Hyperkalemia Treatment and Prevention in Chronic Kidney Disease

By Sarah Williams, PhD, and Takeesha Roland-Jenkins, MS, MS

Nearly 25% of patients with stage 5 chronic kidney disease will at some point need emergency hemodialysis to treat hyperkalemia, a common comorbidity.¹ Hyperkalemia is recognized clinically as a significant electrolyte abnormality and can potentially lead to severe electrophysiologic disruptions, including life-threatening cardiac arrhythmias.^2,3

Hyperkalemia is characterized by serum potassium levels greater than 5.5 mmol/L (levels between 5.5 and 5.9 mmol/L are considered ‘mild’; levels between 6.0 and 6.4 mmol/L are considered ‘moderate’; and levels at or above 6.5 mmol/L are considered ‘severe’)². Patients with chronic renal disease are particularly at risk for cardiovascular events and death from this condition.⁴ Thus, prevention and treatment of hyperkalemia is a critical component of treatment of patients with chronic kidney disease.

Renin Angiotensin Aldosterone System Inhibitors and Hyperkalemia

Drugs that impact the renin-angiotensin-aldosterone system, including angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), have been found to significantly increase the risk of hyperkalemia.^5-7 These drugs reduce the excretion of renal potassium by inhibiting the renin-angiotensin-aldosterone system (RAAS).⁶

RAAS inhibitors are typically the recommended treatment for patients with chronic renal disease, as they have been shown to slow the progression of renal disease, prolong survival across several disease states, and even reduce morbidity.^5,8 However, the use of these drugs is associated with significantly increased risk of hyperkalemia, especially in patients with chronic kidney disease and in those who are treated with several RAAS inhibitors at once.⁹ 

Aldosterone antagonists are also a major concern for people with hyperkalemia. In 1999, a landmark trial reported a 30% reduction in deaths for heart failure patients who were treated with the aldosterone antagonist spironolactone (Aldactone).¹⁰ This trial was followed by another study that reported a significant reduction in deaths among patients with left ventricular dysfunction after myocardial infarction and heart failure who were treated with eplerenone, another aldosterone antagonist.¹¹ Prescriptions for aldosterone antagonists subsequently increased rapidly.¹²

However, as prescriptions for spironolactone increased, so did the number of admissions for hyperkalemia, as well as incidents of death attributed to hyperkalemia.¹² Research now indicates close monitoring for congestive heart failure patients who are at risk for hyperkalemia and have been prescribed aldosterone antagonists.¹³

Recognizing Risks of Hyperkalemia

When a patient with chronic renal disease is initiated on RAAS inhibitors, it is important to assess for and continually monitor risk for hyperkalemia. Recognizing the signs of hyperkalemia while it is in the early stages can be difficult. Patients who meet clinical criteria for mild-to-moderate hyperkalemia may often present as asymptomatic.¹⁴ 

During physical examination, patients with elevated serum potassium levels characteristic of hyperkalemia may complain of abdominal pain, muscle weakness, muscle twitching, muscle cramping, fatigue, diarrhea, myalgia, or flaccid paralysis of the extremities.^15,16 Vital signs generally tend to be normal,¹⁷ but these types of symptoms generally initiate a diagnostic evaluation that indicates the presence of hyperkalemia. Hyperkalemia is also often discovered through routine laboratory tests.¹⁸ 

Electrocardiogram (ECG) may also be used to assess for hyperkalemia, but it is typically insensitive for diagnosing and guiding the management of this condition. ECG readings often do not accurately reflect the degree or severity of hyperkalemia.¹² One study involving a sample of 90 patients with known hyperkalemia showed that the ECG was insensitive for diagnosing hyperkalemia in 80% of those with serum potassium levels less than or equal to 7.1 mEq/L.¹⁹ 

However, ECG can be a useful tool for diagnosing hyperkalemia by demonstrating changes such as the narrowing and peaking of the T-wave (ie, “tenting”) along with a shortening of the QT interval.¹⁹ Additionally, results of an ECG may reveal prolongation of the PR-interval or QRS widening.¹⁵ Cardiac arrhythmias such as ventricular fibrillation, bradyarrhythmias, and asystole may also be noted on the electrocardiogram.¹⁵ 

Managing Risks of Hyperkalemia

Until only recently, treatments that were approved for hyperkalemia have primarily centered on emergency and intermediate care, as well as long-term management strategies that focus on reducing chronic risk or recurrent hyperkalemia.^8,20 Treatments classified as emergent are those that work to lower serum potassium within minutes by promoting the transfer of potassium from the plasma space to within the cell while supporting membrane stabilization. Such treatments include insulin/glucose, calcium gluconate, and b₂ receptor agonists.^1,15,21,22 Calcium gluconate salt, in particular, stabilizes the membrane and appears to be administered along with medications that cause a transcellular shift of potassium.⁸

Hyperkalemia can lead to life-threatening cardiac arrhythmias, so it is critical to ensure that patients are not in immediate danger. Patients should be immediately assessed in an acute facility, including close cardiac monitoring, if they present with very high serum potassium levels (ie, serum potassium level above 6.5 mmol/L), exhibit a rapid elevation in serum potassium levels, or show other clinical signs of hyperkalemia (eg, paresthesia, muscle weakness, cardiac arrhythmia).²³ 

Once serum potassium levels have returned to safe levels, it is recommended that treatment options focus more on reducing the body’s total potassium using either intermediate or maintenance therapies.^8,21 Intermediate therapies include the use of sodium bicarbonate, loop diuretics, hemodialysis, and potassium-binding resin sodium polystyrene sulfonate.^11,21,22 Maintenance therapies tend to include shifting toward a lower potassium diet and discontinuing or reducing the dose of current RAAS inhibitors.^8,22

Encouraging patients to reduce potassium in their diet can be challenging, as adherence is often difficult.^8,22 Side effects of this strategy include constipation, and a diet of reduced potassium can worsen hypertension, as well as contradict the DASH (Dietary Approaches to Stop Hypertension).⁸

Long-term treatment of hyperkalemia may also involve the administration of a nonspecific sodium-cation exchange resin called sodium polystyrene sulfonate (Kayexalate).²⁴ However, sodium polystyrene sulfonate use is linked to systemic toxicities that include sodium retention, hypocalcemia, hypomagnesemia,²⁵ and colonic necrosis²⁶ as well as gastrointestinal adverse events such as diarrhea and constipation.²⁶ As a result, it is a limited form of treatment. Potassium-binding agents such as sodium zirconium cyclosilicate (ZS-9) and patiromer (Veltassa) appear to be more beneficial than sodium polystyrene sulfonate.²⁷

Treatment Options

Sodium zirconium cyclosilicate (ZS-9) is in the clinical trial phase as a potential treatment approach for hyperkalemia, as it has demonstrated efficacy at lowering serum potassium levels.^28-30 It selectively binds to potassium ions and does not bind to magnesium, sodium, or calcium ions as sodium polystyrene sulfonate does.³¹ In 4-week clinical trials, participants who received sodium zirconium cyclosilicate did not report any serious adverse events, and the most common adverse events were diarrhea, constipation, edema, and a few cases of hypokalemia that resolved after the treatment doses were adjusted.^29,30

Similarly, patiromer has been shown through clinical trials to reduce hyperkalemia in patients with hypertension, heart failure, diabetes mellitus, and chronic kidney disease, as well as in those who were taking RAAS inhibitors.³² This high-capacity polymer exchanges calcium for potassium primarily in the distal colon, thereby preventing the reabsorption of potassium into systemic circulation and effectively reducing serum potassium levels.³² No serious adverse events have been linked to patiromer use, and the most commonly reported acute adverse events are similar to those experienced while taking ZS-9.^{33, 34}

Discontinuing or reducing the dosage of RAAS inhibitors may be the most effective strategy for preventing recurrent hyperkalemic events.^8,20 Physicians considering this strategy for their patients with chronic renal disease must weigh the benefits of reducing future risk for hyperkalemia with the potential for ceasing or achieving suboptimal utilization of the recommended renal therapy.⁸ That is, when hyperkalemia precludes treatment with RAAS inhibitors (eg, patients with chronic kidney disease whose pretreatment serum potassium is > 5.0 mmol/L), it is important to assess and treat other factors that are known to cause hyperkalemia. It is also critical to frequently recheck serum potassium levels in order to improve the outcomes for patients with this disease.³⁵

Sarah Williams, PhD, and Takeesha Roland-Jenkins, MS, MS, are medical writers at Health Economics Institute, located in Ponte Vedra Beach, Florida.

References

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