Evidence-Based Hyperkalemia Management: Translating Guidelines Into Pharmacy Practice

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Hyperkalemia, defined as a serum potassium concentration exceeding 5.0 mEq/L to 5.5 mEq/L, is a potentially life-threatening electrolyte disorder that requires timely identification and management.^1,2 Reported rates of hyperkalemia described in the literature vary greatly. In 2014, the estimated US prevalence of hyperkalemia based on commercial claims data was 1.55% of the general population.³ The prevalence of hyperkalemia among hospitalized patients has been estimated at up to 10%.²

Hyperkalemia prevalence increases with age and is more common among men than women.³ Other risk factors are worsening of kidney function and comorbid conditions, such as diabetes mellitus (DM), heart failure (HF), hypertension, and coronary artery disease (CAD).¹ Patients with HF are also at elevated risk due to decreased renal perfusion and the use of RAAS inhibitors (RAASi), which include angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs); these agents are cardioprotective, but they may impair potassium excretion.³

This article focuses on the underlying causes, risk factors, and clinical impact of hyperkalemia in patients with chronic kidney disease (CKD), HF, or both comorbidities. In particular, it examines guideline recommendations to identify, monitor for, and manage hyperkalemia in acute and chronic settings, including the role of pharmacists in systematically preventing and treating hyperkalemia.

What Is Hyperkalemia?

While a universal definition does not exist, hyperkalemia refers to a condition in which serum potassium levels exceed the normal range.^1,2 As the most abundant intracellular cation in the human body, potassium is vital for a host of physiological functions.⁴ Over 98% of the body’s potassium is stored within cells, establishing a steep concentration gradient between the intracellular and extracellular environments.⁴ Potassium plays a critical role in normal cardiac function and skeletal muscle activity.^2,4 Even mild elevations can disrupt this delicate balance, increasing the risk of cardiac arrhythmias, muscle weakness, and, in severe cases, sudden cardiac death.^2,4

Pathophysiology

Dietary intake is the primary source of potassium, which is absorbed in the gastrointestinal (GI) tract.⁴ Potassium then is distributed into intracellular compartments.⁴ Healthy kidneys maintain potassium homeostasis by excreting excess potassium in urine; this regulation becomes impaired in certain disease states or with use of medications, leading to an accumulation of potassium in the bloodstream.⁴

Hyperkalemia may arise primarily from impaired renal excretion, excessive potassium release from intracellular compartments, and increased potassium intake or retention due to pharmacologic agents.⁴ In CKD, progressive loss of nephron function impairs potassium filtration and excretion, predisposing patients to hyperkalemia.⁴ Tissue damage from trauma, rhabdomyolysis, tumor lysis syndrome, or metabolic acidosis can cause a rapid release of intracellular potassium into the extracellular space.⁴ In addition, several medications can contribute to hyperkalemia. These include RAASi and potassium-sparing diuretics, which reduce renal potassium excretion.⁴

Causes and Risk Factors

CKD is a major independent risk factor for hyperkalemia, with risk increasing with declining estimated glomerular filtration rate (eGFR).⁵ Patients with CKD do not have the same ability to excrete potassium naturally.⁴ However, even mild renal impairment can increase vulnerability when combined with contributing medications or comorbidities.¹

Pharmacologic therapies, particularly guideline-directed use of RAASi for HF and CKD, are frequently implicated in the development of hyperkalemia.^1,4 This presents a clinical conundrum—patients most likely to benefit from RAASi therapy are also those most at risk for hyperkalemia. Discontinuation or dose reduction of RAASi to manage elevated potassium levels can compromise cardiovascular and renal outcomes, posing a significant therapeutic dilemma for providers.⁶ Additionally, potassium supplementation and potassium-based salt substitutes may also contribute to hyperkalemia development.¹

A large, retrospective logistic regression study analyzing over 15,800 patients further highlighted risk factors for hyperkalemia.⁷ Alongside CKD, comorbidities such as DM, CAD, and peripheral vascu­lar disease along with hospital admissions, and advanced age were associated with increased risk.⁷ Importantly, the use of ACEi, ARBs, and b-blockers was also predictive.⁷

High-Risk Populations

The clinical implications of hyperkalemia are profound, particularly in high-risk populations.^8,9 Hyperkalemia is a marker of disease burden and a predictor of all-cause mortality.⁸ Patients with diabetes, CKD, or HF face heightened risk; patients with all 3 conditions experience the greatest mortality risk when serum potassium levels rise above normal.⁸ A large, retrospective database analysis examined the association between mortality and serum potassium values across nearly 1 million patients in US integrated delivery networks.⁸ Mortality risk was highest in the combined DM-CKD-HF cohort, who had an all-cause mortality rate per index potassium of 29.7% versus 22.4% in the HF group, 16.6% in the CKD group, 6.7% in the DM group, and 1.2% in the control group.⁸ This underscores the importance of careful hyperkalemia monitoring and management in these high-risk groups.

Clinical Implications of Hyperkalemia in CKD and HF

Hyperkalemia has far-reaching clinical implications for patients with CKD and HF in terms of disease progression and overall outcomes.^6,8 These populations are already at elevated risk for cardiovascular events, hospitalization, and mortality—risks that are further compounded by the presence of hyperkalemia.^6,8 Importantly, the development of hyperkalemia often precipitates medication changes that can undermine disease management, making effective monitoring and treatment strategies essential.⁶

Effects on Disease and Patient Outcomes

Evidence indicates that hyperkalemia significantly increases the risk of all-cause mortality in patients with CKD and HF.⁸ This risk is further magnified in individuals with coexisting diabetes.⁸ In such high-risk groups, even mild hyperkalemia can disrupt disease stability and trigger clinical adverse events (AEs).⁸

A major challenge in managing hyperkalemia lies in the balancing act between potassium control and continued guideline-directed medical therapy. RAASi are foundational treatments for slowing CKD progression and improving outcomes in HF.⁶ However, their use is often curtailed by dose reduction or discontinuation, which may cause hyperkalemia.⁶ Such changes are intended to prevent further potassium elevation, but they also are associated with worse clinical outcomes, including increased rates of HF-related hospitalizations and all-cause mortality.⁶

Absent Symptoms, Severe Outcomes

Hyperkalemia often presents silently.¹ In many cases, elevated potassium levels are discovered incidentally during routine laboratory testing.¹ However, symptomatic hyperkalemia can progress rapidly and present as a clinical emergency.^1,4 Patients may experience worsening muscle weakness, paralysis, and, most concerningly, arrhythmias.¹ Cardiac involvement represents a significant complication; elevated potassium levels can lead to conduction abnormalities, increased risk of arrhythmias, and sudden cardiac arrest.^4,10

Electrocardiogram (ECG) findings, although useful, are not always reliable indicators of severity.¹¹ Patients with chronically elevated potassium levels, such as those with CKD, may show minimal or no ECG abnormalities due to gradual physiological adaptation.^10,12 This lack of consistent ECG findings in chronic hyperkalemia means clinicians cannot rely solely on ECG to assess the urgency or severity of hyperkalemia and must act based on serum potassium concentrations and clinical context.

When ECG changes do occur, they typically follow a predictable progression. ECG changes for hyperkalemia most commonly manifest as peaked T waves followed by prolonged QRS interval; increasing of the potassium levels result in gradual loss of P waves, widening or PR interval, and, eventually, sinusoidal wave.^10,12 These changes are more commonly observed during acute hyperkalemic events, when serum potassium levels rapidly rise.⁴ While ECG changes should not be relied upon to classify hyperkalemia severity, they can be a useful piece of the full disease picture.

As such, clinicians must maintain a high level of suspicion and act swiftly when laboratory results confirm hyperkalemia, regardless of the presence or absence of ECG abnormalities and particularly in patients with predisposing comorbidities like CKD and HF.

Diagnosis and Treatment Initiation

Hyperkalemia requires a thoughtful and evidence-based approach to diagnosis and management, especially in patients with CKD and HF, who are frequently affected and at greater risk of adverse outcomes.¹⁰ Timely recognition and intervention can mitigate the risk of life-threatening cardiac complications while preserving the therapeutic benefits of RAASi.⁶ Pharmacists play a key role in helping clinicians navigate diagnostic nuances, apply clinical guidelines, and implement treatment strategies tailored to patient severity and chronicity.

Staging and Severity Differentiation

The Kidney Disease: Improving Global Outcomes (KDIGO) conference defines acute hyperkalemia as a serum potassium concentration that exceeds the upper limit of normal without a known history of persistently elevated levels.¹² In contrast, chronic hyperkalemia is characterized by a persistently elevated serum potassium concentration over time.¹² KDIGO did not reach consensus on specific thresholds regarding duration, magnitude, or frequency that
distinguish acute from chronic cases, but the chronic form is typically identified in patients who undergo routine electrolyte monitoring due to underlying medical
conditions like CKD, HF, or DM.¹²

Hyperkalemia can be classified as mild, moderate, or severe based on serum potassium concentration and the presence or absence of ECG changes (Table 1).¹² A serum potassium level of 5.0 to 5.9 mEq/L without ECG changes defines mild hyperkalemia; of 5.0 to 5.9 mEq/L with ECG changes or 6.0 to 6.4 mEq/L without ECG changes defines moderate hyperkalemia; and of 6.0 to 6.4 mEq/L with ECG changes or of 6.5 mEq/L or more alone defines the term severe hyperkalemia.¹²

Comparison of Treatment Guidelines

Multiple clinical guidelines—including those from the KDIGO Consensus Conference, American Heart Association (AHA), and American College of Cardiology (ACC)—offer structured approaches to managing hyperkalemia. While these recommendations share common principles, they differ slightly in thresholds and emphasis depending on the underlying condition, such as HF or CKD.^1,13

KDIGO Guidelines

For acute management of hyperkalemia in the setting of kidney disease, typically defined as a serum potassium level of at least 5.5 mEq/L (with ECG management recommended at ≥ 6.0 mEq/L), KDIGO guidelines recommend immediate assessment and potential intervention.¹ The first priority is to assess for ECG changes, which may signal impending cardiac instability, and measure blood pressure and oxygen saturation.¹ If ECG changes are present or if potassium levels are confirmed to be above 6.5 mEq/L on repeat testing, intravenous (IV) calcium (ie, calcium gluconate or calcium chloride) is recommended to stabilize cardiac membranes.¹ When ECG changes are absent but the patient is at high risk (eg, has CKD, HF, or diabetes) or the serum potassium is at least 6.0 mEq/L, a combination of temporizing and elimination therapies is advised.¹ For patients with potassium levels of 6.0 to 6.5 mEq/L, these include IV insulin with glucose to promote intracellular potassium shifting, IV sodium bicarbonate for patients with concomitant acidosis without volume overload, and IV furosemide to enhance renal potassium excretion in patients who are not anuric or severely volume-depleted.¹ Potassium binders may also be initiated to promote GI elimination of potassium.¹ Simultaneously, patients should be evaluated for acute kidney injury or underlying CKD.¹ If potassium remains elevated or refractory to medical
therapy, hemodialysis may be warranted, especially in patients with advanced CKD or end-stage renal disease.¹

In managing chronic hyperkalemia in kidney disease, KDIGO guidelines emphasize a more gradual and sustained approach. Lifestyle modifications are a common first-line strategy. ¹² Dietary potassium restriction is often recommended, although its efficacy depends heavily on patient adherence.¹² Furthermore, restrictions of potassium-rich foods, many of which are part of heart-healthy diets, may compromise overall nutritional quality.¹²

In addition to dietary changes, clinicians often adjust or discontinue medications (eg, RAASi) that contribute to hyperkalemia.⁶ However, these medications provide significant cardiovascular and renal benefits, and reducing or stopping them may result in disease progression or increased mortality, especially in patients with HF or CKD.^4,6 Pharmacologic therapy with oral furosemide may also be used to facilitate potassium excretion; this strategy remains effective even in patients
with significantly reduced kidney function (eg, eGFR < 20 mL/min/1.73 m²), although it carries a risk of hypokalemia and may require supplemental potassium chloride.^12,14

Potassium-binding agents have also become key tools in the long-term management of hyperkalemia (Table 2).^2,15,16,20 Older generation binders (eg, sodium polystyrene sulfonate [SPS]) are still in use but are associated with serious GI effects and complex dosing requirements due to interactions with other medications.¹² Newer potassium-binding agents, such as patiromer and sodium zirconium cyclosilicate (SZC), offer improved safety and tolerability profiles.^15,16 Evidence supports their use in decreasing the incidence of hyperkalemia with durations of up to 1 year.¹² While effective in lowering serum potassium over time, they have a delayed onset of action and are not appropriate for emergency treatment.^15,16 Dosing frequency, cost, and adherence may still pose barriers to widespread use.^15,16

AHA/ACC Guidelines

The AHA and ACC do not have hyperkalemia-specific guidelines, but they offer hyperkalemia management recommendations through the lens of HF management. The AHA/ACC Guideline for the Management of Heart Failure emphasizes that medications such as ACEi and ARBs should be prescribed with caution in patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium levels (> 5.0 mEq/L). These medications can increase serum potassium concentrations and may exacerbate hyperkalemia in vulnerable populations.¹³

For patients with HF with reduced ejection fraction and New York Heart Association class II to IV symptoms, the use of mineralocorticoid receptor antagonists (MRAs), specifically spironolactone or eplerenone, is recommended to reduce morbidity and mortality. However, these agents should only be initiated in patients with an eGFR greater than 30 mL/min/1.73 m² and a baseline serum potassium level below 5.0 mEq/L. Initiating MRAs in patients with impaired renal function or elevated potassium increases the risk of hyperkalemia and related adverse outcomes. Therefore, the guidelines stress the importance of careful and frequent monitoring of serum potassium, renal function, and diuretic dosing when treatment begins and during follow-up.¹³

If hyperkalemia develops during treatment, the MRA should be temporarily discontinued, and a comprehensive evaluation of the patient’s clinical status and overall medication regimen should be undertaken. Hyperkalemia may signal acute decompensation or disease progression that demands timely reassessment and a potential change in therapy.¹³

The guidelines also address the role of patiromer and SZC in managing hyperkalemia in patients with HF.¹³ By facilitating the continuation of RAASi therapy, they may help preserve the benefits of guideline-directed medical therapy.¹³ For example, the PEARL-HF trial (NCT01035255) showed that patiromer use led to reduced potassium levels, fewer hyperkalemia events, and a greater ability to up-titrate spironolactone compared with placebo.^13,17 Notably, each agent carries specific AEs; patiromer is associated with hypomagnesemia, whereas SZC can lead to edema.^13,15,16

The Pharmacist’s Role in Prevention and Patient Education

Pharmacists are uniquely positioned to play a central role in the prevention and early detection of hyperkalemia and related patient education, particularly for individuals with chronic conditions such as CKD, HF, and diabetes. These patients often are prescribed medications that can increase serum potassium levels, and pharmacists’ accessibility in both community and health system settings allows them to support early intervention strategies, reduce preventable hospitalizations, and ensure safe continuation of guideline-directed therapy (Table 3).

Identifying Patients With Risk Factors or Symptoms

A key responsibility of the pharmacist is to proactively identify patients at increased risk of developing hyperkalemia. As previously described, among the most important medication-related risk factors is the use of RAASi, which includes ACEi, ARBs, and MRAs.^1,4,6 While these agents are indispensable in managing CKD and HF, they are known to raise serum potassium levels by reducing renal potassium excretion.^6,18,19 Pharmacists dispensing RAASi medications should assess patients for additional risk factors, such as reduced kidney function or use of potassium supplements, NSAIDs, or potassium-sparing diuretics.

Education on Hyperkalemia for At-Risk Patients

In addition to conducting medication reviews, pharmacists can counsel patients on recognizing signs and symptoms of hyperkalemia, which are often nonspecific or absent during the early stages. When symptoms occur, pharmacists can warn patients that they may experience muscle weakness, fatigue, paresthesia, palpitations, or, in severe cases, flaccid paralysis and cardiac arrhythmias.¹ Pharmacists can instruct patients about when they should seek immediate medical attention, particularly if symptoms such as chest pain, irregular heartbeat, or profound weakness occur.

Educational outreach by pharmacists can significantly enhance patient understanding of hyperkalemia and support early detection. For patients taking hyperkalemia-inducing medications like RAASi, pharmacists should routinely educate patients regarding the potential AEs, reinforce the importance of regular blood tests to monitor potassium levels, and review dietary potassium sources that may inadvertently contribute to elevated serum potassium levels.

Pharmacists can tailor this counseling to the individual’s literacy level, disease state, and medication regimen. Advice to avoid salt substitutes that contain potassium chloride or limit intake of high-potassium foods (eg, bananas, potatoes, and tomatoes) can be extremely helpful.²¹ Additionally, when patients begin to use medications known to affect potassium levels or start taking a new dose, pharmacists can ensure that they know about potential risks and understand how to manage them.

Preventing Medication Interactions

Pharmacists are also instrumental in preventing medication-related complications that may exacerbate hyperkalemia. This includes identifying high-risk combinations (eg, dual RAAS blockade, NSAID plus RAASi) and ensuring appropriate timing and administration of newer potassium-lowering agents.⁴ The potassium binders SPS, patiromer, and SZC have properties that can interfere with the absorption of other medications if dosing is not spaced appropriately.^12,15,16 For example, patiromer should be taken at least 3 hours before or after other oral medications, whereas SZC may require a 2-hour separation window.^15,16 Pharmacists can verify these spacing recommendations during counselling and clarify them on prescription labels to prevent subtherapeutic effects or treatment failure of co-administered agents.

Through their medication expertise, accessibility, and frequent patient contact, pharmacists are vital to a team-based approach in managing hyperkalemia. Their role in identifying risk, educating patients, and preventing harmful interactions supports safer pharmacotherapy and contributes to the broader goals of managing chronic disease and sustaining the health care system.

Conclusion

Hyperkalemia is a clinically significant and modifiable risk factor that must be monitored carefully in patients with CKD, HF, and DM.⁴ Causes of hyperkalemia may include impaired renal excretion, tissue injury, or medication-related effects, particularly from agents like RAASi.⁴ Fortunately, serum potassium levels can often be normalized through dietary modifications, medication adjustments, or targeted therapies, although each approach requires careful consideration of risks and benefits tailored to the individual patient’s clinical status.¹²

Pharmacists play an essential role in hyperkalemia management by supporting prevention and patient education efforts. To help reduce complications and improve patient outcomes, pharmacists can identify at-risk individuals, provide education on symptoms and when to seek care, review medication regimens for potential interactions, and reinforce appropriate dosing strategies. As frontline health care providers, pharmacists are uniquely positioned to contribute meaningfully to safe and effective management of this vital metabolic condition.

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