The role of cation-exchange resins in hyperkalemia management

Abstract

Hyperkalemia, characterized by elevated serum potassium levels, poses significant health risks, including life-threatening cardiac arrhythmias. The management of hyperkalemia has evolved, incorporating calcium polystyrene sulfonate (CPS) and newer agents such as sodium zirconium cyclosilicate (SZC) and patiromer alongside traditional treatments. This review provides a comprehensive examination of current management strategies for hyperkalemia, focusing on the comparative effectiveness, safety profiles, and patient preferences concerning CPS, SZC, and patiromer. Through an analysis of clinical trials, safety data, and guidelines, we highlight SZC's rapid action and favorable safety profile compared to CPS, which has been a standard treatment option for years. Additionally, the review explores patiromer, other emerging treatments, and future directions in hyperkalemia management, including the potential benefits of combination therapies and the role of personalized medicine. The findings suggest a shift toward newer potassium-binding agents in clinical practice, underscored by the need for individualized treatment approaches based on patient-specific factors. This article aims to guide clinicians in optimizing hyperkalemia management, ensuring effective, safe, and patient-centered care.

Introduction

Hyperkalemia, characterized by elevated serum potassium levels exceeding 5.0 mEq/L emerges as a critical electrolyte disturbance with significant implications for cardiac and neuromuscular function. Its prevalence varies widely, with higher incidence among those with renal insufficiency or heart failure (HF).¹ The prevalence depends on thresholds used to define hyperkalemia, but in general, it is around 14%–20% for serum potassium levels measuring ≥5.0 mEq/L and 3%–8% for serum potassium levels measuring ≥5.5 mEq/L.² In the United States, around 3.7 million adults were estimated to have hyperkalemia in 2014, a figure that has been on the rise since 2010. Among patients with chronic kidney disease (CKD) and/or HF, the annual prevalence of hyperkalemia was 6.35% in 2014, with nearly half of all hyperkalemic patients having either CKD or HF.³ This condition not only poses a risk for life-threatening arrhythmias and death but also complicates the management of chronic conditions such as CKD and HF, where it limits the use of renin-angiotensin-aldosterone system inhibitors (RAASis), despite their proven benefits in these populations.^{4, 5, 6}

The pathophysiology of hyperkalemia is multifaceted (Table 1), primarily involving impaired renal potassium excretion due to renal dysfunction, alterations in the distribution of potassium between the intracellular and extracellular compartments, and excessive potassium intake.^7,8 In patients with CKD, the reduced glomerular filtration rate compromises potassium excretion, a situation exacerbated by the use of RAASis, which inhibit potassium excretion by the kidneys.^{8, 9, 10} Additionally, conditions that shift potassium out of cells, such as acidosis or the breakdown of cell membranes, can precipitate hyperkalemia. Medications, including non-steroidal anti-inflammatory drugs (NSAIDs; e.g., rofecoxib, celecoxib, diclofenac, and indomethacin), potassium-sparing diuretics (e.g., spironolactone, eplerenone, filnerenone), angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and certain antibiotics (e.g., trimethoprim-sulfamethoxazole), have also been implicated in the development of hyperkalemia by affecting renal potassium handling or by promoting potassium release from cells.^{11, 12, 13, 14, 15}

Table 1.

Multifaceted causes of hyperkalemia.

Category	Causes	Description/examples
Decreased renal excretion	Chronic kidney disease	Impaired renal function leads to decreased potassium excretion.
	Acute kidney injury	Sudden reduction in kidney function affecting potassium regulation.
	Aldosterone deficiency or resistance	Conditions such as Addison's disease (deficiency) or pseudohypoaldosteronism (resistance) impair potassium excretion.
	Renin-angiotensin-aldosterone system inhibitors	Drugs such as ACE inhibitors, ARBs, and aldosterone antagonists reduce potassium excretion.
	Potassium-sparing diuretics	Such as spironolactone and amiloride, these drugs limit potassium secretion in the urine.
	NSAIDs	Can impair renal function and potassium handling.
Increased intake	Excessive dietary potassium	Uncommon without renal impairment but can occur with supplements or salt substitutes.
	Intravenous potassium administration	Overadministration or rapid infusion of potassium.
	Blood transfusion	Especially with stored blood, which may have higher potassium levels.
Shifts from intracellular to extracellular space	Acidosis	Metabolic and respiratory acidosis can lead to potassium moving out of cells.
	Tissue breakdown	Rhabdomyolysis, hemolysis, or tumor lysis syndrome releases intracellular potassium.
	Hyperglycemia	Insulin deficiency or resistance can cause potassium to shift out of cells.
	Medications	Beta blockers, digoxin toxicity, and succinylcholine can affect cellular potassium distribution.
	Exercise	Intense physical activity can transiently increase serum potassium levels.

ACE: Angiotensin Converting Enzyme, ARB: Angiotensin Receptor Blocker.

The management of hyperkalemia encompasses a spectrum of strategies aimed at promptly reducing serum potassium levels and addressing the underlying causes (Table 2).¹⁶ Traditional treatments have focused on dietary potassium restriction, insulin and glucose infusions, beta-2 agonists, and renal replacement therapy. However, each of these modalities comes with its own set of limitations and potential complications, necessitating careful consideration in clinical practice. Dietary potassium restriction, while fundamental in managing chronic hyperkalemia, often proves challenging for patients to adhere to and may not be sufficient for acute management or in severe cases.^16,17 Insulin and glucose infusions represent a rapid and effective method to lower serum potassium by shifting potassium intracellularly. However, this approach requires monitoring for hypoglycemia, a potentially dangerous side-effect, especially in patients without diabetes.^18,19 Beta-2 agonists, such as albuterol, can also lower potassium levels through intracellular shifting but are generally less effective and reliable than insulin therapy and may induce tachycardia or exacerbate HF in susceptible individuals.^20,21 Renal replacement therapy, including hemodialysis, is the most effective method for removing potassium in life-threatening hyperkalemia or when other treatments are contraindicated or ineffective. However, it is resource-intensive, requires vascular access, and is not without risks, including hypotension and infections.^{22, 23, 24}

Table 2.

Available therapeutic modalities to treat hyperkalemia.

Therapy	Mechanism of action	Advantages	Limitations
Dietary restriction	Reduces oral potassium intake	Simple, no cost	Limited effectiveness, requires patient compliance
Loop diuretics	Increases renal potassium excretion	Effective for volume overload conditions	Requires renal function, risk of dehydration and electrolyte imbalances
SPS	Exchanges sodium for potassium in the colon	Widely used, effective for mild hyperkalemia	Slow onset, risk of gastrointestinal side-effects, not for acute management
Calcium polystyrene sulfonate	Similar to SPS, exchanges calcium for potassium	Option for those on sodium-restricted diets	Gastrointestinal side-effects, limited data on efficacy
Sodium zirconium cyclosilicate	Binds potassium in the gastrointestinal tract	Rapid onset, well-tolerated	Expensive, drug interactions due to binding
Patiromer	Binds potassium in the colon	Effective for chronic management	Delayed onset, cost, gastrointestinal side effects
Insulin with glucose	Shifts potassium into cells	Rapidly effective for severe hyperkalemia	Short duration, risk of hypoglycemia, requires monitoring
Beta-2 agonists (e.g., Albuterol)	Shifts potassium into cells	Can be used adjunctively	Less effective when used alone, potential for cardiac side effects
Hemodialysis	Removes potassium directly from blood	Most effective for severe hyperkalemia	Requires vascular access, not always readily available

Abbreviation: SPS: sodium polystyrene sulfonate.

Cation-exchange resins such as sodium polystyrene sulfonate (SPS) and calcium polystyrene sulfonate (CPS) have been used for decades to promote gastrointestinal potassium excretion. Nevertheless, concerns regarding gastrointestinal side-effects, including rare but serious complications such as colonic necrosis, have limited their use in certain patient populations.^{25, 26, 27} The risk of serious gastrointestinal side-effects associated with SPS/CPS remains unchanged despite the FDA's recommendation to avoid using sorbitol. Sorbitol, an osmotic cathartic, was initially administered to prevent SPS-related bowel obstruction; however, it has been reported to cause colonic perforation.¹⁷ The limitations of SPS/CPS have spurred interest in newer agents such as sodium zirconium cyclosilicate (SZC) and patiromer, which have shown promise in managing hyperkalemia with a better safety profile and fewer gastrointestinal side-effects than older cation-exchange resins.^17,28,29 The aim of this review is to provide a comprehensive update on the current management strategies for hyperkalemia, with a particular focus on elucidating the roles and comparative efficacy of CPS, SZC, and patiromer in its treatment.

Calcium polystyrene sulfonate

CPS's mechanism of action involves the exchange of calcium ions for potassium ions in the gastrointestinal tract, particularly within the colon. This ion-exchange process facilitates the removal of excess potassium from the body through fecal excretion. CPS is administered orally or rectally and begins to act within hours of administration, but its full effect on lowering serum potassium levels may take up to one to two days.²⁵ Unlike its sodium-based counterpart, SPS, CPS offers an advantage for patients who require sodium restriction (Table 3).³⁰ Clinical trials and observational studies over the past decade have provided insights into the efficacy of CPS in managing hyperkalemia.³¹ A meta-analysis examined the effectiveness of cation-exchange resins, including CPS, in reducing serum potassium levels. The study found that these agents were associated with a significant reduction in serum potassium, with SPS conferring the most significant potassium-lowering effect, followed by CPS.³² CPS is especially a valuable tool in the management of hyperkalemia in CKD patients who are not on dialysis as it provides a non-systemic option to control serum potassium levels over time.

Table 3.

Comparison between sodium polystyrene sulfonate and calcium polystyrene sulfonate.

Feature	SPS	CPS
Mechanism of action	Exchanges sodium ions for potassium ions in the colon, reducing serum potassium levels.	Exchanges calcium ions for potassium ions in the colon, reducing serum potassium levels.
Formulation	Available as a powder that can be mixed with water or syrup for oral administration or as a suspension for rectal use.	Primarily available in powder form for oral or rectal administration, mixed with a small amount of liquid.
Onset of action	Variable; effects typically observed within hours to a day.	Similar to SPS, with effects usually starting within hours but may take longer for full effect.
Clinical efficacy	Effective for mild to moderate hyperkalemia, particularly as a chronic management strategy.	Efficacy similar to SPS for managing mild to moderate hyperkalemia. Less commonly used, hence less data on efficacy compared to SPS.
Safety profile	Associated with gastrointestinal side-effects such as nausea, vomiting, and constipation. Serious but rare complications include colonic necrosis.	Similar gastrointestinal side-effects to SPS, including constipation and nausea. Risk of hypercalcemia. Rare cases of gastrointestinal complications.
Advantages	Widely used and studied; a well-established option for hyperkalemia management.	Useful alternative for patients on sodium-restricted diets or those at risk of fluid overload.
Limitations	Sodium load can be problematic for patients with heart failure or hypertension. Risk of serious gastrointestinal complications.	Calcium load could be an issue for patients with hypercalcemia. Less data available on efficacy and safety compared to SPS.
Contraindications	Obstructive bowel disease, hypovolemia, and patients at risk for sodium overload.	Obstructive bowel disease, hypovolemia, and patients with hypercalcemia or risk for calcium overload.
Usage considerations	Should be used cautiously in patients with renal failure or those at risk for sodium retention.	May be preferable in patients needing to avoid additional sodium intake. Monitoring for calcium levels is advisable.

Abbreviations: SPS: sodium polystyrene sulfonate; CPS: calcium polystyrene sulfonate.

Its safety profile is generally considered favorable, especially when used appropriately and with due consideration of patient-specific factors. However, as all medications, CPS is associated with potential side-effects and contraindications that must be carefully managed. Common side-effects of SPS/CPS include gastrointestinal disturbances such as nausea, vomiting, constipation, and, in some cases, diarrhea. These effects are generally mild and manageable but can occasionally lead to more severe complications such as intestinal obstruction, particularly in patients with predisposing conditions such as bowel motility disorders.^25,33 More serious but rare side-effects include gastrointestinal necrosis and perforation, which have been reported in a small number of cases. These severe adverse events are more likely in patients with significant comorbidities or those receiving high doses of SPS/CPS.^34,35 Studies noted an increase in serious adverse gastrointestinal events such as ulcers, perforations, and ischemia. Hazard ratios for these events range from 1.25 to 1.94, with incidence rates per 1000 person-years ranging from 16 to 22.97. These adverse events often occur within 2–14 days post administration of SPS and can persist throughout a 30-day follow-up period.^36,37 Although specific data for CPS use are lacking, the incidence of gastrointestinal side-effects is thought to be similar.³¹ Contraindications to CPS use include hypercalcemia as the exchange process may further increase calcium level, and in patients with obstructive bowel disease, given the risk of bowel obstruction and perforation.

Sodium zirconium cyclosilicate

SZC is a highly selective potassium binder that operates in the gastrointestinal tract to lower serum potassium levels. Its mechanism is based on its structure as a zirconium silicate compound, which has a high affinity for potassium ions. SZC exchanges hydrogen and sodium ions for potassium ions in the gastrointestinal lumen, particularly in the small intestine where the potassium concentration is highest. This ion exchange process prevents the absorption of potassium and facilitates its excretion in the stool, thereby reducing serum potassium levels.^38,39 The efficacy of SZC in managing hyperkalemia has been demonstrated in several key clinical trials: The HARMONIZE Trial is a randomized, phase 3 trial that evaluated the efficacy and safety of SZC in patients with hyperkalemia. The study found that SZC rapidly reduced serum potassium levels within 48 h of treatment initiation and maintained normokalemia during a 28-day maintenance phase. SZC was well-tolerated, with a safety profile similar to that of placebo.^28,39 The ZS-003 Trial is a multicenter, randomized, placebo-controlled study, assessing SZC in patients with hyperkalemia, including those with CKD, HF, and on RAASi therapy. SZC significantly reduced potassium levels compared to placebo and was effective in both acute and chronic settings of hyperkalemia management.²⁹ The HARMONIZE-Global Trial extended the findings of the HARMONIZE trial to a broader patient population, including individuals from different geographic regions. This trial reinforced the efficacy of SZC in rapidly correcting hyperkalemia and maintaining potassium levels within the normal range over a month, with a safety profile consistent with earlier studies.⁴⁰ Next, in the open-label extension of the HARMONIZE study, SZC demonstrated efficacy in maintaining normokalemia in patients with hyperkalemia for up to 11 months, with 88.3% achieving a mean serum potassium level of ≤5.1 mmol/L. SZC was well tolerated with no new safety concerns, highlighting its potential as a long-term management option for hyperkalemia.⁴¹

SZC has been evaluated for safety in multiple clinical trials, which have generally found it to be well-tolerated by patients with hyperkalemia, including those with CKD and HF. The most common side-effects associated with SZC are gastrointestinal effects, including mild to moderate nausea, vomiting, and constipation. Unlike other potassium binders, SZC has a minimal risk of causing serious gastrointestinal complications such as colonic necrosis, a significant advantage over some other treatments.^28,39 Edema has been reported as a side-effect in a small percentage of patients, likely related to the sodium-exchange component of SZC's mechanism. However, this side-effect is generally manageable and does not outweigh the benefits of potassium reduction in patients at risk of hyperkalemia-related complications. While SZC is used to treat hyperkalemia, there is a potential risk of overcorrection leading to hypokalemia. Clinical trials have reported this as a rare outcome, emphasizing the importance of monitoring serum potassium levels to adjust treatment as necessary.²⁹ SZC is contraindicated in patients with a history of hypersensitivity to the product. Caution is advised in patients with severe constipation, bowel obstruction, or other gastrointestinal motility disorders due to the potential for gastrointestinal adverse effects.

Recent guidelines and expert consensus statements have started to incorporate SZC as a recommended treatment option for hyperkalemia. The 2017 American Heart Association/American College of Cardiology/Heart Failure Society of America HF guidelines acknowledge the role of SZC in managing hyperkalemia, particularly in HF patients who are at increased risk of developing hyperkalemia due to RAASi therapy. SZC is recommended as an option to allow the continuation or initiation of RAASis in patients with HF and chronic hyperkalemia.⁴² Kidney Disease: Improving Global Outcomes (KDIGO) 2020 Clinical Practice Guideline for diabetes management in CKD recommend the consideration of SZC for patients with CKD and persistent hyperkalemia, highlighting its effectiveness in managing potassium levels and enabling the use of guideline-directed medical therapy.⁴³ The 2021 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD recognizes the role of SZC in managing hyperkalemia, particularly in CKD patients on RAASis.⁴⁴ The incorporation of SZC into these guidelines underscores its importance in the management of hyperkalemia, particularly in patient populations where maintaining optimal potassium levels is crucial for the use of life-saving medications such as RAASis.

Patiromer

Patiromer functions by exchanging calcium ions for potassium ions in the colon, thereby effectively lowering serum potassium levels. The active compound, patiromer sorbitex calcium, is a non-metabolized polymer that is excreted via feces rather than being absorbed systemically. This mechanism is particularly advantageous for patients on sodium-restricted diets, as it uses calcium instead of sodium as the counter ion, thereby avoiding additional sodium intake.⁴⁵ The pharmacodynamic profile of patiromer indicates that the drug is most active in its ionized form within the colon, particularly in the distal sections. It has been rigorously evaluated through various studies that have demonstrated its capacity to substantially reduce serum potassium levels. Significant reductions in serum potassium were observed within hours of administration, with continued effectiveness over prolonged treatment periods. These studies illustrate patiromer's rapid onset and sustained efficacy in potassium management, and it is generally well-tolerated among patients.⁴⁵ The most common gastrointestinal side-effects include constipation, diarrhea, flatulence, and vomiting. Hypomagnesemia, or low magnesium levels, is another frequently reported adverse effect, occurring in up to 7.2% of patients.⁴⁶ Additionally, there have been rare reports of hypercalcemia, although this side-effect is not commonly observed in clinical trials.⁴⁷ Furthermore, patiromer can interfere with the absorption of other oral medications, necessitating careful timing when administering other drugs.

The clinical efficacy and safety of patiromer have been robustly demonstrated across several Phase I, II, and III trials. These trials affirm the drug's ability to manage and sustain reduced serum potassium levels in patients with CKD and those at risk for hyperkalemia due to conditions such as HF or diabetes. Notably, the PEARL-HF trial evaluated the safety and efficacy of patiromer in managing potassium levels in HF patients, revealing its effectiveness in enabling the continued use of vital medications that may increase potassium levels, such as spironolactone.⁴⁸ Moreover, the AMBER trial highlighted the utility of patiromer in improving treatment outcomes for patients with resistant hypertension. This trial underscored patiromer's significant role in enabling these patients to maintain necessary pharmacological treatments without the risk of hyperkalemia.⁴⁹

Comparative analysis of CPS, SZC, and patiromer

CPS has been a standard treatment for hyperkalemia since its FDA approval in 1958. However, CPS is often considered for chronic management rather than acute hyperkalemia due to its slower onset of action than of other agents.³⁴ Despite past studies being observational, recent clinical trials have reaffirmed CPS's efficacy in a chronic setting. However, its use in acute hyperkalemia is limited by a variable onset of up to 6 h, a variable duration of action up to 24 h, and a lack of robust efficacy data. These factors make CPS less ideal for emergency interventions where rapid potassium reduction is critical.⁵⁰ SZC, introduced more recently, has demonstrated rapid and sustained reduction in serum potassium levels in clinical trials, including the HARMONIZE and ZS-003 trials. These trials highlighted SZC's ability to quickly normalize potassium levels within hours to days and maintain this effect with chronic administration.^28,39 SZC's mechanism, which involves exchanging sodium and hydrogen for potassium in the gastrointestinal tract, allows for a rapid onset of action without significant systemic side-effects. Data from SZC clinical trials suggest a significant role for it in managing acute hyperkalemia, with a rapid onset of effect within 1 h and a predictable, dose-dependent potassium-lowering response.⁵⁰ Patiromer plays a significant role in the management of chronic hyperkalemia, particularly when compared to CPS and SZC. Clinical trials have shown that patiromer enables a dose-dependent reduction in potassium levels, with efficacy demonstrated through follow-up periods of 12 weeks–52 weeks. This highlights its utility for long-term management.^46,51 Although the onset of action for patiromer is slower, making it less suitable for acute settings, its ability to effectively maintain normokalemia makes it the preferred agent for chronic hyperkalemia management compared to CPS and SZC.⁵⁰

Financially, CPS provides a considerable advantage compared to alternative treatments, making it an economically attractive option for many patients. For instance, a month's supply of CPS is priced between US$20 and US$30, which is substantially lower than the price of other treatments in the same category. In contrast, treatments such as patiromer and SZC are significantly more expensive, with monthly costs typically ranging between US$600 and US$1000. This stark price difference makes CPS a viable and cost-effective alternative for those seeking affordable healthcare solutions.⁵²

Patient adherence is a significant concern due to the complex administration requirements of these treatments. CPS is often used in chronic settings, requiring regular administration that can impact patient compliance, especially given its gastrointestinal side-effects. Its taste and the need for mixing with liquids can also affect patient willingness to maintain therapy. Both patiromer and SZC are suspensions that require proper mixing by the patient to ensure the correct dose is administered. Initially, SZC requires dosing three times daily, which can be cumbersome. Additionally, patiromer's binding to other medications necessitates a separation of at least 3 h from other drug administrations (Table 4) complicating treatment for patients on multiple medications. Proper education on drug interactions, mixing, administration, and timing is critical to ensure adherence and, ultimately, effectiveness.⁵⁰

Table 4.

Comparison between calcium polystyrene sulfonate, patiromer, and sodium zirconium cyclosilicate.

Feature	CPS	Patiromer	SZC
Mechanism of action	Exchanges calcium for potassium in the colon.	Binds free potassium in the GI tract, using calcium as a counterion.	Exchanges sodium and hydrogen for potassium in the GI tract.
Efficacy	Effective for chronic management of hyperkalemia.	Effective for chronic management.	Effective for both acute and chronic management of hyperkalemia.
PK	Not systemically absorbed; acts locally in the colon.	Not systemically absorbed; acts locally in the GI tract.	Not systemically absorbed; acts locally in the GI tract.
PD	Reduces serum potassium by increasing fecal potassium excretion.	Reduces serum potassium by increasing fecal potassium excretion.	Rapidly reduces serum potassium by increasing fecal potassium excretion.
PK/PD insights	Effectiveness dependent on exchange capacity and GI transit time.	Binds potassium throughout the GI tract, leading to a gradual reduction in serum potassium.	High affinity for potassium, leading to a rapid and sustained reduction in serum potassium.
Drug interactions	May bind to other orally administered medications, reducing their absorption.	Binders like patiromer can decrease the absorption of many oral medications; timing of administration is critical.	May bind to other orally administered medications, reducing their absorption.
Recommended dosage	Initial: 15–30 g orally or rectally 1–4 times a day	Initial: 8.4 g once daily	Initial: 10 g three times a day for up to 48 h
Maintenance dosage	Adjust based on serum potassium levels.	Maintenance: 8.4 g once daily, can adjust based on serum potassium.	For chronic management: 10 g once daily, can be adjusted based on serum potassium levels.
Onset of action	Slow, several hours to days.	Within hours to days, with maximum effect seen within 7 days.	Rapid, within hours.
Duration of action	Long-term management, requires continuous use for sustained effect.	Long-term management, requires continuous use for sustained effect.	Both acute and chronic management of hyperkalemia.
Safety and side-effects	Nausea, vomiting, constipation. Rare: intestinal necrosis.	Constipation, hypomagnesemia.	Mild edema, hypokalemia, GI disturbances.
Contraindications	Hypercalcemia, obstructive bowel disease.	Severe GI motility disorders, hypersensitivity to the active substance or any excipients.	Hypokalemia, mechanical bowel obstruction.
Special considerations	Caution in patients with congestive heart failure or renal failure due to calcium load.	Requires separation from other oral medications by at least 3 h.	Monitor for sodium overload in patients with heart failure or hypertension.
Patient preference/compliance issues	Taste and consistency may affect acceptability; GI side-effects may impact compliance.	Requires mixing with water and has specific administration instructions relative to other medications, which might affect compliance.	Generally well-tolerated, but the need for daily administration in chronic management may affect compliance.
Monitoring requirements	Serum electrolytes, especially calcium and potassium.	Serum potassium and magnesium levels, especially during the initiation phase.	Serum potassium levels, renal function, and signs of edema.

Abbreviations: PK: Pharmacokinetics; PD: Pharmacodynamics; CPS: calcium polystyrene sulfonate; SZC: sodium zirconium cyclosilicate; GI: gastrointestinal.

Emerging treatments and future directions

SZC and patiromer have already made significant impacts as novel potassium binders. However, the pipeline for hyperkalemia treatments continues to evolve, with several investigational therapies under development. Cyclophosphamide analogs are being explored for their potential to selectively bind potassium in the gastrointestinal tract with minimal systemic effects. Additionally, advances in polymer technology have led to the development of new compounds that can effectively bind potassium in the gut, potentially offering advantages in terms of specificity and side-effects. These emerging agents are in various stages of clinical development, and their introduction could further expand the options available for hyperkalemia management. The use of combination therapies represents a strategic approach to managing hyperkalemia, particularly in complex or refractory cases. Combining different classes of potassium-lowering agents, such as CPS or SZC with diuretics or RAASis, can provide a synergistic effect, enhancing the overall efficacy of treatment. For example, the combination of a potassium binder with a loop diuretic can not only enhance potassium excretion but also address volume overload, a common issue in patients with HF or CKD. Clinical trials exploring the efficacy and safety of such combination therapies are ongoing, and preliminary results are encouraging. However, careful consideration of potential drug–drug interactions and the cumulative risk of side-effects are essential when designing combination therapy regimens.

Personalized medicine, tailored to the individual patient's genetic makeup, underlying health conditions, and specific treatment needs, is gaining traction across various medical disciplines, including the management of hyperkalemia. Pharmacogenomics and biomarker research are paving the way for more personalized treatment strategies that could optimize efficacy and minimize adverse effects. For instance, identifying genetic variants that affect potassium handling or drug metabolism could help predict a patient's response to specific hyperkalemia treatments, allowing for more targeted therapy choices. Similarly, biomarkers indicative of drug efficacy or risk of side-effects could guide treatment selection and dosing, ensuring that patients receive the most appropriate and effective therapy.

Conclusion

CPS has been a longstanding option in the management of hyperkalemia, recognized for its ability to reduce serum potassium through calcium exchange, albeit with a relatively slower onset of action and concerns regarding gastrointestinal side-effects. In contrast, SZC is highlighted as a more contemporary choice, praised for its rapid effectiveness and favorable safety profile, significantly mitigating systemic impacts while quickly normalizing potassium levels. Our comparative analysis emphasizes SZC's superior efficacy and safety, establishing its integral role in both acute and chronic hyperkalemia management. SZC's profile recommends its broader application across various patient demographics, particularly those with renal challenges or heart conditions traditionally susceptible to hyperkalemia. While SZC and patiromer are pivotal in advancing hyperkalemia treatment, acknowledging CPS's value in specific scenarios remains important, especially in resource-limited settings or where cost considerations predominate.

Patients/ Guardians/ Participants consent

Not applicable.

Ethical clearance

Nil.

Source of support

None.

Disclosure of competing interest

The authors have none to declare.