechanical trauma of cells during phlebotomy [46] or a transcellular shift of K out of cells in the test tube. It is commonly seen when there is extremely elevated leukocyte [47], erythrocyte, or thrombocyte counts [48]. One study suggested that every 100,000/ml rise in platelet count correlated with a K rise by 0.15 meq/L. There is a rare autosomal dominant disease called familial pseudohyperkalemia where at lower temperatures (usually <20°C), red blood cell membranes can leak K leading to pseudohyperkalemia [49]. This can also occur in hereditary spherocytosis [50]. Rarely reverse pseudohyperkalemia can be seen when plasma K is falsely elevated over the serum K. It has been reported in patients with severe leukocytosis and heparin-induced cell lysis [51]. In such cases, arterial blood gas analysis is more accurate.

Pseudohypokalemia can occur in vitro if there is an extremely high leukocyte count (>100,000/ml) or can be temperature-induced [52]. Delayed transport of samples in hot temperatures has been implicated in pseudohypokalemia due to the temperature-mediated stimulation of Na⁺/K⁺ ATPase [53, 54]. It can be prevented with cold storage of samples at 4 deg. C or if plasma or serum is rapidly separated from cells.

2. Hypokalemia

2.1 Epidemiology

Hypokalemia is defined as serum K level less than 3.5 mEq/L, whereas severe hypokalemia is defined as K level below 2.5 meq/L [55]. Hypokalemia is common with its prevalence reaching 14% in the community setting and 20% among hospitalized patients [56, 57]. In a study of patients with CKD, hypokalemia was associated strongly with an increased mortality (Hazard ratio 1.49, 95% confidence interval 1.26–1.76) [58]. Similar mortality association was observed in another study in patients with CKD and other comorbidity [59].

2.2 Etiopathogenesis

Etiologies of hypokalemia include intracellular shifting, reduced intake, increased excretion, or a combination of these factors. Reduced intake should always be suspected in patients whom are ill with evidence of malnutrition, having eating disorders, or abusing alcohol. Excessive K loss may occur from the gastrointestinal tract, as seen in diarrhea, malabsorption, colonic diseases such as inflammatory bowel disease, and hypersecretory adenomas.

Renal losses could be due to endocrine disorders or tubular cell defects including channelopathies or receptor abnormalities. Proximal tubular defects can lead to a variety of electrolyte problems including hypokalemia and metabolic acidosis. These defects could be inherited (Fanconi syndrome) or acquired in the setting of systemic disease or drug use. In the thick ascending limb, inherited (Bartter syndrome) or acquired defects (i.e., hypercalcemia, loop diuretic use) in NKCC2 or in any other relevant channels/sensors at this nephron segment can also lead to hypokalemia, along with volume depletion and metabolic alkalosis 60 [60, 61, 62, 63]. Several transporters orchestrate K reabsorption in the thick ascending limb. Na⁺/K⁺ ATPase provides the driving force for NKCC2, which reabsorbs sodium, K, and chloride. Additionally, there is a calcium-sensing receptor in the basal-lateral surface, which can inhibit NKCC2 upon stimulation. Similarly, in DCT1, several channels work alongside to promote salt absorption. A defect in NCC will lead to Gitelman syndrome, and its suppression by medications such as thiazide diuretics will share a similar phenotype [64]. The salt wasting present in both Bartter and Gitelman syndrome is associated with an increase in distal urine flow and secondary RAAS stimulation and subsequent K loss.

In the CD, hypokalemia is usually caused by an overactive RAAS axis such as renin tumor, renovascular hypertension, aldosterone oversecretions, and glucocorticoid remediable hypertension (GRA) [65]. De novo activation of ENaC, can also result from non-aldosterone-mediated activation of MR or gain-of-function mutation of MR [66, 67, 68, 69]. Finally, drugs such as licorice, carbenoxolone, and gossypol can also lead to an enhanced mineralocorticoid action [16]. Magnesium deficiency in the presence of aldosterone stimulation will exacerbate K losses in the distal nephron via ROMK [70].

2.3 Clinical features

Clinical symptoms depend on the timing and severity of hypokalemia, as well as the presence of certain comorbidities. Symptoms are more evident if serum K falls below 3 meq/L, hypokalemia is relatively rapid, concomitant use of digoxin [71, 72], and ischemic heart disease [16]. Since K is critical for maintaining and modulating resting membrane potential, both cardiac and skeletal muscles can exhibit electrophysiologic changes in response to hypokalemia leading to arrhythmias, paresis, and paralysis [73]. The electrocardiogram (ECG) may show tall P waves, prominent J waves, ST-segment depression, prolonged QT interval, T wave flattening, U wave, premature ventricular contraction, and ventricular tachycardia [74].

Other symptoms of hypokalemia include generalized ascending muscle weakness, pain, and ileus. Severe hypokalemia can also trigger rhabdomyolysis. Renal effects of hypokalemia include nephrogenic diabetes insipidus, ammoniagenesis with subsequent activation of alternative complement pathways [75] resulting in inflammation and fibrosis [76].

3. Diagnostic approach

3.1 Initial evaluation

The clinical investigation of hypokalemia starts with a thorough history and physical examination, followed by laboratory testing including a full metabolic panel (Figures 2 and 3). It is important to rule out pseudohypokalemia and assess cellular shifting.

Figure 2.

A diagnostic approach to hypokalemia (part 1).

Figure 3.

A diagnostic approach to hypokalemia (part 2). Abbreviations: RTA renal tubular acidosis, GRA glucocorticoid remediable Aldosteronism, AME apparent mineralocorticoid excess (11 beta hydroxysteroid dehydrogenase deficiency), CAH congenital adrenal hyperplasia (17 alpha hydroxylase, 11 beta hydroxylase deficiency), HTN hypertension. * adrenal adenoma, adrenal hyperplasia, adrenal carcinoma. # loop diuretics, thiazide diuretics.

3.2 Renal potassium excretion

The normal kidney responds to hypokalemia by lowering the K excretion. However, even if a patient has no oral intake, the obligatory K excretion is ~15 meq/day [77]. It’s useful to quantify renal K excretion (spot or 24 hours) to determine if there is appropriate renal conservation [55].

3.3 Blood pressure and acid: Base status

If a patient has metabolic acidosis, consider differentials of gastrointestinal losses, proximal renal tubular acidosis (pRTA), distal renal tubular acidosis (RTA type 1), or diabetic ketoacidosis (DKA) [77]. Of note, typically gastric losses tend to cause metabolic alkalosis while intestinal losses will cause nongap metabolic acidosis. When metabolic alkalosis is present with normal or low blood pressure, the differential diagnosis should include salt wasting syndromes beyond the proximal tubule such as Bartter syndrome, Gitelman syndrome, and diuretic use [55]. When hypertension and metabolic alkalosis are present, plasma renin, aldosterone, and aldosterone-to-renin ratio (ARR) should be checked for a deranged RAAS axis (Figures 2 and 3). High renin levels may indicate renin-secreting tumor or renovascular hypertension. When aldosterone is high and renin is suppressed, there is suspicion for hyperaldosteronism or glucocorticoid remediable hypertension (GRA). When both renin and aldosterone are suppressed, there is pathological activation of ENaC via non-aldosterone mechanism (some types of CAH, apparent mineralocorticoid excess (AME), Liddle’s syndrome, Geller syndrome, hypercortisolism). Further testing includes checking the adrenal axis with imaging and endocrine labs (11 beta hydroxylase, or 17 alpha hydroxylase deficiency) [78, 79], cortisol, genetic testing for AME, Liddle syndrome, GRA, and Geller’s syndrome [80].

3.4 Management

An ECG is recommended to rule out cardiac dysrhythmias. It is important to treat the underlying cause, reduce losses, and replenish body K stores. Severe hypokalemia warrants closer cardiac monitoring. There is a rough estimation that a 1 meq/L fall in serum K represents a total body K deficit of 200–400 meq [6]. This could be repleted orally or intravenously. Intravenous K repletion warrants cardiac monitoring. It’s preferable to give the solution in saline as dextrose causes insulin release and may further drop the serum K. In patients with CKD or ESRD, K repletion is based on cautious evaluation by the nephrology team. Hypomagnesemia should also be corrected if present.

4. Hyperkalemia

4.1 Epidemiology

Hyperkalemia is defined as serum K > 5.2 meq/L. It is also a common and clinically relevant problem. Studies reported 2.5–4% prevalence rates in emergency visits and inpatient hospitalizations in the United States and Canada [81, 82]. As expected, the prevalence rate is much higher in patients with compromised kidney function. In a study of 238 patients with estimated GFR of 15 ml/min/1.73m², 31.5% had serum K > 5.5 meq/L, [83]. In another study of men with GFR < 37 ml/min/1.73 m², 7.7% had serum K > 5.3 meq/L [84]. Its prevalence is also high (5–40%) in renal transplant recipients due to calcineurin inhibitor use [85]. Like hypokalemia, hyperkalemia is also associated with a higher mortality. In a meta-analysis of over 1.2 million patients with CKD (average GFR 83 ml/min/1.73m²), serum K concentrations >5.5 meq/L were associated with a hazard ratio of 1.22 for mortality (95% confidence interval 1.15–1.29) [58].

4.2 Etiopathogenesis

Hyperkalemia is caused by excessive intake, extracellular shift or release, and reduced renal excretion. In diabetic ketoacidosis, the relative insulin deficiency along with osmotic forces and extracellular acidosis can lead to hyperkalemia despite total body K depletion [9]. Normal saline can induce hyperchloremic acidosis and cause K shifting [86]. Both rhabdomyolysis and tumor lysis can also result in extensive K release into the extracellular space leading to severe hyperkalemia.

GFR is a critical factor in the renal excretion of K [87]. A GFR < 15 ml/min/1.73 m2 is an important risk factor for hyperkalemia [88]. Patients with diabetes mellitus and RAAS inhibition also have reduced renal K excretion and can develop hyperkalemia. The elimination of K for the most part is controlled via aldosterone, but an elusive aldosterone-independent mechanism also appears to exist [89]. Aldosterone is synthesized by aldosterone synthase (AS) in the adrenal cortex in response to volume depletion and hyperkalemia. Aldosterone deficiency or lack of its action can lead to hyperkalemia. Common causes are hypoaldosteronism (seen in diabetes, Addison’s disease, obstructive uropathy, renal tubular acidosis type 4), and pseudohypoaldosteronism (PHA). PHA type I is caused by mutations in MR, whereas PHA type II is caused by mutations in WNK 1 or WNK 4 leading to increased activation of NCC, reduced distal sodium delivery, and ultimately reduced K secretion via ROMK. Other genetic defects in enzymes involved in cortisol or aldosterone synthesis can also lead to hyperkalemia, i.e., 21 hydroxylase, or aldosterone synthase deficiency [90, 91].

Drugs are important causes of hyperkalemia (Table 1). Most of them act on the RAAS axis. Calcineurin inhibitors (CNI) are commonly used in the transplant population and can reduce the expressions of both aldosterone and its receptor [94, 95]. CNIs may also increase NCC activity leading to sodium retention and a reduction in K excretion in the distal nephron [96]. Finally, constipation can also contribute to hyperkalemia especially in patients with end-stage kidney disease. As in those patients, a compensatory increase in colonic K excretion contributes to daily K homeostasis.

Mechanism of Action	Examples of Drugs
Blocks ENaC	Amiloride, trimethoprim, pentamidine
Inhibits Renin	DRI, heparin
Inhibits ACE	ACEI
Blocks AR 1	ARB
Inhibit PG Synthesis	NSAID
Na^+/K^+ ATPase	Digoxin
Potassium Leakage from Cells	Succinylcholine
Inhibits Aldosterone Synthesis	CNI, heparin

Table 1.

Drugs causing Hyperkalemia [92, 93].

4.3 Clinical features

The most important manifestation of hyperkalemia is cardiac dysrhythmia. ECG changes often follow the severity of hyperkalemia. Initially “peaked T wave” is seen due to shortening of depolarization. With progressive worsening of hyperkalemia, PR prolongation, disappearance of P wave, and marked widening of QRS complex will follow [97]. Ultimately patients can develop intraventricular blocks, bradycardia, ventricular arrhythmias [97, 98, 99, 100] such as asystole, ventricular fibrillation, pulseless idioventricular rhythm [97] and cardiac arrest [101]. On rare occasions, it can cause myopathy or paralysis [102].

5. Approach to diagnosis

5.1 Initial evaluation

Assessment of hyperkalemia starts with patient history, physical examination, followed by full metabolic panel, blood gas, urine studies, and ECG. Pseudohyperkalemia (Figure 4) should be suspected in a patient with abnormally high blood cells. Cellular shifting is mainly due to mineral acidosis, beta blockade, insulin resistance or deficiency. To check for cellular breakdown, serum measurements for creatine phosphokinase and lactate dehydrogenase will be helpful. Rarely patients with normal renal function can develop hyperkalemia if intake is excessive and/or concomitant inhibition of RAAS [103, 104].

Figure 4.

A diagnostic approach to hyperkalemia. Abbreviations: RTA renal tubular acidosis, GFR glomerular filtration rate, PHA Pseudohypoaldosteronism, CAH congenital adrenal hyperplasia (21 hydroxylase deficiency). *Beta blocker, alpha 2 agonist, non-steroidal anti-inflammatory agent. **angiotensin converting enzyme inhibitor, angiotensin receptor blocker, renin inhibitor.

5.2 Renal function and RAAS assessment

To assess the renal K excretion, random urine K, K/Cr ratio, fractional excretion of K, or 24 hr. urine K should be measured. The RAAS axis should also be evaluated by checking the plasma levels of renin and aldosterone. A high aldosterone level indicates a downstream antagonism of aldosterone action, commonly seen with obstructive uropathy, PHA, distal RTA type 4, and the use of certain drugs. If plasma aldosterone level is low, then inherited or acquired causes of hypoaldosteronism should be suspected (Figure 4). Further testing can be done to evaluate for adrenal axis, such as ruling out cortisol deficiency with serum cortisol, ACTH, and 21 hydroxylase [88].

5.3 Management

Management of hyperkalemia depends on the severity, underlying cause and signs of serious complication, i.e., high-risk ECG changes. If hyperkalemia is severe and there are significant ECG changes, patients should get intensive care unit monitoring. Hyperkalemia enhances depolarization of cardiac membrane, activates inward rectifying K channels [73, 99]. If a patient has ECG changes, intravenous calcium gluconate should be given to stabilize cardiac membrane potential. Calcium raises cell depolarization threshold, which reduces myocardial excitation [105]. Intracellular shifting of K by insulin, beta agonists, bicarbonate is also helpful.

In addition to restricting intake, medications including RAAS blockers should be temporarily discontinued. Due to their established benefit in renal and cardiovascular disease outcomes, RAAS blockers can be reinstituted after successful management of hyperkalemia and preventive measures are in place [106]. Potassium elimination can be increased via the kidneys and the colon. These decisions are based on serum K, urine output, GFR, and other comorbidities. In a patient with reasonable GFR, loop and thiazide diuretics can be used.

Potassium binders are resins that can be administered enterally (Table 2). These resins bind to K in the colon and promote its elimination in the stool, and they are very effective. However, they require one to several hours for onset of action and an intact bowel function [10, 107, 116]. With life-threatening cardiac changes and low GFR, dialysis may be indicated. Hemodialysis is most efficacious in eliminating K and will remove 50–80 meq of K in a standard 4-hour session. Peritoneal dialysis can be tried, but it is slower in removal of K [117, 118].

	Sodium Polystyrene Sulfonate [108, 113]	Patiromer [109]	Sodium Zirconium Cyclosilicate [107, 110, 111, 114, 115]
FDA Approval	1958	2015	2018
Chemical Structure	Organic polymer/ resin	Cross-linked polymer	Inorganic microporous compound
Sodium Content	100 mg/g	None	80 mg/g
Mechanism of Action	Sodium/ Potassium exchange, nonspecifically binds potassium, magnesium, calcium	Calcium/ Potassium exchange, also binds magnesium	Potassium exchanged with sodium and hydrogen
Onset of Action	Hours to Days	7 hours	1 hour
Amount of Potassium lowered	1 meq/L with 30 g	1 meq/L with 8.4 g	0.7 meq/L with 10 g
Adverse Effects	Intestinal necrosis	Hypomagnesemia, diarrhea, abdominal discomfort, flatulence	Nausea, vomiting, hypokalemia

Table 2.

Colonic potassium binders [107, 108, 109, 110, 111, 112].

6. Conclusion

Potassium is an integral intracellular cation. Any major disturbances in its homeostasis can be detrimental. Transcellular shifting represents an effective initial body response to such disturbances, with the kidney as the ultimate site for final regulation. Both hypo- and hyperkalemia are serious clinical problems and are associated with poor survival. Effective management includes correction of K, investigating underlying causes, and cardiac monitoring.

DRI Direct Renin Inhibitor, ACEI Angiotensin converting enzyme inhibitor, ARB Angiotensin Receptor Blocker, AR Angiotensin Receptor, CNI Calcineurin Inhibitor, NSAID Nonsteroidal anti-inflammatory drugs ENaC Epithelial Sodium Channel.