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Correspondence: Address to Biff F. Palmer, MD, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390.
Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Despite various guidelines, no universally accepted consensus exists on best practices for hyperkalemia monitoring, with variations in precise potassium (K+) concentration thresholds or for the management of acute or chronic hyperkalemia. Based on the available evidence, this review identifies several critical issues and unmet needs with regard to the management of hyperkalemia. Real-world studies are needed for a better understanding of the prevalence of hyperkalemia outside the clinical trial setting. There is a need to improve effective management of hyperkalemia, including classification and K+ monitoring, when to reinitiate previously discontinued renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and when to use oral K+-binding agents. Monitoring serum K+ should be individualized; however, increased frequency of monitoring should be considered for patients with chronic kidney disease, diabetes, heart failure, or a history of hyperkalemia and for those receiving RAASi therapy. Recent clinical studies suggest that the newer K+ binders (patiromer sorbitex calcium and sodium zirconium cyclosilicate) may facilitate optimization of RAASi therapy. Enhancing the knowledge of primary care physicians and internists with respect to the safety profiles of these newer K+ binders may increase confidence in managing patients with hyperkalemia. Lastly, the availability of newer K+-binding agents requires further study to establish whether stringent dietary K+ restrictions are needed in patients receiving K+-binder therapy. Individualized monitoring of serum K+ among patients with an increased risk of hyperkalemia and the use of newer K+-binding agents may allow for optimization of RAASi therapy and more effective management of hyperkalemia.
An unmet need exists for new hyperkalemia management guidelines that effectively incorporate classification and monitoring for hyperkalemia, optimization of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and use of the newer potassium (K+) binders.
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Treatment gaps exist between guideline recommendations and RAASi use in clinical practice among patients with an increased risk of hyperkalemia; if discontinued, RAASi therapy should be reinitiated after acute hyperkalemia has resolved.
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The frequency of K+ monitoring should be individualized on the basis of patient comorbidities and medications (eg, RAASi), particularly in patients at high risk for development of hyperkalemia.
•
Patients with chronic hyperkalemia may benefit from long-term K+-binding therapy, initiated at the recommended dose and titrated according to serum K+ levels.
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Use of the newer K+ binders may enable the optimization of RAASi therapy in more patients with hyperkalemia.
Hyperkalemia, defined as an elevated serum potassium (K+) concentration of greater than 5.0 or greater than 5.5 mEq/L (mmol/L), is an electrolyte abnormality with potentially life-threatening consequences.
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
The risk for development of hyperkalemia is increased in patients with chronic kidney disease (CKD), diabetes, and heart failure (HF) and in individuals receiving renin-angiotensin-aldosterone system inhibitors (RAASis).
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Canadian Cardiovascular Society Heart Failure Guidelines Panels The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management: an expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology.
However, no universally accepted consensus exists regarding best practices, particularly in consideration of newer K+ binders and their use in patients with hyperkalemia due to CKD or the adverse effects of RAASis, a widely used drug class with significant cardiorenal benefits.
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Thus, new management guidelines are needed to incorporate these K+ binders into hyperkalemia treatment.
This review summarizes the physiology of hyperkalemia and suggests evidence-based clinical considerations that may provide improvements in care and outcomes in patients with an increased hyperkalemia risk.
Methods
We conducted a literature search of the PubMed database for articles published between January 1, 2000, and October 14, 2019. Search terms included chronic kidney disease, diabetes, heart failure, hyperkalaemia, hyperkalemia, patiromer, potassium, renin-angiotensin-aldosterone system inhibitor, sodium polystyrene sulfonate, SPS, sodium zirconium cyclosilicate, SZC, and ZS9. The results of this literature search were reviewed by researchers, epidemiologists, clinicians, dietitians, and trialists in the field of hyperkalemia.
Potassium Homeostasis and Hyperkalemia
Potassium homeostasis is largely maintained by the kidneys, although the gastrointestinal tract and other systems are also involved to a lesser extent (Figure 1).
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
Figure 1Regulation of potassium (K+) homeostasis. Absorbed K+ is largely redistributed from the blood to the intracellular space by active transport (Na+/K+-ATPase), which is stimulated by insulin and catecholamines. In individuals with normal kidney function, K+ is filtered through the glomerulus and reabsorbed in the proximal tubule and loop of Henle; less than 10% of filtered K+ reaches the distal nephron. Potassium excretion in the distal nephron and collecting duct is stimulated by aldosterone, increased urine flow, and increased delivery of sodium to the distal nephron. Increased K+ intake may also promote renal excretion via enteric sensing and stimulation of aldosterone release from the adrenal gland. Excess extracellular K+ is usually managed by increased renal excretion of K+; however, impaired kidney function can cause dysregulation of K+ homeostasis and increase the risk of hyperkalemia. GI = gastrointestinal; Na+/K+-ATPase = sodium-potassium pump.
The risk of mortality, cardiovascular morbidity, progression of CKD, and hospitalization is increased in patients with hyperkalemia, especially those with CKD, HF, and diabetes.
However, the exact K+ concentration that clinicians should consider to be life-threatening remains controversial. The risk of hyperkalemia and the optimal range for serum K+ concentrations vary according to individual patient comorbidities, such as CKD, HF, or diabetes. For example, a patient with atrioventricular heart block may experience worsening of cardiac symptoms at a lower K+ concentration than another patient without the same condition.
Validity of the International Classification of Diseases 10th revision code for hyperkalaemia in elderly patients at presentation to an emergency department and at hospital admission.
The rate of increase in K+ concentrations must also be considered, as a rapid increase in serum K+ is more likely to result in cardiac abnormalities than a slow steady rise over several months.
In patients with CKD, compensatory mechanisms may result in tolerance to elevated circulating K+, and several studies have suggested that hyperkalemia is a less threatening condition in CKD.
A retrospective study found a stronger association between hyperkalemia (K+ ≥5.5 mEq/L) and 1-day mortality among inpatients and outpatients with normal kidney function than in those with CKD (estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m2).
In a cohort study of patients with stage 3 to 5 CKD, the risk of pre–end-stage renal disease (ESRD) mortality was lower when serum K+ concentrations were 4.0 to 5.5 mEq/L compared with 4.0 mEq/L or less and was not increased with serum K+ levels of 5.5 mEq/L or greater.
Lastly, in a large cohort study evaluating the potential reduction in mortality risk from hyperkalemia with worsening CKD in more than 800,000 individuals, an evaluation of 90-day mortality risk in relation to K+ concentrations revealed that the observed optimal K+ range was broader toward higher K+ concentration in patients with stage 4 to 5 CKD (optimal range, 3.3 to 5.5 mEq/L) than in those with stage 1 to 2 CKD (optimal range, 3.5 to 5.0 mEq/L).
Figure 2The risk of hypokalemia- or hyperkalemia-associated mortality (a) in patients with chronic kidney disease (CKD) and other comorbidities over 18 months. DM = diabetes mellitus; HF = heart failure. From Am J Nephrol,
The mechanisms underlying this possible increase in tolerance to hyperkalemia among patients with advanced CKD are not fully understood. It has been suggested that patients with CKD adapt to elevated K+ concentrations through modifications in gastrointestinal K+ secretions
However, it is unknown whether these adaptations to increased serum K+ exist in other cells (eg, cardiomyocytes). Potassium channels in the myocardium are known to be sensitive to shifts in endogenous factors and may change in number or functioning in response to structural
alteration. Therefore, future studies should investigate whether these changes in myocardial K+ channels may explain the observed reductions in the relative risk of death from hyperkalemia in patients with advanced CKD. In addition, given the relationship between serum K+, acidosis, and calcium/magnesium concentrations,
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
However, because it is a transient condition, no prospective studies monitoring intraindividual serum K+ concentrations have been conducted, and therefore, the exact incidence of hyperkalemia in the general population is unclear. Different K+ thresholds also affect the reported incidence of hyperkalemia. Among hospitalized patients, hyperkalemia incidence has been reported as 3.5% (>5.5 mEq/L) in Canada
Validity of the International Classification of Diseases 10th revision code for hyperkalaemia in elderly patients at presentation to an emergency department and at hospital admission.
However, the likelihood of detecting hyperkalemia depends on the frequency of K+ monitoring. Two studies of inpatients and/or outpatients undergoing K+ testing over 3 years, one in Sweden
respectively). The worldwide incidence of hyperkalemia could be underestimated because of the lack of routine K+ monitoring even in some high-risk patient populations. Therefore, further epidemiological research in real-world populations is needed to more accurately estimate hyperkalemia incidence, which may be higher than observed in clinical trials because of the lack of consistent K+ monitoring and the lack of a standardized hyperkalemia definition (eg, serum K+ >5.0, >5.5, or >6.0 mEq/L).
Risk Factors
Certain patient populations have an increased risk of hyperkalemia-associated morbidity and mortality, including patients with advanced stages of CKD, HF, resistant hypertension, diabetes, myocardial infarction (MI), and/or combinations of these conditions.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
and drugs such as heparin, β-blockers, nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, trimethoprim, pentamidine, and K+-sparing diuretics.
Because chronic loss of kidney function is associated with an adaptive response in the remaining functional nephrons, allowing for an increase in fractional K+ excretion and maintenance of serum K+ levels of less than 5.5 mEq/L, the risk of hyperkalemia is generally increased once the eGFR is less than 15 mL/min per 1.73 m2.
Furthermore, patients receiving RAASi therapy who have an eGFR of less than 60 mL/min per 1.73 m2 have an elevated hyperkalemia risk, which progressively increases as eGFR decreases.
Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists [published correction appears in Eur J Heart Fail. 2019;21(4):540].
In patients with CKD and/or chronic HF receiving RAASi, risk factors for repeated hyperkalemia within 6 months of the first event include moderate to severe initial hyperkalemia (≥5.6 mEq/L), low eGFR (<45 mL/min per 1.73 m2), diabetes, and spironolactone use.
These factors currently do not impact hyperkalemia management; however, the potentially additive effects of these differences may increase hyperkalemia risk.
A low-K+ diet is recommended in patients with advanced-stage CKD to reduce hyperkalemia risk
; however, a recent Kidney Disease: Improving Global Outcomes (KDIGO) conference found that direct evidence supporting a link between dietary K+ intake and serum K+ concentrations is limited and that interventional trials are needed to determine optimal recommendations for dietary K+ in patients with CKD.
Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
A low-K+ diet is difficult for patients to adhere to, particularly those who may have additional dietary restrictions due to diabetes and reduced sodium intake for CKD or HF. Furthermore, evidence indicates that a K+-rich diet has multiple health benefits including blood pressure reductions and reduced risks of CKD progression, cardiovascular disease, and stroke.
Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC); developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
Task Force Members 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology [published correction appears in Eur Heart J. 2014;35(33):2260-2261].
Kidney Disease: Improving Global Outcomes Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD – summary: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD).
Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials.
Efficacy of mineralocorticoid receptor antagonists in postmyocardial infarction patients with or without left ventricular dysfunction: a meta-analysis of randomized controlled trials.
Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data [published correction appears in Ann Intern Med. 2002;137(4):299].
Many patients who would otherwise benefit from RAASis either do not receive these medications, receive suboptimal doses, or discontinue therapy because of the associated increased risk of recurrent hyperkalemia.
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists [published correction appears in Eur J Heart Fail. 2019;21(4):540].
Compared with those for maximum RAASi dosing, mortality rates are higher with suboptimal dosing among patients with CKD, diabetes or HF and are highest among patients who discontinue RAASis.
In one study, 74% of patients who discontinued mineralocorticoid receptor antagonists (MRAs) because of hyperkalemia did not reinitiate therapy during the subsequent year.
Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists [published correction appears in Eur J Heart Fail. 2019;21(4):540].
Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: an analysis of 11 215 patients from the Swedish Heart Failure Registry.
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).
Despite a lack of randomized controlled trial data to document improved clinical outcomes with correction of hyperkalemia and reinitiation of RAASi therapy in patients with an increased hyperkalemia risk, there is an increasing body of real-world evidence of increased morbidity and mortality among patients with CKD, HF, or diabetes who receive suboptimal or no RAASi therapy because of hyperkalemia.
Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate.
Heart Failure Long-Term Registry Investigators Group Unravelling the interplay between hyperkalaemia, renin-angiotensin-aldosterone inhibitor use and clinical outcomes: data from 9222 chronic heart failure patients of the ESC-HFA-EORP Heart Failure Long-Term Registry [published online ahead of print April 3, 2020].
For example, in a cohort study of patients who experienced a decline in eGFR to less than 30 mL/min per 1.73 m2 while receiving RAASi therapy, discontinuation of RAASi therapy was associated with a higher risk of mortality or major adverse cardiovascular events than continuation of RAASis.
Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate.
Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management: an expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology.
suggest that treatment with the newer K+ binders (discussed subsequently) may allow for optimization of RAASi therapy in patients with HF. Therefore, maximum RAASi therapy, as tolerated, should be considered when RAASis are indicated. Hyperkalemia should be treated if it develops, and reinitiation of RAASis (if discontinued) should be considered after resolution of acute hyperkalemia. Other potential risk factors for hyperkalemia should be identified and removed, whenever possible, and patients should be monitored closely, with reassessment of K+ concentrations within 1 week.
Hyperkalemia Management
Management of hyperkalemia occurs across a continuum ranging from urgent to short-term treatment and then long-term treatment and involves both inpatient and outpatient settings. Different management strategies are utilized in patients with acute vs chronic hyperkalemia (Figure 3).
Figure 3Treatment options for the management of acute and chronic hyperkalemia. In patients with acute hyperkalemia, intravenous (IV) calcium reduces membrane excitation in cardiac tissue within 1 to 3 minutes, while insulin and β-agonists redistribute potassium (K+) to the intracellular space (30 to 60 minutes) but do not reduce total body K+. β-Agonists have a short duration of effect (2 to 4 hours), and glucose must be administered with insulin to prevent hypoglycemia. Sodium bicarbonate use, which promotes K+ elimination through increased urinary K+ excretion, is limited to patients with metabolic acidosis, and effective diuretic therapy depends on residual kidney function. Hemodialysis increases total K+ elimination and may be used for resistant acute hyperkalemia. ECG = electrocardiography; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; NSAIDs = nonsteroidal anti-inflammatory drugs; OTC = over-the-counter; RAASi = renin-angiotensin-aldosterone system inhibition.
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
Canadian Cardiovascular Society Heart Failure Guidelines Panels The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
Hyperkalemia-associated adverse outcomes may extend beyond hyperkalemia thresholds (serum K+ >5.0 or >5.5 mEq/L) and include high “normal” K+ concentrations in patients with acute or chronic HF,
When deciding how to treat hyperkalemic episodes, it may be useful to focus on hyperkalemia with clinical impact, as well as rapid fluctuations in serum K+, rather than rigid and somewhat arbitrary serum K+ thresholds.
Potassium concentration thresholds for the classification of mild, moderate, and severe hyperkalemia are useful; however, patient risk- and clinical impact-based classification may also guide clinical intervention. Clinicians should consider using individualized serum K+ concentration thresholds that take into account patient comorbidities and “normal” K+ concentration ranges, as well as the rate or degree of change in serum K+ levels over time, which enables proactive or preventive interventions and is a useful clinical variable for hyperkalemia management.
Frequency of K+ Monitoring
The use of serum or plasma for determination of K+ concentrations affects laboratory results. Plasma K+ concentrations are usually 0.1- to 0.4-mEq/L lower than serum levels,
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
Complications such as pseudohyperkalemia (resulting from repeated fist clenching and poor phlebotomy techniques), hemolysis, slow specimen processing, and other factors
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
need to be assessed prior to hyperkalemia treatment. The timing of sample collection may influence K+ results because of the circadian rhythm of K+ homeostasis.
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
Clinical guidelines recommend K+ measurement in at-risk patients prior to initiation of drugs that influence hyperkalemia risk and periodically thereafter.
Canadian Cardiovascular Society Heart Failure Guidelines Panels The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
Kidney Disease: Improving Global Outcomes Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
National Institute for Health and Care Excellence Chronic kidney disease in adults: assessment and management; clinical gudiance. National Institute for Health and Care Excellence website.
Kidney Disease: Improving Global Outcomes Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
Potassium monitoring frequency should vary depending on patient comorbidities (eg, diabetes, HF, CKD stage, and the need for dialysis) and medications (eg, RAASi therapy).
Individualized K+ monitoring frequency based on the presence of comorbidities and medications should be considered, with more frequent monitoring in patients with increased hyperkalemia risk (eg, those with CKD, diabetes, HF, or a history of hyperkalemia and those taking RAASis). In particular, serum K+ concentrations should be assessed 7 to 10 days after starting RAASi therapy and increasing RAASi doses.
Acute Hyperkalemia
Acute hyperkalemia is defined as a serum K+ concentration exceeding the upper limit of normal that is not known to be chronic.40 Management of acute hyperkalemia depends on the magnitude or severity of the increase in K+ concentration, especially when combined with marked electrocardiographic (ECG) changes and severe muscle weakness.
Canadian Cardiovascular Society Heart Failure Guidelines Panels The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
However, as noted in the observational REVEAL-ED (Real World Evidence for Treatment of Hyperkalemia in the Emergency Department) study of emergency department patients who presented with K+ concentrations of 5.5 mEq/L or greater,
REVEAL-ED Study Investigators Real world evidence for treatment of hyperkalemia in the emergency department (REVEAL-ED): a multicenter, prospective, observational study.
the symptoms of hyperkalemia can be nonspecific, and although recommended for determining the clinical relevance of elevated serum K+, ECG findings can be highly variable and not as sensitive as a laboratory test in predicting hyperkalemia or its associated complications. A deep learning model that may allow for noninvasive screening for hyperkalemia using ECG is currently being developed
; however, this tool is not yet available for use in routine clinical practice. Therefore, K+ measurements should be conducted on the basis of the patient’s risk factors rather than clinical symptoms (Figure 3).
The goal of managing acute hyperkalemia is to prevent or minimize electrophysiologic effects on the heart to reduce the immediate risk of arrhythmias.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
Treatment options for acute hyperkalemia include intravenous calcium gluconate, insulin/glucose, inhaled β-agonists (eg, salbutamol), intravenous sodium bicarbonate, and hemodialysis (Figure 3). Intravenous calcium gluconate administration rapidly reduces the membrane excitatory effects of K+ on cardiac tissue within 1 to 3 minutes, thereby minimizing the potential for cardiac arrhythmia, but only minimally reduces serum K+ concentrations.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Acute hyperkalemia in the emergency department: a summary from a Kidney Disease: Improving Global Outcomes conference [published online ahead of print March 24, 2020].
Intravenous insulin (plus glucose) and inhaled β-agonists act within 30 minutes to promote redistribution of serum K+ into the intracellular space but do not change total body K+ levels.
Short-term treatment with oral sodium bicarbonate may be used to promote K+ elimination through increased urinary K+ excretion in patients with concurrent metabolic acidosis,
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
countering the release of K+ into the blood that is caused by metabolic acidosis by decreasing blood acidity and promoting K+ excretion through increased distal sodium delivery.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Several deficiencies associated with current management of acute hyperkalemia were highlighted by the REVEAL-ED study, including a lack of standard, universally accepted treatment protocols or algorithms for managing hyperkalemia in the emergency department.
REVEAL-ED Study Investigators Real world evidence for treatment of hyperkalemia in the emergency department (REVEAL-ED): a multicenter, prospective, observational study.
The study documented the use of different treatments, alone or in combination, depending on the institution and initial blood K+ concentration, including intravenous calcium, inhaled β2-agonists, oral sodium polystyrene sulfonate (SPS), intravenous sodium bicarbonate, dialysis, and intravenous diuretics. Insulin/glucose (alone or in combination with other therapy) was the most commonly utilized option (64% of patients) within the first 4 hours,
REVEAL-ED Study Investigators Real world evidence for treatment of hyperkalemia in the emergency department (REVEAL-ED): a multicenter, prospective, observational study.
whereas the treatment option most likely to achieve normokalemia within 4 hours was dialysis.
Chronic Hyperkalemia
Chronic hyperkalemia is defined as recurrent episodes of elevated serum K+ concentrations that require ongoing maintenance therapy; however, based on the recent KDIGO report,
Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
there is no consensus on the frequency, severity, or duration of these episodes that describes chronicity. In general, chronic hyperkalemia is more likely to be identified in individuals who have more frequent testing and is often asymptomatic.
Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
Current recommendations regarding the management of chronic hyperkalemia (long-term elevated serum K+) include the use of loop or thiazide diuretics, modification of RAASi dose, and removal of other hyperkalemia-causing medications (Figure 3).
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Despite the beneficial effects of diuretics on volume status and blood pressure in patients with CKD or HF, these agents may increase the risk of gout, volume depletion, decreased distal nephron flow, worsening kidney function, and reduced K+ excretion, and their effectiveness in managing hyperkalemia relies on residual kidney function. Discontinuation or dose reduction of RAASi therapy may lead to adverse cardiorenal outcomes, and current guidelines differ with regard to recommendations on when to reinitiate RAASi (Table 1).
Canadian Cardiovascular Society Heart Failure Guidelines Panels The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
Kidney Disease: Improving Global Outcomes Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
National Institute for Health and Care Excellence Chronic kidney disease in adults: assessment and management; clinical gudiance. National Institute for Health and Care Excellence website.
Recently US Food and Drug Administration–approved K+-binding agents may provide benefits for the management of chronic hyperkalemia while avoiding these limitations. Educational initiatives on the safety and efficacy of the newer K+ binders are needed for primary care physicians and internists to increase their knowledge of hyperkalemia management, especially in regions where specialist services may not be readily available. A team approach for chronic hyperkalemia management is optimal, which may include specialists (eg, cardiologists, nephrologists), primary care physicians, nurses, pharmacists, social workers, or dietitians.
Table 1Summary of Guideline Recommendations for RAASi Therapy
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
Canadian Cardiovascular Society Heart Failure Guidelines Panels The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
RAASi not usually stopped If RAASi therapy is stopped, reinitiate therapy once any concurrent condition contributing to changes in K+ is under control AND serum K+ has decreased to <5.0 mEq/L or to within patient’s usual range (whichever is higher)
Moderate (K+ 5.6-5.9) or severe (K+ >5.9) HK
Reinitiate RAASi therapy once any concurrent condition contributing to changes in K+ is under control AND serum K+ has decreased to <5.0 mEq/L or to within patient’s usual range (whichever is higher) Reintroduce RAASi agents one at a time with monitoring of kidney function and electrolytes
Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.
If not taking maximum-tolerated guideline-recommended dose, initiate/up-titrate RAASi therapy and closely monitor K+; start K+-lowering therapy if K+ increases to >5.0 mEq/L
>5.0 to ≤6.5
If receiving maximum-tolerated guideline-recommended RAASi dose, initiate K+-lowering therapy; closely monitor K+ and continue K+-lowering therapy unless another treatable etiology for hyperkalemia is identified
If not taking maximum-tolerated guideline-recommended RAASi dose, start K+-lowering therapy and titrate RAASi when K+ is <5.0 mEq/L; closely monitor K+ and maintain K+-lowering therapy unless another etiology for hyperkalemia is identified
>6.5
Discontinue or reduce RAASi therapy; K+-lowering therapy may be started as soon as K+ is >5.0 mEq/L; closely monitor serum K+
Kidney Disease: Improving Global Outcomes Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
National Institute for Health and Care Excellence Chronic kidney disease in adults: assessment and management; clinical gudiance. National Institute for Health and Care Excellence website.
All K+ binders used for hyperkalemia management are nonabsorbed and consist of a counterion that is exchanged for K+, facilitating the elimination of bound K+ in feces.
Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review [published correction appears in Core Evid. 2019;14:1].
was the only K+ binder available for hyperkalemia management and may continue to be the only agent available in parts of the world. However, 2 other K+ binders, patiromer sorbitex calcium (Veltassa)
Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review [published correction appears in Core Evid. 2019;14:1].
The efficacy of patiromer and SZC has been documented in clinical trials, whereas clinical data for SPS is limited (discussed subsequently and summarized in Table 3).
PEARL-HF Investigators 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.
AMETHYST-DN Investigators Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial [published correction appears in JAMA. 2015;314(7):731].
Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
A phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia.
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
National Institute for Health and Care Excellence Sodium zirconium cyclosilicate for treating hyperkalaemia: guidance. National Institute for Health and Care Excellence website.
The National Institute for Health and Care Excellence has recently provided recommendations regarding SZC and patiromer use for the treatment of acute life-threatening hyperkalemia, stating that these agents may be considered for use in conjunction with standard care.
National Institute for Health and Care Excellence Sodium zirconium cyclosilicate for treating hyperkalaemia: guidance. National Institute for Health and Care Excellence website.
AMBER = Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease; AMETHYST-DN = Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy; BID = twice daily; CKD = chronic kidney disease; DIALIZE = A Study to Test Whether ZS (Sodium Zirconium Cyclosilicate) Can Reduce the Incidence of Increased Blood Potassium Levels Among Dialized Patients; DKD = diabetic kidney disease; ENERGIZE = A Study to Evaluate a Potassium Normalization Treatment Regimen Including Sodium Zirconium Cyclosilicate (ZS) Among Patients With S-K ≥5.8; ESRD = end-stage renal disease; HARMONIZE = Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance; HARMONIZE-OLE = HARMONIZE open-label extension; HF = heart failure; K+ = potassium; LS = least squares; max = maximum; min = minimum; OPAL-HK = A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia; PEARL-HF = Evaluation of Patiromer in Heart Failure Patients; QD = once daily; RAASi = renin-angiotensin-aldosterone system inhibitor; SOC = standard of care; SPS = sodium polystyrene sulfonate; SZC = sodium zirconium cyclosilicate; TID = three times daily.
PEARL-HF Investigators 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.
AMETHYST-DN Investigators Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial [published correction appears in JAMA. 2015;314(7):731].
Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
A phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia.
Defined as predialysis serum K+ >5.4 mEq/L after the long interdialytic interval and predialysis serum K+ >5.0 mEq/L after ≥1 short interdialytic interval.
; N=196
SZC 5, 10, or 15 g or placebo QD on nondialysis days for 4 wk
Maintenance of predialysis serum K+ 4.0-5.0 mEq/L during ≥3 of 4 hemodialysis sessions after long interdialytic interval without requiring rescue therapy:
41% with SZC
1% with placebo
P<.001 vs placebo
a AMBER = Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease; AMETHYST-DN = Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy; BID = twice daily; CKD = chronic kidney disease; DIALIZE = A Study to Test Whether ZS (Sodium Zirconium Cyclosilicate) Can Reduce the Incidence of Increased Blood Potassium Levels Among Dialized Patients; DKD = diabetic kidney disease; ENERGIZE = A Study to Evaluate a Potassium Normalization Treatment Regimen Including Sodium Zirconium Cyclosilicate (ZS) Among Patients With S-K ≥5.8; ESRD = end-stage renal disease; HARMONIZE = Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance; HARMONIZE-OLE = HARMONIZE open-label extension; HF = heart failure; K+ = potassium; LS = least squares; max = maximum; min = minimum; OPAL-HK = A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia; PEARL-HF = Evaluation of Patiromer in Heart Failure Patients; QD = once daily; RAASi = renin-angiotensin-aldosterone system inhibitor; SOC = standard of care; SPS = sodium polystyrene sulfonate; SZC = sodium zirconium cyclosilicate; TID = three times daily.
b Spironolactone dosage increased to 50 mg/d after 2 weeks in patients with serum K+ >3.5 to ≤5.1 mEq/L.
c Patiromer was titrated to achieve and maintain serum K+ ≤5.0 mEq/L.
d Spironolactone dosage increased to 50 mg/d after 3 weeks in patients with systolic blood pressure ≥120 mm Hg and serum K+ ≤5.1 mEq/L.
e SZC was titrated to maintain serum K+ 3.5-5.0 mEq/L.
f Defined as predialysis serum K+ >5.4 mEq/L after the long interdialytic interval and predialysis serum K+ >5.0 mEq/L after ≥1 short interdialytic interval.
The initiation of newer K+-binding agents should be considered in patients with chronic hyperkalemia despite optimized diuretic therapy and correction of metabolic acidosis. After starting therapy at the recommended dose, K+ binders should be titrated for optimization of serum K+ concentration, with individualized monitoring of serum or plasma K+. Long-term K+-binder therapy may be considered in patients with chronic hyperkalemia. The use of one of the newer K+-binding agents (patiromer or SZC) may allow for the continuation and optimization of RAASi therapy in patients with hyperkalemia. Consideration of the costs of patiromer or SZC may influence their use in clinical practice for some patients. Although such data are limited, cost-effectiveness analysis from the US payer perspective found that the benefits of adding patiromer to treatment in patients with HF and hyperkalemia outweighed the incremental total costs, with lower hospitalization costs, improved survival, and increased quality of life.
Cost-effectiveness analysis of patiromer and spironolactone therapy in heart failure patients with hyperkalemia [published correction appears in Pharmacoeconomics. 2019;37(8):1071].
With only one small randomized, double-blind, 7-day trial, clinical studies supporting its long-term use in patients with hyperkalemia are lacking (Table 3).
Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
Initiation of sodium polystyrene sulphonate and the risk of gastrointestinal adverse events in advanced chronic kidney disease: a nationwide study [published online ahead of print August 4, 2019].
However, although cohort studies have reported a higher relative risk of gastrointestinal AEs with SPS use, the incidence of events with SPS was rare (16 or 23 events per 1000 person-years).
Initiation of sodium polystyrene sulphonate and the risk of gastrointestinal adverse events in advanced chronic kidney disease: a nationwide study [published online ahead of print August 4, 2019].
However, in 2009, the US Food and Drug Administration added a warning label to SPS regarding the concomitant use of sorbitol and the associated risk of colonic necrosis and other serious gastrointestinal AEs (bleeding, ischemic colitis, and perforation).
Initiation of sodium polystyrene sulphonate and the risk of gastrointestinal adverse events in advanced chronic kidney disease: a nationwide study [published online ahead of print August 4, 2019].
Of note, the release of sodium from SPS during K+ exchange may potentially increase sodium and volume load. Sodium polystyrene sulfonate should be used with caution in patients with congestive HF, severe hypertension, edema, or decreased kidney function who may not tolerate increased sodium loads.
The efficacy of patiromer was established in randomized, placebo-controlled, phase 2 and 3 trials of patients with hyperkalemia, including those with CKD and HF, and/or receiving RAASis (Table 3). In a pilot study of emergency department patients with ESRD and serum K+ levels of 6.0 mEq/L or higher, single-dose administration of patiromer, 25.2 g, in addition to standard of care effectively reduced serum K+ concentrations over 6 hours.
In patients with chronic hyperkalemia, patiromer, 4.2 to 16.8 g twice daily, provided significant dose-dependent reductions in serum K+ levels by 0.2 to 1.0 mEq/L over 4 weeks
PEARL-HF Investigators 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.
AMETHYST-DN Investigators Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial [published correction appears in JAMA. 2015;314(7):731].
In patients with advanced CKD and resistant hypertension, significantly more patients continued spironolactone, 25 to 50 mg once daily, while receiving patiromer, 8.4 g once daily, vs placebo for 12 weeks.
Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
Among patients with diabetes and CKD, including those with HF receiving RAASis, normokalemia was maintained with patiromer therapy for up to 12 months.
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.
In a real-world study of patients undergoing long-term hemodialysis, serum K+ concentrations were significantly reduced following initiation of patiromer over three 30-day periods, and the proportion of patients with serum K+ levels of 6.0 mEq/L or higher decreased from approximately 50% before patiromer initiation to 22% at 90 days after patiromer initiaton.
No serious AEs have been associated with patiromer therapy in randomized trials. The most common AEs include gastrointestinal events (constipation, diarrhea, nausea/vomiting, abdominal discomfort, and flatulence) and electrolyte disturbances (hypokalemia and hypomagnesemia).
suggesting that it may be an underreported AE that clinicians should be aware of when initiating patiromer therapy. Currently, there are no real-world safety data for patiromer.
Sodium Zirconium Cyclosilicate
Sodium zirconium cyclosilicate (SZC) is the most recently approved K+-binding agent, with its efficacy and safety established in phase 2 and 3 clinical trials of patients with hyperkalemia including those with CKD, HF, and/or diabetes or those receiving RAASis (Table 3).
Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
A phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia.
In a study of emergency department patients with serum K+ concentrations of 5.8 mEq/L or higher, SZC therapy (up to three 10-g doses within 10 hours) added to insulin plus glucose provided reductions in mean serum K+ levels of 0.72 mEq/L within 2 hours.
Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
In studies of patients with chronic hyperkalemia, 3-times-daily SZC significantly reduced serum K+ concentrations within 48 hours, and a once-daily 5- or 10-g SZC dose effectively maintained normokalemia over 14 to 28 days.
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
In the DIALIZE (A Study to Test Whether ZS [Sodium Zirconium Cyclosilicate] Can Reduce the Incidence of Increased Blood Potassium Levels Among Dialized Patients) study of patients with ESRD and persistent hyperkalemia, once-daily SZC on nondialysis days effectively maintained normal predialysis serum K+ levels over 8 weeks.
A phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia.
Normalization of serum bicarbonate with sodium zirconium cyclosilicate (ZS-9) in the phase 3 randomized, double-blind, placebo-controlled HARMONIZE study.
which may provide an added benefit for patients with metabolic acidosis.
Unlike SPS and patiromer, SZC is nonpolymeric with high selectivity for K+ and ammonium ions (1.25-fold higher affinity for K+ than ammonium) in exchange for hydrogen and sodium throughout the gastrointestinal tract.
Because SZC may affect absorption of other oral medications with pH-dependent solubility due to a transient increase in gastric pH, SZC administration should be separated from these medications by 2 or more hours.
Sodium zirconium cyclosilicate has not been associated with any serious AEs in randomized trials. The most common AEs were hypokalemia and a dose-dependent increase in edema.
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
National Kidney Foundation Hyperkalemia: survey of awareness and experience among adults with CKD; a report of findings. National Kidney Foundation website.
These actions include using educational tools to facilitate communication about hyperkalemia (eg, https://www.kidney.org/atoz/content/what-hyperkalemia) and encouraging nurse practitioners, physicians, physician assistants, pharmacists, and dietitians to proactively engage patients in dialogue about the associated risk of hyperkalemia and provide ongoing dietary and other lifestyle information relevant to patients with increased hyperkalemia risk.
National Kidney Foundation Hyperkalemia: survey of awareness and experience among adults with CKD; a report of findings. National Kidney Foundation website.
Educational initiatives and campaigns are needed to improve patient awareness of hyperkalemia risk and its potentially life-threatening consequences, including awareness that hyperkalemia is often asymptomatic and that routine K+ monitoring is important. Allied health care professional involvement in patient education may help to increase awareness of the hyperkalemia risk associated with RAASi and other medications. Health care practitioners should be involved in patient education regarding hyperkalemia to promote shared care responsibility and treatment planning.
Conclusion
Critical unmet needs exist regarding effective hyperkalemia management, including classification and monitoring for hyperkalemia, reinitiation and maximization of RAASi therapy, and use of K+-binding agents. Hyperkalemia incidence may be higher than previously reported, and the risks associated with acute and chronic hyperkalemia may be reduced through vigilant individualized serum K+ monitoring. With the availability of newer K+-binding agents, clinicians have increased need for education on their use as well as to increase patient awareness about the signs, symptoms, and risks of hyperkalemia. Newer K+-binding agents may enable the optimization of RAASi therapy in more patients with hyperkalemia.
Acknowledgments
All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this article and take responsibility for the integrity of the work as a whole. Medical writing support was provided by Sarah Greig, PhD (Auckland, New Zealand), and Meri Pozo, PhD (New York, NY), of inScience Communications, Springer Healthcare, in accordance with Good Publication Practice and funded by AstraZeneca . The authors had full editorial control of the submitted manuscript, reviewed and edited successive drafts, provided final approval of all content and submission of the manuscript, and are fully accountable for all aspects of the work.
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Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
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Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials.
Efficacy of mineralocorticoid receptor antagonists in postmyocardial infarction patients with or without left ventricular dysfunction: a meta-analysis of randomized controlled trials.
Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease: a meta-analysis of patient-level data [published correction appears in Ann Intern Med. 2002;137(4):299].
Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: an analysis of 11 215 patients from the Swedish Heart Failure Registry.
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Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate.
Heart Failure Long-Term Registry Investigators Group
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2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Acute hyperkalemia in the emergency department: a summary from a Kidney Disease: Improving Global Outcomes conference [published online ahead of print March 24, 2020].
Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review [published correction appears in Core Evid. 2019;14:1].
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.
Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial [published correction appears in JAMA. 2015;314(7):731].
Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial.
Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015;313(5):526].
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