Novel Potassium Binders for CKD Patients with Hyperkalemia

Abstract

Hyperkalemia is defined as a serum or plasma potassium level that is greater than 5.0 or 5.5 mmol/L, and this variation is because the definition of the upper limit of normal level used in research and guidelines is varied. Hyperkalemia is a potentially life-threatening condition that may lead to muscle paralysis, cardiac arrhythmia, and death. It is a common clinical problem seen in patients with chronic kidney disease (CKD), and this is particularly true with the progressive and advanced deterioration of the glomerular filtration rate (GFR). The management of such patients could be a challenge to nephrologists, especially since the therapeutic interventions that are used to slow the progression of CKD may themselves lead to or worsen hyperkalemia. This chapter will discuss the issue of hyperkalemia in CKD patients and will focus on the role of novel potassium binders in the management of such patients.

1. Introduction

Potassium is the major intracellular cation, and 98% of the total body potassium is confined to the intracellular space [1]. The ratio between the intracellular and extracellular potassium concentrations is a very important determinant of the cellular membrane potential [2]. Therefore, any disturbance to this ratio may affect the function of the cardiovascular and neuromuscular systems. In general, hyperkalemia develops when there is increased potassium release from cells or reduced urinary potassium excretion. Chronic kidney disease patients are at particular risk of hyperkalemia because of multiple factors [3]. These factors are summarized in Figure 1. With the progressive reduction in the GFR, the urinary excretion of potassium is also progressively decreased. Especially when the dietary potassium intake is not restricted. Additionally, patients with CKD tend to have metabolic acidosis, which will lead to a shift of potassium from the intracellular to the extra-cellular space with subsequent hyperkalemia. Renin–angiotensin–aldosterone system inhibitors (RAASi) are commonly used in patients with CKD to slow the progression to end-stage renal disease. However, this comes with the price of increased risk of hyperkalemia, as RAASi therapy will reduce the secretion of aldosterone, thereby impairing the efficiency of urinary potassium excretion. In addition, CKD patients often have comorbidities, such as DM and heart failure, which are frequently associated with hyperkalemia through different mechanisms [3]. The presence, or even the coexistence, of all aforementioned factors, make hyperkalemia a common encounter for nephrologists when managing CKD patients. This chapter will give a brief overview of the extent of the hyperkalemia problem among CKD patients and its clinical implications but will discuss in detail the role of the novel potassium binders in mitigating the risk of hyperkalemia in patients with CKD.

Figure 1.

Mechanisms of hyperkalemia in chronic kidney disease (CKD) patients.

2. Epidemiology

When looking at the general population, hyperkalemia is most prevalent in patients with CKD [4]. The rate of hyperkalemia among CKD populations is variable depending on multiple factors including the level that was used to define hyperkalemia, the GFR or the stage of CKD, the use of RAASi therapy, and presence of certain comorbidities, such as diabetes and heart failure [5]. Studies focusing on pre-dialysis CKD patients have shown that hyperkalemia is not only common but also recurrent [6, 7, 8, 9, 10]. Patients with CKD spend 13–32% of their time in a chronic state of hyperkalemia [9]. In these studies, low GFR seems to be the most important factor associated with hyperkalemia. For example, in a cross-sectional study of pre-dialysis outpatients with an estimated GFR of 14.5 ± 4.8 ml/min/1.73 m², the prevalence rate of hyperkalemia, defined as potassium level ≥ 5.0, ≥ 5.5, and ≥ 6.0 mmol/L, was 54.2%, 31.5%, and 8.4%, respectively [7]. In another study of CKD patients with an average GFR of 35.0 ± 17.3 ml/min/1.73 m², the prevalence of hyperkalemia was 35.0 ± 17.3% and was dependent on the CKD stage [8]. In the later study, most patients had mild to moderate hyperkalemia (defined as a potassium level of 5.0–5.4 mml/L; and 5.5–5.9 mmol/L, respectively) [8]. Severe hyperkalemia with potassium level ≥ 6.0 mmol/L was rare [8, 9, 10].

3. Clinical implications

When encountering patients with hyperkalemia, physicians worry the most about the potential risk of cardiac arrhythmias. However, other consequences of hyperkalemia are also serious [11]. The following summarizes other potential consequences of hyperkalemia observed in patients with CKD:

• Mortality risk: Across all CKD stages, hyperkalemia is associated with increased all-cause mortality as well as cardiovascular mortality [12, 13].

• Hospitalization risk: The rate of hospitalization related to hyperkalemia is likely the highest in patients with CKD [13]. Some data suggest that hyperkalemia is responsible for more than one-third of total hospitalization in pre-dialysis CKD patients [14]. These hospitalizations could be due to ventricular arrhythmia, cardiac arrest, or other cardiac events [10]

• A predictor of progression to end-stage renal disease (ESRD): A multivariable competing-risk analysis of pre-dialysis CKD patients showed that new-onset or persistent hyperkalemia portends per se a 30% higher risk of ESRD, which is independent of the rate of GFR decline [8].

• Reduction of dose/or cessation of RASSi therapy: The utilization of RASSi therapy in patients with CKD has been shown to slow the progression of CKD, decrease the risk of cardiovascular events, and decrease the risk of death [15, 16, 17, 18, 19]. Additionally, patients with CKD may have co-existing morbidities (like heart diseases), for which RASSi therapy could be beneficial [3]. However, this utilization of RASSi is not always easy or feasible because of the risk of hyperkalemia [3, 20]. Hyperkalemia frequently leads to a reduction of the RASSi dose or even discontinuation in patients with CKD [20, 21, 22]. This suboptimal use of RASSI in CKD results in increased rates of death and other major adverse cardiovascular events [20, 22].

• Other consequences: neuromuscular abnormalities are seen in patients with CKD, and hyperkalemia could contribute to uremic depolarization and the development of neuropathy [23]. Some data suggest that controlling hyperkalemia may limit the progression of peripheral neuropathy in these patients [24]. Hyperkalemia is also associated with a substantial increase in economic burdens, primarily driven by higher inpatient costs [25].

4. Traditional lines of management

In situations where CKD patients present with a hyperkalemic emergency (e.g., symptomatic hyperkalemia, presence of electrocardiogram (ECG) changes, severe hyperkalemia with a level more than 6.5 mmol/L…. etc.); the usual rapidly acting interventions (i.e., intravenous calcium, salbutamol nebulizer, insulin, and glucose) should be instituted promptly [26]. These interventions are usually followed by therapies that remove potassium from the body, either through the kidneys or through the gastrointestinal tract. However, CKD patients usually have chronic, asymptomatic, mild to moderate hyperkalemia, which may allow for chronic and slowly-acting interventions to be instituted. These traditional interventions are commonly used concomitantly by nephrologists, especially when trying to mitigate the risk of hyperkalemia associated with the use of RASSi therapy. However, all these traditional lines of management have their limitations or possible side effects. For example, CKD patients with hyperkalemia are advised to restrict their dietary potassium intake to 2 to 3 gm per day [26, 27]. However, this approach has many limitations, starting with the fact that CKD patients have many other dietary restrictions which may lead to a high rate of poor compliance [28]. Additionally, strong data to suggest the effectiveness of dietary potassium restriction is lacking [26]. Some data suggest that dietary potassium restriction has the potential to be harmful to overall health and cardiovascular outcomes in such patients [29].

Another example of a common therapeutic intervention for hyperkalemia is the use of sodium polystyrene sulfonate (SPS). SPS is a non-absorbed cation-exchange resin that is sold under the brand names Kayexalate, SPS, or Kionex [30]. It was first introduced for the treatment of hyperkalemia in the early 1950s based on 2 small case series and was then approved by the US Food and Drug Administration (FDA) for short-term treatment of hyperkalemia in 1958 [30]. It works by binding to potassium in the colon in exchange for sodium leading to increased fecal excretion of potassium. It is given orally as 15 gm up to 4 times per day or 30–60 gm rectally up to 4 times per day [30, 31]. Although SPS is a famous intervention that has been used for a long time, randomized clinical trials supporting its efficacy for the management of chronic hyperkalemia are limited [30, 32]. There is only one randomized clinical trial with a small sample size of CKD patients which showed that SPS leads to a small reduction in the serum potassium level compared to placebo [30, 32], but the clinical significance of this effect is not clear [30]. Moreover, in 2009, the FDA released a black box warning about the risk of intestinal necrosis (which could be fatal) associated with the use of SPS in combination with sorbitol [30, 32, 33]. However, some data suggests that intestinal necrosis may still occur in patients receiving SPS alone without sorbitol suggesting that this complication is likely related to the SPS itself and independent of sorbitol [30, 34]. Patients with advanced CKD are at particular risk of developing gastrointestinal complications including intestinal ischemia, thrombosis, ulceration, or perforation [35], and the risk of hospitalization because of SPS-related gastrointestinal complications is increased in elderly patients [36]. Looking at all aforementioned concerns about SPS, some have recommended that it should no longer be used [26, 30, 37], or to limit its use to a situation where all the following criteria are met [37]:

• potentially life-threatening hyperkalemia

• Novel potassium binders (i.e., patiromer or sodium zirconium cyclosilicate) are not available,

• dialysis is not readily available, and

• other therapies (like diuretics) have failed or are not possible.

For postoperative patients, patients with intestinal obstruction/ileus, patients with chronic bowel disease, and patients with constipation, hypovolemia, or renal insufficiency, SPS should not be used even in the above-mentioned situation, and such patients can be managed with repeated doses of insulin and glucose until dialysis is feasible [33, 37].

The limitations of traditional lines of management of chronic hyperkalemia before the era of novel potassium binders are summarized in Table 1.

Dietary Restriction of Potassium (2 to 3 grams/day)
Limitations	Patients may already need to follow other dietary restrictions
	Low compliance rate
	Potential Increase in the risk of cardiovascular outcomes and stroke
Loop Diuretics
Limitations	Its role is mainly in hypervolemic patients
	May cause other electrolyte disturbances and acute kidney injury
	Its efficacy depends on renal function
Sodium Bicarbonate Tablets
Limitations	Lack of strong evidence to support its role
	Its role is mainly in patients with coexisting metabolic acidosis
	May lead to fluid retention and hypertension
Reduction of Dose /Cessation of Renin– Angiotensin–Aldosterone System Inhibitors
Limitations	Increase the rate of major adverse cardiovascular events
	Increase the rate of death
	Loss of renoprotective effect of RASSI
Sodium Polystyrene Sulfonate
Limitations	Rare but serious adverse gastrointestinal side effects
	Limited evidence to support its efficacy, especially as chronic therapy
	May bind other medications reducing their efficacy

Table 1.

Limitations of traditional lines of management of chronic hyperkalemia.

5. Novel potassium binders

The limitations of all the aforementioned interventions in the management of chronic hyperkalemia have identified an unmet need to find a reliable and effective intervention or strategy to address this problem. The introduction of the novel potassium binders has filled a major gap in this regard. In 2015, patiromer was approved by FDA as a novel potassium binder, followed by sodium zirconium cyclosilicate (SZC) which was approved by FDA in 2018. Many trials have demonstrated the efficacy of both drugs in short and long-term management of hyperkalemia [38]. Therefore, many guidelines are now advocating for the use of these novel binders to manage hyperkalemia, especially for those using RASSi therapy [26, 38, 39, 40]. Table 2 compares different potassium binders.

Property	Sodium Polystyrene Sulfonate	Patiromer	Sodium Zirconium Cyclosilicate
Brand name	Kayexalate, SPS, or Kionex	Veltassa	Lokelma
Approval year	1958	2015	2018
Mechanism of action	binds potassium in exchange for sodium	binds potassium in exchange for calcium	binds potassium in exchange for sodium and hydrogen
Onset of action	Hours to days	7 hours	1 hour
Site of action	Colon	Distal colon	Entire gastrointestinal tract
Dosing	15–60 g orally (1–4 times daily), or 30–50 g rectally (1–4 times daily)	8.4 g daily, and if needed, may increase the dose after a week to 16.8 g to a maximum of 25.2 g daily	LA: 10 g orally three times daily for 48 hours, then; MD: 5 g orally daily. If needed, increase the dose after a week to 10 gm. The maximum dose is 15 g daily
Na content	1500 mg per 15 g	None	400 mg per 5 g
Serious S/E	Colonic necrosis	None	None
Common S/E	Constipation, diarrhea, nausea, and vomiting Hypokalemia, hypomagnesemia	Constipation, diarrhea, nausea, and vomiting Hypokalemia, hypomagnesemia	Hypokalemia Edema
Cost	15 g/60 mL (per mL): $1.21	8.4 g: $54.77 16.8 g: $40.99 25.2 g: $40.99	5 g: $32.82 10 g: $32.82

Table 2.

Comparison of potassium binders.

G: gram, LA: loading dose, MD: maintenance dose, Na: sodium, S/E: side effects.

5.1 Patiromer

Patiromer is a cross-linked polymer of 2-fluoroacrylic acid with divinylbenzenes and 1,7-octadiene. It is used in form of its calcium salt and with sorbitol, a combination called patiromer sorbitex calcium.

See Figure 2.

Figure 2.

Chemical structure of patiromer. (by Anypodetos – Own work, based on RxList, CC0, https://commons.wikimedia.org/w/index.php?curid=45569546).

5.1.1 Clinical pharmacology

Patiromer, which is sold under the brand name Veltassa, is a cation exchange polymer that binds potassium in the colon in exchange for calcium. The net result is increased fecal excretion of potassium with subsequent reduction in the serum potassium level. It is available as a powder for oral suspension that is taken once daily without regard to food. The initial dose is 8.4 grams, and if needed, the dose can be increased after a week to 16.8 grams to a maximum of 25.2 grams once daily [33, 41, 42].

It is a slowly–acting drug with an onset of action of 7 hours after administration, and the potassium level continues to decrease for at least 48 hours if treatment is continued [42]. The potassium level remains stable for 24 hours after administration of the last dose and does not increase before the next dose [42]. If patiromer is discontinued, the potassium level starts to rise again at least four days from the last dose [42]. Patiromer is not absorbed from the gut, is not metabolized, and is excreted unchanged with feces [41, 42].

5.1.2 Indication and utilization

Patiromer is indicated for the management of chronic hyperkalemia, especially for those who are on RAASi therapy [38, 39, 40]. Because patiromer acts relatively slowly, it is not usually recommended as an emergency treatment for life-threatening hyperkalemia. However, some data suggest that patiromer can acutely reduce serum potassium within 2 hours in patients with severe hyperkalemia [43]. Therefore, different guidelines are now recommending using patiromer in acute settings for patients with severe hyperkalemia alongside the standard of care [26, 37, 44].

5.1.3 Available evidence

• DIAMOND trial (Butler et al. – 2022): A multicenter, randomized, double-blind, placebo-controlled study on the use of patiromer in patients with hyperkalemia on RAASi therapy and/or on mineralocorticoid receptor antagonists (MRA). It included 878 patients with heart failure with reduced ejection fraction with a follow-up period of up to 43 weeks (median 27 weeks). Almost 42.4% of patients had stage 3 CKD. Patiromer significantly reduced the serum potassium level and reduced the MRA discontinuation or dose reduction [45].

• AMBER trial (Agarwal et al. – 2018): A multicenter, randomized, double-blind, placebo-controlled study on the use of patiromer in patients with CKD and resistant hypertension requiring spironolactone. It included 295 patients with a follow-up period of up to 12 weeks. It concluded that patiromer enabled more patients to continue treatment with spironolactone with less hyperkalemia [46].

• TOURMALINE trial (Pergola et al. – 2017): An open-label-randomized study on the efficacy and safety of patiromer administered once daily with or without food. It included 114 adult patients with hyperkalemia, of which 75.9% had CKD. It concluded that patiromer is equally effective and well tolerated when taken without food or with food, thereby offering the potential for dosing flexibility [47].

• OPAL-HK trial (Weir et al. – 2015): A multinational, randomized, single-blind, and placebo-controlled study on CKD patients receiving RAASi therapy who had hyperkalemia. It included 243 with a follow-up period of 12 weeks. It concluded that patiromer treatment was associated with a decrease in serum potassium levels and, as compared with placebo, a reduction in the recurrence of hyperkalemia [48].

• AMETHYST-DN trial (Bakris et al. – 2015): A multicenter, randomized, open-label study evaluating the efficacy and safety of patiromer in hyperkalemic patients with type 2 diabetes and CKD. It included 306 patients with a follow-up period of 52 weeks. It concluded that patiromer resulted in statistically significant decreases in serum potassium levels after 4 weeks of treatment, lasting through 52 weeks [49].

• PEARL-HF Study (Pitt et al. – 2011): A randomized, double-blind, placebo-controlled study evaluating the efficacy of patiromer on serum potassium levels and safety in patients with chronic heart failure receiving the standard therapy (with or without CKD) and spironolactone. It included 105 patients with a follow-up period of 4 weeks. It concluded that patiromer significantly reduced potassium levels and is well tolerated in patients with HF receiving standard therapy and spironolactone [50].

5.1.4 Side effects of patiromer

Patiromer is generally well tolerated [42]. Its safety and tolerability in clinical practice are predictable and consistent with clinical trial data [50].

Reported side effects were uncommon and mild, and did not lead to stopping patiromer [42, 51]. These include:

• Gastrointestinal side effects: constipation (6.9–7.2%), diarrhea (3.5–4.8%), abdominal discomfort (1.4–2%), flatulence (1.3–2%), nausea (1.7–2.3%). These side effects are usually mild and do not appear to be dose-dependent. In most cases, they improve spontaneously. The currently available evidence indicates that patiromer does not cause severe gastrointestinal complications, such as gastrointestinal ischemia, necrosis, or perforation.

• Electrolyte disturbance: Hypokalemia of less than 3.5 mmol/L may occur in 4.7–5% of patients. Mild to moderate hypomagnesemia may also occur with a risk ranging between 0.02–5.3%. Therefore, serum magnesium level should be monitored for at least 1 month after initiating patiromer. Because patiromer exchanges calcium for potassium, there is a theoretical risk of hypercalcemia, however, this risk is very uncommon and may occur in 0.06 and 0.09% of patients.

• Hypersensitivity reactions may occur in 0.3% of patients.

• Mild hypotension has been reported in 8% of patients.

• Drug interaction: patiromer can bind with other drugs in the gastrointestinal tract and decrease their absorption. The most clinically important interactions are with ciprofloxacin, thyroxine, and metformin. Therefore, these drugs should be administered more than three hours before or after patiromer [52].

Serious events like requirement of dialysis, sudden death, myocardial infarction, and sudden cardiac death were not seen in the global pharmacovigilance database [51].

5.2 Sodium zirconium cyclosilicate (SZC)

SZC has a unique crystal lattice structure, and its chemical formula is Na ~ 1.5H ~ 0.5ZrSi3O92–3H2O. See Figure 3 [54].

Figure 3.

Crystal structure of sodium zirconium cyclosilicate. Blue spheres =  oxygen atoms, red spheres =  zirconium atoms, green spheres =  silicon atoms. (Ref. [53], https://commons.wikimedia.org/w/index.php?curid=44596225).

5.2.1 Clinical pharmacology

Sodium zirconium cyclosilicate (SZC), which is sold under the brand name Lokelma, is an inorganic, insoluble compound that binds potassium in the colon in exchange for hydrogen and sodium. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, which leads to increased fecal excretion of potassium and lowering of serum potassium level.

SZC is available as a powder for oral suspension, and its starting or loading dose is 10 grams three times a day for 48 hours, followed by a maintenance dose of 5 grams daily. The dose could then be gradually increased, if needed, at a weekly interval to a maximum of 15 grams per day [54].

SZC has an onset of action of 1 hour, i.e., reduction in serum potassium level is observed one hour after initiation of therapy. However, serum potassium concentrations continue to decline over the 48-hour of the loading dose. Patients with higher starting serum potassium levels or receiving a higher dose have greater reductions in serum potassium level [54]. SZC is not systemically absorbed, it is not metabolized, and it is excreted unchanged with feces [54].

5.2.2 Indication and utilization

SZC is indicated for the management of chronic hyperkalemia, especially in patients receiving RAASi therapy [54]. As with patiromer, SZC was not initially approved in acute setting for the management of life-threatening hyperkalemia. But again, as with patiromer, data suggest that SCZ can acutely reduce potassium levels [55]. Therefore, different guidelines including the National Institute for Health and Care Excellence have recommended the use of SCZ for acute life-threatening hyperkalemia, in conjunction with standard care [26, 56]. In fact, for acute management of hyperkalemia, SZC is preferred over patiromer because of its more rapid onset of action [37].

5.2.3 Available evidence

• HARMONIZE-GLOBAL trial (Zannad et al. - 2020): A multi-center, randomized, double-blind, placebo-controlled studying the effect of SZC on outpatients with hyperkalemia (76.4% were on RAASi,78.3% had CKD). It included 267 patients with a follow-up period of 28 days. It concluded that SZC is more effective than placebo in achieving normokalemia at 48 hours; and can maintain it up to 28 days [57].

• HARMONIZE OLE trial (Roger et al. - 2019): An open-label extension (OLE) of the HARMONIZE study evaluating the efficacy and safety of SZC for ≤11 months in outpatients with serum K+ level 3.5–6.2 mmol/L. It included 123 patients (68.6% were on RAASi, 74% had eGFR <60 ml/minute/1.73 m²) with a follow-up period of ≤337 days. It found that SZC was able to achieve the target potassium level for ≤11 months during ongoing SZC treatment [58].

• ZS-005 trial (Spinowitz et al. - 2019): A multi-center, open-label study evaluating the use of SZC on adult outpatients with hyperkalemia (65% were on RAASi, 74% had eGFR <60 ml/minute/1.73 m²). It included 751 patients with a 52-week follow-up period. It concluded that SZC was associated with maintenance of normokalemia without substantial changes in RAASi therapy for ≤12 months [59].

• ZS-003 trial (Packham et al. - 2015): A multi-center, randomized, double-blind, placebo-controlled study evaluating the use of SCZ for the management of adult outpatients with hyperkalemia (66.7% were on RAASi, 74.5% had an eGFR <60 ml/minute/1.73 m²). It included 754 patients with a follow-up period of 16 days. It concluded that patients with hyperkalemia who received SZC, as compared with those who received placebo, had a significant reduction in potassium levels at 48 hours, with normokalemia maintained during 12 days of maintenance therapy [60].

• HARMONIZE trial (Kosiborod et al. - 2014): A multi-center, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of SZC for adult outpatients with hyperkalemia (69.8% on RAASi, 66% had an eGFR <60 ml/minute/1.73 m²). It included 258 patients with a follow-up period of 28 days. It concluded that SZC is more effective than placebo in achieving normokalemia at 48 hours and maintaining it for 28 days [61].

5.2.4 Side effects of SZC

SZC is generally well tolerated, and there were no reported serious adverse events in clinical trials involving SZC [54, 58]. Reported side effects were [54, 57]:

• Hypokalemia: in clinical trials, hypokalemia (defined as serum potassium less than 3.5 mmol/L) developed in 4.1% of treated patients. Hypokalemia resolved with dose adjustment or discontinuation of SZC.

• Edema-related events ((edema, generalized edema, and peripheral edema): SZC contains approximately 400 mg sodium per 5 g dose. In placebo-controlled trials in which patients were treated with once-daily doses of SZC for up to 28 days, edema was reported in 4.4% of patients receiving 5 g, 5.9% of patients receiving 10 g, and 16.1% of patients receiving 15 g SZC compared to 2.4% of patients receiving placebo. In longer-term uncontrolled trials in which most patients were maintained on doses s < 15 g once daily, edema was reported in 8–11% of patients. Edema was generally mild to moderate in severity [54]. Patients need to be instructed to reduce their salt intake, and adjusting the diuretic dose may be required.

When using SZC, the following precautions must be considered [54]:

• Drug-interaction: SZC may transiently increase gastric pH and can change the absorption of co-administered drugs that exhibit pH-dependent solubility (e.g., furosemide, atorvastatin, and dabigatran), potentially leading to altered efficacy or safety of these drugs. Therefore, other oral medications should be administered at least 2 hours before or 2 hours after SZC.

• SZC safety and efficacy were not studied in patients with severe constipation or impaction, bowel obstruction, postoperative patients, or patients with bowel motility disorders; so it may be ineffective or may worsen these conditions. Therefore, it must be avoided in such patients.

• SZC agent has radio-opaque properties and, therefore, may appear when imaging the abdomen with X-ray of computed scans. This is to be considered in patients receiving SZC to avoid improper analysis of imaging [62].

Considering all aforementioned data showing the efficacy of patiromer and SCZ in reducing the potassium level, nephrologists are now able to use these novel binders to control chronic hyperkalemia in patients with CKD. Moreover, these binders will facilitate the optimization of RAASi therapy in such patients. RAASi medications are disease-modifying therapies in patients with CKD, and before the era of these novel binders, nephrologists would either reduce the dose or discontinue RAASi therapy in response to their common side effect of hyperkalemia. Now that patiromer and SCZ are mitigating this risk, they are functioning as “RAASi enablers” and allowing for RAASi proper utilization and dose optimization. Such an “enabling” effect was seen mainly as a secondary outcome in the previously summarized randomized studies of each binder. However, it was reproduced as a primary outcome of a meta-analysis of some of these studies [63]. This meta-analysis and systematic review investigated the efficacy of patiromer and SCZ on the optimization of RAASi therapy and reduction of hyperkalemia events [63]. Although the aim was to clarify the importance of their use in the clinical practice for heart failure patients, 2 of the 6 included studies targeted only CKD patients, and the remaining included a significant percentage of CKD patients [63]. This “enabling” effect may in the future extend the use of RAASi medications to other patients who are otherwise unable to take them due to hyperkalemia. The additional role of patiromer and SZC in managing acute hyperkalemia, together with the above-mentioned benefits, may reduce the risk of hospitalizations caused by hyperkalemia. This will reduce the economic burden and offset any cost associated with the acquisition of these drugs. Table 2 mentions the cost of the available potassium binders. Based on cost-effective analyses, both patiromer and SCZ were cost-effective when used in patients with CKD [64, 65]. These novel potassium binders are changing the path of the management of CKD patients. Trials to evaluate whether these clinical practice benefits of patiromer and AZC result in a lower rate of major adverse events (e.g., mortality, requirement of dialysis, cardiac events…etc.) are still needed.

5.3 Novel potassium binders for dialysis patients

Patiromer is also effective in the management of pre-dialysis hyperkalemia in chronic hemodialysis patients [66, 67]. Because patiromer is not systemically absorbed, no dosage adjustment is necessary for any degree of kidney dysfunction [68]. Patiromer is unlikely to be dialyzed and no supplemental dose or dose adjustment necessary for hemodialysis, peritoneal dialysis or patients on prolonged or continuous renal replacement therapy [68].

SCZ can also be used for patients receiving chronic hemodialysis and have persistent pre-dialysis hyperkalemia [54, 69]. It is to be administered only on non-dialysis days, and the recommended starting dose is 5 grams once daily. If the pre-dialysis serum potassium is more than 6.5 mmol/L, SZC can be started at 10 grams once daily on non-dialysis [54]. Patients on chronic hemodialysis who are receiving SZC may develop significant hypokalemia and serum potassium levels must be closely monitored. During initiation and after a dose adjustment, assess serum potassium after one week [54]. SCZ is not systemically absorbed (or minimal absorption), so no dosage adjustment is necessary for patients with CKD or peritoneal dialysis patients [54].

6. Conclusions

The introduction of the novel potassium binders has filled a gap in the management of chronic hyperkalemia. Both patiromer and SZC have demonstrated their efficacy in maintaining normokalemia over the long term, in addition to their role in the short-term management of severe hyperkalemia [38]. This is particularly true for CKD patients, and more importantly, the fact that these novel binders enabled the continuation of RAASi therapy at stable or increased doses in many eligible patients (e.g., diabetes, CKD, heart failure patients) [38]. Patiromer and SZC are both generally well tolerated [38, 42, 51, 54, 58]. Common side effects of patiromer include hypomagnesemia, constipation, diarrhea, abdominal pain, and flatulence [42, 51]. Side effects of SZC treatment include constipation and edema-related events [54, 58]. For short and long-term management of hyperkalemia, it is encouraged to perform randomized controlled trials with a head-to-head comparison of efficacy and safety between patiromer and SZC. Additionally, trials to evaluate the effect of these novel potassium binders on clinical outcomes (e.g., mortalities, requirement of dialysis, cardiac events…etc) are required.

Acknowledgments

We would like to acknowledge the copyrights of Figures 2 and 3 as indicated in the links posted below the figures.

Conflict of interest

The authors declare no conflict of interest.