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A new look at managing hyperkalemia in high-risk patients

Earl, Grace PharmD, BCACP

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doi: 10.1097/01.CCN.0000660380.54808.53
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Moderate hyperkalemia, defined as a serum potassium level greater than 5.5 mEq/L (normal, 3.5 to 5 mEq/L), and severe hyperkalemia, defined as a serum potassium level greater than 6.0 mEq/L, are indicators of a potentially serious disorder requiring immediate medical attention.1 In a critical care setting, management includes pharmacotherapy such as inhaled beta-2-adrenergic agonists as well as I.V. insulin administered with I.V. dextrose.2 Dialysis is instituted for managing life-threatening hyperkalemia not responding to medical management.3,4 In this situation, dialysis is indicated when potassium levels are between 6 and 7 mEq/L, which can precipitate cardiac dysrhythmias.3

In an acute setting, elevated serum potassium levels adversely affect cardiac conduction, resulting in changes on the ECG. Hyperkalemia is associated with peaked T waves, first-degree atrioventricular block, and other ECG changes.5 With extremely high potassium levels greater than 9 mEq/L, ventricular tachycardia, ventricular fibrillation, and asystole may develop.5 If uncorrected, hyperkalemia can lead to hospitalization, life-threatening dysrhythmias, asystole, and death.5,6

Evidence from registries and meta-analyses point to an association between hyperkalemia and increased mortality.7 Data were collected from over 36,000 patients with chronic kidney disease (CKD) between 2005 and 2009.7 The analysis showed that the mortality events followed a U-shaped curve with an increase in mortality with time-varying potassium levels greater than 5.5 mEq/L (hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.48-1.84) and levels less than 3.5 mEq/L (HR 1.95, 95% CI 1.74-2.18).

Hyperkalemia in chronic disease

The presence of hyperkalemia also complicates the management of chronic medical disorders such as kidney disease, heart failure, and diabetes. Guideline-directed medical therapy for these disorders recommends prescribing medications blocking the renin-angiotensin-aldosterone system (RAAS).6-9 These agents are prone to cause increases in serum potassium levels.3 Several prescription medication classes affect the RAAS. Subsequently, RAAS blockade, or use of RAAS blockers, is associated with hyperkalemia. (See Medications causing elevated serum potassium levels.) Aldosterone receptor antagonists may also be known as mineralocorticoid receptor antagonists.

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Table:
Medications causing elevated serum potassium levels

The RAAS blockers are used for multiple indications. Angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin-receptor blockers (ARBs) are recommended for prevention of proteinuric nephropathy in diabetes and CKD.7 ACE inhibitors, ARBs, and aldosterone receptor antagonists are recommended for chronic treatment of hypertension as well as systolic heart failure.6 Sacubitril-valsartan is a combination of a neprilysin-inhibitor with an ARB and is indicated for reduced ejection fraction heart failure. Aldosterone receptor antagonists are being investigated for reducing albuminuria in patients with CKD.8 They can also prevent remodeling following a myocardial infarction and heart failure with preserved ejection fraction, and refractory hypertension.8

Potassium physiology

The approach to managing hyperkalemia involves an understanding of the underlying physiologic processes impacting potassium homeostasis and elimination.10 The choice of drug therapy is based on augmenting the normal metabolic and elimination pathways. Potassium enters the gastrointestinal (GI) tract when food is consumed or goes directly into the bloodstream when I.V. potassium electrolytes are administered. Potassium ions are taken up by the liver and muscle cells by the action of insulin.1 At the cell membrane, beta-adrenergic receptors facilitate transport of potassium intracellularly.1

Ninety-eight percent of total body potassium is mainly stored inside the cells.1 Total body potassium is approximately equivalent to 50 mEq/kg to 75 mEq/kg of body weight.1 The blood levels of potassium measured in routine lab tests represent a small fraction of total body potassium.1 (See Potassium level definitions.)

Potassium is eliminated by several pathways in the body, including sweat, feces, and urine.1 The major route of elimination is through the kidneys at the level of the distal tubule and collecting tubules.1 At the cell membrane in the distal tubule, an increase in sodium and water flow to the distal tubule enhances potassium secretion into the urine. Potassium excretion in the collecting tubules is controlled by aldosterone.1

Hyperkalemia can be diagnosed in the inpatient setting in patients with acute illnesses as well as in the outpatient setting in patients with chronic medical problems. There are acute and chronic pathophysiologic processes that place the patient at risk for hyperkalemia. Recurrent episodes of hyperkalemia may complicate management of other conditions, and there have been limited options for treatment in the outpatient setting.

Factors associated with hyperkalemia

Older patients are at greater risk for developing hyperkalemia because of an age-related decline in kidney function.7 The presence of diabetes mellitus, heart failure, and CKD places a patient at risk for hyperkalemia. Patients with an estimated glomerular filtration rate less than 45 mL/min/1.73 m2 are at greatest risk. A modifiable risk factor is prescribing drug therapy targeting RAAS.7 The incidence of hyperkalemia is consistently higher in trials examining RAAS blockade versus placebo, calcium channel blockade, or beta-blockade used for treating CKD.7 The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study evaluated patients with diabetic nephropathy.7 The incidence of hyperkalemia with losartan was twice as high when compared with placebo (HR 2.0 [95% CI 1.56-2.57]).7

Table
Table:
Potassium level definitions

Potassium-binding agents

Sodium-polystyrene sulfonate (SPS), a cation exchange resin, had been the sole potassium-binding medication available to manage hyperkalemia until relatively recently. SPS is administered in sorbitol to promote a cathartic effect that is necessary to enhance elimination of the potassium ions from the body.11 Its effectiveness in lowering serum potassium levels may be due to the presence of elevated baseline potassium levels.7 The FDA required a boxed warning to alert prescribers to the potential for life-threatening colonic necrosis.6,11 These events occurred with and without sorbitol.7 SPS exchanges potassium for sodium ions and a significant adverse reaction is hypernatremia and fluid retention. SPS is associated with adverse reactions such as diarrhea and other GI symptoms, such as nausea and vomiting.

Two new potassium binders are patiromer and sodium zirconium cyclosilicate (SZC). Patiromer, approved in 2015, is a potassium-binding polymer that acts by exchanging calcium for potassium ions.12 Patiromer does not contain sodium.12 SZC works in the GI tract to exchange potassium ions for sodium and hydrogen ions.13 SZC was approved by the FDA in 2018.13 (See Product overview.)

Review of the evidence

The recent trials evaluating patiromer and SZC enrolled patients with hyperkalemia or established hyperkalemia. Trials enrolled patients with conditions placing them at risk for hyperkalemia by virtue of the underlying organ dysfunction or because of the concomitant medication treatments (such as RAAS blockade). Trials enrolling patients with CKD base eligibility on an estimated GFR (eGFR) less than 60 mL/min/1.73 m2. The criteria for enrollment are defined as mildly-to-moderately decreased kidney function (stage 3a), moderately-to-severely decreased function (stage 3b), and severely decreased kidney function (stage 4). Patients with kidney failure (stage 5) receiving dialysis were excluded from the trials.

A search of the literature identified trials designed as blinded or open-label studies with no active comparator or a placebo-comparator, or as a dosing-ranging study. SPS was not used as an active comparator in any of the trials.15 The clinical trials can be characterized as acute (24 hours to 48 hours), short-term (4 weeks), and maintenance studies (52 weeks or longer).

Patiromer trials

Patiromer was studied in populations with hyperkalemia plus heart failure, CKD, and multiple chronic conditions that included patients with diabetes.

The AMETHYST-DN trial. In the Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (AMETHYST-DN) trial, a 4-week dose-determination study was performed with patiromer in adult outpatients with diabetes and stage 3 or higher CKD.16 In the AMETHYST-DN trial, patients were eligible if their serum potassium level was 5.0 mEq/L or higher and if they were taking medications affecting the RAAS. This was a randomized, multicenter, multinational study that enrolled 306 patients in an ambulatory setting. The patients were stratified based on hyperkalemia severity and were randomized to receive one of six regimens ranging from 4.2 to 16.8 g given twice daily. The primary outcome was the change in serum potassium from baseline to week 4. Patients were assessed at day 3, then weekly. The results for 300 patients were included in the analysis. When patients were given patiromer 12.6 g twice daily, this caused a decrease of 0.55 mEq/L (95% CI 0.42-0.68) in the mild hyperkalemia arm, and a decrease of 0.92 mEq/L (95% CI 0.67-1.17) in the moderate hyperkalemia arm (P < .001 for both arms). They concluded that doses between 4.2 g and 16.8 g twice daily resulted in statistically significant decreases in potassium in patients taking standard RAAS blockers for heart failure management. Patients were followed for 1 year and safety data revealed adverse events including hypokalemia (5.6%), constipation (6.3%), and hypomagnesemia (7.2%).16

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Table:
Product overview12-14

The AMETHYST-DN trial was important in examining a population with type 2 diabetes mellitus (T2DM) and hypertension when RAAS blockers are a crucial component of standard drug therapy. The percent of patients in the study with stage 3 CKD was 65% and 22% for stage 4 CKD. Patients needing to continue RAAS blockade in the presence of CKD and hyperkalemia were successfully managed with a 4-week course of a potassium binder.

The OPAL-HK study. The OPAL-HK (Hyperkalemia) study provided additional information on the onset of potassium lowering in patients with CKD and mild-to-moderate hyperkalemia.17 This short-term study evaluated the effectiveness and safety of twice-daily patiromer in 107 patients with stage 3-to-stage 4 CKD. The study was a phase 3 single-blind study where subjects were randomized to patiromer 4.2 versus 8.4 g twice daily versus placebo. Subjects were eligible if they had stable potassium levels within 5.1 mEq/L to 6.5 mEq/L, and stable doses of RAAS blockers. After 4 weeks, the percent of subjects achieving the target potassium levels (3.8 mEq/L to less than 5.1 mEq/L) were 74% with mild hyperkalemia and 77% with moderate-to-severe hyperkalemia. The onset of action was rapid with the mild hyperkalemia group achieving a potassium level of less than 5.1 mEq/L in 2 days and those with moderate-to-severe hyperkalemia achieving the target of less than 5.5 mEq/L in 2 days.

A substudy of the OPAL-HK trial enrolled patients with heart failure (65% NYHA II).18 Patients were monitored during the withdrawal phase. A greater proportion of subjects in the placebo arm (52%) developed hyperkalemia versus those who had received patiromer (8%).

The TOURMALINE study. A recent study evaluated the effect of patiromer in subjects taking RAAS blockers versus those who were not. The TOURMALINE study (N = 67) was an open-label, post-hoc analysis of the effects of using RAAS blockers in patients with mild hyperkalemia for up to 4 weeks.19 The primary endpoint was the proportion of patients at a target potassium level of 3.8 to 5.0 mEq/L at 4 weeks. The study included patients with CKD, hypertension, and heart failure who were on stable doses of an RAAS blocker for at least 2 weeks. Baseline serum potassium levels were 5.37 mEq/L in patients taking a RAAS inhibitor versus 5.42 mEq/L for those not taking a RAAS inhibitor. The mean eGFR was 45.8 mL/min/1.73 m2 in the RAAS group versus 34.7 mL/min/1.73 m2 not taking RAAS blockers. The proportion of patients achieving the target was similar: 85% (95% CI 74-93) achieved target with a RAAS inhibitor versus 84% (95% CI 71-94) no RAAS inhibitor. The mean reduction in serum potassium was 0.67 mEq/L with a RAAS inhibitor versus 0.56 mEq/L without a RAAS inhibitor (P < .001 versus baseline, P = NS between group comparisons). The TOURMALINE study was exploratory but revealed similar effectiveness of patiromer in a setting of moderate kidney dysfunction and use of RAAS blockers.

The PEARL-HF trial. The PEARL-HF (heart failure) trial evaluated the effect of patiromer in controlling serum potassium in patients with advanced heart failure who would be started on an aldosterone antagonist.20 In this double-blind trial, adult outpatients (N = 105) were randomized to patiromer 15 g twice daily versus placebo for 28 days. The subjects were monitored for an additional 7 days after discontinuation of patiromer as part of the safety analysis. Subjects were enrolled with chronic heart failure, CKD, and who were taking a RAAS blocker or beta-adrenergic blocker. The treatment intervention included initiating spironolactone 25 mg to 50 mg daily if potassium levels were <5.1 mEq/L after 2 weeks. There was a change from baseline seen as a decrease in serum potassium in the patiromer arm (-0.22 mEq/L) and increase in the placebo arm (+0.23 mEq/L). The proportion of participants with serum potassium >5.5 mEq/L decreased significantly at 4 weeks with 7% in the patiromer group versus 25% in the placebo group (P = .015). Potassium levels increased slightly upon discontinuation of patiromer.

The PEARL-HF trial demonstrated a meaningful impact to overall heart failure drug therapy management. In this study, use of a potassium binder resulted in successful up-titration of the spironolactone dose in 91% of the patiromer arm as compared with 74% of the placebo arm (P = .019). One concern with chronic use of potassium binders is the impact when the medications are discontinued. The OPAL-HK study conducted in patients with heart failure taking patiromer revealed sustained reductions in potassium when the potassium binder was discontinued.18

The AMETHYST-DN retrospective subanalysis. The AMETHYST-DN trial in patients with heart failure assessed the long-term safety and effectiveness of patiromer at 52 weeks.21 The original randomized controlled trial evaluated patiromer dose regimens and stratified patients by degree of hyperkalemia. This retrospective subanalysis evaluated patients who were enrolled with or without a clinical diagnosis of heart failure. There were 105 subjects with HF (75% New York Heart Association class II) versus 199 subjects without heart failure. Subjects were randomized to a starting dose of patiromer between 4.2 and 16.8 twice daily. Eligibility criteria included T2DM, CKD, and NYHA class I or II heart failure, and patients were taking RAAS blockers such as an ACE inhibitor, ARB, or aldosterone antagonist. The severity of hyperkalemia was defined as having a baseline serum potassium greater than 5 mEq/L to 5.5 mEq/L (mild hyperkalemia) or greater than 5.5 mEq/L to 6.0 mEq/L (moderate hyperkalemia). At week 4, the mean change in potassium was -0.64 mEq/L (95% CI -0.72 to -0.55) in mild hyperkalemia arm and -0.97 mEq/L (95% CI -1.14 to -0.80) in moderate hyperkalemia arm (P < .0001 for both versus baseline). At the end of the study, at least 88% of patients in the mild hyperkalemia arm and at least 73% of patients with moderate hyperkalemia had levels within the 3.8 mEq/L to 5 mEq/L target. The study concluded that patiromer was effective in promoting long-term control of hyperkalemia in patients with heart failure taking RAAS blockers.

Trials with SZC

SZC was evaluated in an outpatient setting in populations that were similar as the trials evaluating patiromer. The studies examined the effect of SZC at 48 hours as well as a longer maintenance period (28 days versus 52 weeks).22-25

Sodium Zirconium Cyclosilicate in Hyperkalemia. Stable patients with CKD and diabetes taking RAAS blockers were evaluated in this study. Adult outpatients (N = 753) with hyperkalemia (5 mEq/L to 6.5 mEq/L) were enrolled in a double-blind study randomizing subjects to an initial SZC dose from one of four dosing regimens versus placebo.22 The dose ranged between 1.25 g and 10 g given three times daily with meals. The study included patients (N = 753) with CKD (60%), diabetes (62%), and most were taking RAAS blockers (67%). They excluded patients receiving dialysis, those with potassium levels greater than 6.5 mEq/L, with cardiac dysrhythmias, and other criteria. The differences in the exponential rate of change in serum potassium levels were measured at 48 hours. SZC treatment arms using 2.5 g, 5 g, and 10 g three times daily decreased mean serum potassium by -0.46 mEq/L (95% CI -0.53 to -0.39), -0.54 mEq/L (95% CI -0.62 to -0.47), and -0.73 mEq/L (95% CI -0.82 to -0.65), respectively, versus placebo (-0.25 mEq/L (95% CI -0.32 to 0.19) (P < .001). This robust study demonstrated a dose-related decrease in serum potassium levels at 48 hours.

The HARMONIZE Heart Failure Subgroup.24 Subjects with heart failure from the Hyperkalaemia Randomized Intervention Multidose ZS-9 Maintenance, or HARMONIZE trial, were included in an analysis on maintaining potassium levels.23,24 The study evaluated daily oral SZC in 87 ambulatory patients with chronic heart failure and hyperkalemia (potassium >5.1 mEq/L).23 Open-label SZC was initiated at 10 g daily for 48 hours until potassium levels were controlled. Responders were randomized to three dosage regimens versus placebo for up to 28 days. The results were presented for the treatment phase and maintenance phase. For patients with heart failure, 99% of patients achieved a serum potassium level less than 5.1 mEq/L in 48 hours, and the median onset of effect was 2 hours. During the maintenance phase, the mean serum potassium levels from days 8 through 29 were 5.2 mEq/L for placebo and 4.67 mEq/L (95% CI 4.5-4.9), 4.46 mEq/L (95% CI 4.3-4.6), and 4.39 mEq/L (95% CI 4.2-4.5) for SZC doses of 5 g, 10 g, and 15 g, respectively (P < .001 versus placebo). The most frequently reported adverse reaction was edema in the SZC arms (8/61 patients) versus placebo arm (1/26 patients). Edema was more likely to occur with the SZC 10 g dose.5

Management of patients with multiple morbidities associated with hyperkalemia is challenging. Although the sample size was small and this was an analysis of a subgroup of patients with heart failure, it showed that SZC was highly effective in rapidly lowering serum potassium levels at 2 hours and this maintained at 48 hours.23 The place of therapy for SZC in acute management deserves further investigation.

The HARMONIZE study. The HARMONIZE study (see description above) was designed as a randomized, double-blind study to evaluate the effect of SZC on potassium-lowering at 48 hours and at a 28-day maintenance.24 The study enrolled 258 subjects with a mean age of 64; 57.8% were male, 83% were White, and 14% were Black. The study enrolled patients with CKD (74.5%), diabetes (60%), heart failure (40%), and taking RAAS blockers (67%). The mean estimated GFR at entry was 46.3 mL/min/1.73 m2. SZC maintained the reduction of mean serum potassium of 4.8 mEq/L, 4.5 mEq/L, and 4.4 mEq/L for the 5-, 10-, and 15-g dose groups, respectively, versus 5.1 mEq/L for placebo (P < .001 for all comparisons) at 8 to 29 days. The proportion of subjects with a normal serum potassium was 71% to 85% in the SZC groups versus placebo (48%) (P < .001). This study demonstrated effectiveness of SZC over a 4-week period.

The Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia study. This 12-month phase 3 study was an open-label, single-arm study evaluating safety and efficacy.26 The initial dose of SZC 10 g given three times daily was administered for 24-72 hours in an acute phase followed by a 12-month maintenance phase. The subjects (N = 751) had CKD, diabetes, heart failure, and 65% were taking RAAS blockers. The study was designed to achieve a target serum potassium of 3.5 mEq/L to 5 mEq/L. Ninety-nine percent achieved the goal within the first 48-72 hours. There were 466 (63%) subjects who completed the 12-month trial. The maintenance-phase baseline serum potassium was 4.8 mEq/L with a mean reduction of 0.9 mEq/L. Mean serum potassium levels at 3 to 12 months were 4.7 mEq/L (95% CI 4.6 to 4.7), and 88% of subjects achieved a potassium level less than 5.1 mEq/L. The strength of the study was the 1-year follow-up period and the weakness of the study was the design (nonrandomized). The results reflect real world acute and maintenance use of SZC for up to 1 year.

The DIALIZE study. Patients with end-stage renal disease (ESRD) are at the highest risk for complications that include hyperkalemia-induced dysrhythmias and death.26 Fishbane and colleagues randomized patients with ESRD receiving hemodialysis to SZC (n = 97) or placebo (n = 99) on nondialysis days. They conducted a randomized, placebo-controlled study enrolling patients with persistent hyperkalemia prior to dialysis. The study flow included a 4-week evaluation period where the dose could be titrated, then follow-up continued to monitor for safety. Patients with serious cardiovascular disease, seizure disorders, and thromboembolic disease were excluded. SZC was titrated slowly from 5 g up to 15 g once daily over the 4-week titration period. The primary outcome was the proportion of responders defined as individuals with potassium levels within the target range (4 mEq/L to 5 mEq/L) who did not require rescue therapy. They evaluated the need for rescue therapy to manage hyperkalemia episodes and adverse events. They performed an intention-to-treat analysis.

The study participants had a mean age of 58.1 years and 58.7% were male.26 The proportion of responders was significantly greater with SZC (41.2%) versus placebo (1%) (P < .001). The percentage of subjects needing rescue therapy for hyperkalemia management was low in both arms: SZC (2.1%) versus placebo (5.1%). One subject died in the SZC group.

There were similar rates of adverse events in both arms and most patients reported GI adverse reactions (SZC 19.8% versus placebo 17.2%).26 One patient in the SZC arm reported angina, whereas subjects in the placebo arm needed rescue therapy (3%) and experienced fluid overload (2%). BP, heart rate, and ECG results were not significantly changed during the study.

One patient died, and this was attributed to peripheral artery disease; there were a small yet equal number of hypokalemia events (potassium less than 3.5 mEq/L) in both arms (five subjects per arm).26 The design was robust and used a screening period (1 week), then a 4-week titration period followed by a 4-week stabilization period. Patients were followed for an additional 2 weeks (weeks 9 through 10).

Until now, patients receiving dialysis were excluded from previous trials. Use of once-daily SZC was safe and effective for short-term use in patients receiving outpatient dialysis. Additional data are needed on use in hospitalized patients especially in situations where there is great risk, such as patients with cardiac dysrhythmias or diabetic ketoacidosis.23

Safety

Patiromer is contraindicated with a known hypersensitivity to the drug or its components.12 There is a boxed warning on the product labeling that patiromer will bind to other oral medications. Patients should be warned about worsening GI motility and low serum magnesium levels. The most frequent adverse reactions (2% or higher) are constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort, and flatulence.

SZC has no contraindications in the product labeling.13 There are warnings to avoid in patients with GI conditions such as severe constipation, bowel obstruction, bowel impaction, and postoperative GI dysfunction. The most frequent adverse reactions were mild-to-moderate edema that is dose-related. The packets contain sodium. Patients experienced hypokalemia and edema in clinical trials.14

Implications for practice

Dietary approaches. In a healthy patient, a diet rich in potassium is associated with lowering BP and reducing the risk of myocardial infarction and stroke.27 Potassium is a nutrient and electrolyte found in certain foods. For a healthy adult male or female age 19 or older, the recommended dietary intake of potassium is 4,700 mg per day.27 The Dietary Approaches to Stopping Hypertension, or DASH Diet, encourages consumption of potassium, calcium, and magnesium as well as many other food components.27 Much dietary potassium is supplied through starchy vegetables, fruits, and foods in the dairy group.27

Patients with mild hyperkalemia, with potassium levels between 5.1 mEq/L and 5.9 mEq/L, may benefit from a dietary intervention.3 There are several approaches for limiting dietary potassium intake. In appropriate patients, such as those with kidney and heart failure, a diet low in potassium (less than 2 to 3 g/day) may be considered.6 Patients at risk for hyperkalemia are often instructed to limit dietary sodium and may use salt substitutes.6 Salt substitutes that are labeled “no salt,” “low salt,” or “lite salt” may likely contain a salt substitute such as a potassium salt.28 Therefore, patients should be encouraged to bring their products to their provider visit and should be instructed to measure the product at meal time. Patients should be discouraged from using products like a saltshaker.

Medical management. The patient's medication list should be evaluated in those with high normal potassium levels and levels between 5.0 mEq/L and 5.9 mEq/L.6 Patients may require a dose reduction or discontinuation of RAAS agents, nonsteroidal anti-inflammatory drugs (NSAIDs), or other medications increasing serum potassium.6

Patients with a serum potassium of 6.0 mEq/L or higher require urgent attention.7 RAAS and other medications should be discontinued, as prescribed. Patients who have a serum potassium level with an eGFR less than 30 mL/min/m2 should avoid RAAS agents.7 Administer diuretics to foster greater flow of water and sodium to the distal renal tubule resulting in greater potassium excretion in the urine.5 Sodium bicarbonate is administered to alkalinize the blood and move the potassium intracellularly.5

Acute management is necessary when the serum potassium level is at least 6.5 mEq/L and there are ECG changes.2 The approach to treatment is aimed at halting dysrhythmias by stabilizing myocardial cell membranes, shifting extracellular potassium into the cells, and eliminating potassium in the stool (or dialysis if necessary).2 Calcium gluconate or calcium chloride given I.V. will act within minutes to reverse electrocardiographic changes by stabilizing the cardiac membranes. Three strategies promote potassium redistribution. These are administering a bolus dose of regular insulin along with a bolus of dextrose 50% in water; inhaled beta-adrenergic agonists such as albuterol; or administering sodium bicarbonate I.V.2 Sodium bicarbonate is relegated to scenarios where the patient is experiencing metabolic acidosis.4

I.V. administration of regular insulin along with a bolus of a concentrated dextrose solution acts quickly. Serum potassium levels may decrease by 0.6 mEq/L to 1.2 mEq/L within 1 hour and decreases can be seen within 15 minutes.2 It is prudent to initiate an infusion of dextrose 10% solution at 50 mL/h to 75 mL/h following the bolus doses.4 Nebulized albuterol decreases serum potassium by 0.6 mEq/L within 30 minutes.4 Readers should refer to guidelines for a deeper understanding of the risks and complications of using these therapies.

The final step in managing hyperkalemia is to enhance normal urinary elimination and GI excretion. However, in serious life-threatening situations, serum potassium can be removed from the blood using dialysis. Dialysis is indicated if the patient is not responding to other management strategies and continues to have a serum potassium of 6 mEq/L or more and signs of cardiac instability.4

Medications that promote GI excretion are SPS, patiromer, and SZC. SPS has been studied in patients with oliguria and kidney failure; however, it is not recommended due to serious risk of complications such as colonic necrosis and hypernatremia.2 Currently, the patiromer and SZC are not recommended for the acute management of hyperkalemia.2 Some limiting factors associated with these medications are the delayed onset of action and electrolyte losses (hypomagnesemia with patiromer, edema, and increased sodium with SZC).

Chronic management of hyperkalemia. Lopes and colleagues suggest that newer medications such as patiromer and SZC may have a role in patients who are closely monitored with frequent follow-up visits.4 These medications provide an attractive option that may allow continuation of diet or medications that are associated with an increased serum potassium.4 This addresses use in patients with hyperkalemia who also have CKD or a cardiovascular disease such as hypertension or heart failure.4 Patients with heart failure may be managed with potassium binders as well as appropriate use of low-dose loop or thiazide diuretics.4 More information is needed to evaluate the effect and risks in patients with advanced CKD.4 Patient factors necessitating closer follow-up include history of recurrent hyperkalemic episodes.

Table
Table:
Preparation and storage instructions12,13

Monitoring and follow-up. Potassium binders, including patiromer and SZC, are polymers that absorb other medications.12,13 The timing of the patiromer dose must be separated 6 hours before and after other medications are given.12 Concomitant medications prescribed in patients taking SZC should be given 2 hours before or after SZC.13 In clinical trials, SZC was administered before breakfast. (See Preparation and storage instructions.)

Lab testing should be performed frequently. The serum potassium levels should be monitored so the dose of the potassium-binding agent can be titrated to achieve the target potassium level.12,13 Patients taking a potassium binder who also have CKD, diabetes, and heart failure should have a baseline serum potassium measured before starting a RAAS drug or with a change in dose.6,29 Potassium levels, serum creatinine, and eGFR should be checked again after 1 week.6 An ECG should be monitored during treatment. However, healthcare professionals should be aware of this caveat: 50% of patients with elevated potassium levels above 6.5 mEq/L will not show any evidence of ECG changes.5

Conclusion

A contemporary approach to managing hyperkalemia must consider maintenance interventions in patients with chronic diseases such as proteinuric kidney disease, diabetes, and heart failure.3,29,30 Patients with an estimated GFR less than 45 mL/min/1.73 m2 are at greater risk for hyperkalemia especially when RAAS blockers are prescribed.7 The recent studies support using these new potassium binders for maintenance therapy that fosters continuation of concomitant mono- or combination therapy with RAAS blockade.7,19,25 The evidence supporting this was demonstrated with patiromer and SZC that were studied in patients with diabetes, CKD, and heart failure.19,25 SZC was studied in patients with ESRD on dialysis.26 The DIALYZE trial provides emerging evidence for use of SZC on nondialysis days of hemodialysis patients.26 Future studies should evaluate pharmacoeconomic outcomes including cost-effectiveness, and health outcomes including impact on hospitalization and mortality.5 The results of these trials are not generalizable to unstable patients since patients excluded from clinical trials were those with extremely elevated potassium levels, electrocardiographic changes and dysrhythmias, and undergoing dialysis.3

REFERENCES

1. Mount DB. Causes and evaluation of hyperkalemia in adults. UpToDate. 2020. www.uptodate.com.
2. Long B, Warix JR, Koyfman A. Controversies in management of hyperkalemia. J Emerg Med. 2018;55(2):192–205.
3. Ingelfinger JR. A new era for the treatment of hyperkalemia. N Engl J Med. 2015;372(3):275–277.
4. Lopes MB, Rocha PN, Pecoits-Filho R. Updates on medical management of hyperkalemia. Curr Opin Nephrol Hypertens. 2019;28(5):417–423.
5. Dixon BS. Zirconium cyclosilicate for treatment of hyperkalemia. JAMA. 2014;312(21):2217–2218.
6. DeFilippis EM, Desai AS. Treatment of hyperkalemia in heart failure. Curr Heart Fail Rep. 2017;14(4):266–274.
7. Georgianos PI, Agarwal R. Revisiting RAAS blockade in CKD with newer potassium-binding drugs. Kidney Int. 2018;93(2):325–334.
8. Dhaybi OA, Bakris G. Mineralocorticoid antagonists in chronic kidney disease. Curr Opin Nephrol Hypertens. 2017;26(1):50–55.
9. American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes – 2018. Diabetes Care. 2018;41(suppl 1):S105–S118.
10. Mount DB. Fluid and electrolyte disturbances. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 20th ed. New York, NY: McGraw-Hill; 2018.
11. Prescribing information. Kayexalate®. 9/2018 ed. Quebec, Canada: Sanofi-Aventis; 2018.
12. Prescribing information. Veltassa®. 6/2018 ed. Redwood City, CA: Relypsa, Inc.; 2018.
13. Prescribing information. Lokelma®. 7/2018 ed. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018.
14. Hoy SM. Sodium zirconium cyclosilicate: a review in hyperkalaemia. Drugs. 2018;78(15):1605–1613. Review. Erratum in: Drugs. 2019;79(5):591.
15. Linder KE, Krawczynski MA, Laskey D. Sodium Zirconium Cyclosilicate (ZS-9): a novel agent for the treatment of hyperkalemia. Pharmacotherapy. 2016;36(8):923–933.
16. Bakris GL, Pitt B, Weir MR, et al; AMETHYST-DN Investigators. Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: The AMETHYST-DN Randomized Clinical Trial. JAMA. 2015;314(2):151–161. Erratum in: JAMA. 2015;314(7):731. Dosage error in article text.
17. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211–221.
18. Pitt B, Bakris GL, Bushinsky DA, et al. Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail. 2015;17(10):1057–1065.
19. Kloner RA, Gross C, Yuan J, Conrad A, Pergola PE. Effect of patiromer in hyperkalemic patients taking and not taking RAAS Inhibitors. J Cardiovasc Pharmacol Ther. 2018;23(6):524–531.
20. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J. 2011;32(7):820–828.
21. Pitt B, Bakris GL, Weir MR, et al. Long-term effects of patiromer for hyperkalaemia treatment in patients with mild heart failure and diabetic nephropathy on angiotensin-converting enzymes/angiotensin receptor blockers: results from AMETHYST-DN. ESC Heart Fail. 2018;5(4):592–602.
22. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222–231.
23. Anker SD, Kosiborod M, Zannad F, et al. Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial. Eur J Heart Fail. 2015;17(10):1050–1056.
24. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223–2233. Erratum in: JAMA. 2015;313(5):526. Dosage error in text.
25. Spinowitz BS, Fishbane S, Pergola PE, et al. Sodium zirconium cyclosilicate among Individuals with hyperkalemia: a 12-month phase 3 study. Clin J Am Soc Nephrol. 2019;14(6):798–809.
26. Fishbane S, Ford M, Fukagawa M, et al. A phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia. J Am Soc Nephrol. 2019;30(9):1723–1733.
27. Centers for Disease Control and Prevention. The role of potassium and sodium in your diet. 2018. www.cdc.gov/salt/potassium.htm.
28. Food and Drug Administration. Use the nutrition facts label to reduce your intake of sodium in the diet. 2018. www.fda.gov/food/nutrition-education-resources-materials/use-nutrition-facts-label-reduce-your-intake-sodium-your-diet.
29. Konstam MA. Hyperkalaemia in heart failure: binding the patient to improved treatment. Eur J Heart Fail. 2015;17(10):997–999.
30. Meaney CJ, Beccari MV, Yang Y, Zhao J. Systematic review and meta-analysis of patiromer and sodium zirconium cyclosilicate: a new armamentarium for the treatment of hyperkalemia. Pharmacotherapy. 2017;37(4):401–411.
Keywords:

chronic kidney disease (CKD); hyperkalemia; patiromer; potassium binder; renin-angiotensin-aldosterone system (RAAS); sodium zirconium cyclosilicate (SZC)

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