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Clinical Management of Hyperkalemia

Open AccessPublished:November 04, 2020DOI:https://doi.org/10.1016/j.mayocp.2020.06.014

      Abstract

      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.

      Abbreviations and Acronyms:

      AE (adverse event), CKD (chronic kidney disease), DKD (diabetic kidney disease), ECG (electrocardiographic), eGFR (estimated glomerular filtration rate), HF (heart failure), K+ (potassium), KDIGO (Kidney Disease: Improving Global Outcomes), MI (myocardial infarction), MRA (mineralocorticoid receptor antagonist), RAASi (renin-angiotensin-aldosterone system inhibitor), SPS (sodium polystyrene sulfonate), SZC (sodium zirconium cyclosilicate)
      Article Highlights
      • 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.
      • 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.
      • 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.
      • 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.
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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).
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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.
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
      • Bandak G.
      • Sang Y.
      • Gasparini A.
      • et al.
      Hyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) project.
      Guidelines/consensus statements for hyperkalemia management have been developed.
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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.
      ,
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
      ,
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      Canadian Cardiovascular Society Heart Failure Guidelines Panels
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      National Kidney Foundation
      Best practices in managing hyperkalemia in chronic kidney disease. National Kidney Foundation website.
      UK Renal Association
      Clinical practice guidelines: treatment of acute hyperkalaemia in adults.
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
      • Bianchi S.
      • Aucella F.
      • De Nicola L.
      • Genovesi S.
      • Paoletti E.
      • Regolisti G.
      Management of hyperkalemia in patients with kidney disease: a position paper endorsed by the Italian Society of Nephrology.
      • Seferovic P.M.
      • Ponikowski P.
      • Anker S.D.
      • et al.
      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.
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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).
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
      ,
      • Palmer B.F.
      • Clegg D.J.
      Physiology and pathophysiology of potassium homeostasis: core curriculum 2019.
      Hyperkalemia has depolarizing effects on the heart,
      • Palmer B.F.
      • Clegg D.J.
      Physiology and pathophysiology of potassium homeostasis: core curriculum 2019.
      causing shortened action potentials and increasing the risk of arrhythmias.
      • Pochineni V.
      • Rondon-Berrios H.
      Electrolyte and acid-base disorders in the renal transplant recipient.
      Hyperkalemia causes neuromuscular symptoms,
      • Palmer B.F.
      • Clegg D.J.
      Physiology and pathophysiology of potassium homeostasis: core curriculum 2019.
      ,
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      metabolic acidosis, and suppression of ammoniagenesis.
      • Lee Hamm L.
      • Hering-Smith K.S.
      • Nakhoul N.L.
      Acid-base and potassium homeostasis.
      Figure thumbnail gr1
      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.
      • Collins A.J.
      • Pitt B.
      • Reaven N.
      • et al.
      Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes.
      ,
      • Gasparini A.
      • Evans M.
      • Barany P.
      • et al.
      Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project.
      A U-shaped curve exists between serum K+ and mortality, with both hyperkalemia and hypokalemia associated with adverse clinical outcomes (Figure 2).
      • Collins A.J.
      • Pitt B.
      • Reaven N.
      • et al.
      Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or 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.
      • Fleet J.L.
      • Shariff S.Z.
      • Gandhi S.
      • Weir M.A.
      • Jain A.K.
      • Garg A.X.
      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.
      • Conway R.
      • Creagh D.
      • Byrne D.G.
      • O'Riordan D.
      • Silke B.
      Serum potassium levels as an outcome determinant in acute medical admissions.
      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.
      • Gasparini A.
      • Evans M.
      • Barany P.
      • et al.
      Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project.
      ,
      • Einhorn L.M.
      • Zhan M.
      • Hsu V.D.
      • et al.
      The frequency of hyperkalemia and its significance in chronic kidney disease.
      • Nakhoul G.N.
      • Huang H.
      • Arrigain S.
      • et al.
      Serum potassium, end-stage renal disease and mortality in chronic kidney disease.
      • An J.N.
      • Lee J.P.
      • Jeon H.J.
      • et al.
      Severe hyperkalemia requiring hospitalization: predictors of mortality.
      • Korgaonkar S.
      • Tilea A.
      • Gillespie B.W.
      • et al.
      Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study.
      • Grodzinsky A.
      • Goyal A.
      • Gosch K.
      • et al.
      Prevalence and prognosis of hyperkalemia in patients with acute myocardial infarction.
      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).
      • Einhorn L.M.
      • Zhan M.
      • Hsu V.D.
      • et al.
      The frequency of hyperkalemia and its significance in chronic kidney disease.
      A U-shaped correlation was found between serum K+ and overall mortality risk in patients with non–dialysis-dependent CKD,
      • Nakhoul G.N.
      • Huang H.
      • Arrigain S.
      • et al.
      Serum potassium, end-stage renal disease and mortality in chronic kidney disease.
      and in a study of consecutive hospitalizations for severe hyperkalemia, a graded decrease in the risk of mortality was observed as CKD stage worsened.
      • An J.N.
      • Lee J.P.
      • Jeon H.J.
      • et al.
      Severe hyperkalemia requiring hospitalization: predictors of mortality.
      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.
      • Korgaonkar S.
      • Tilea A.
      • Gillespie B.W.
      • et al.
      Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study.
      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).
      • Gasparini A.
      • Evans M.
      • Barany P.
      • et al.
      Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project.
      Figure thumbnail gr2
      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,
      • Collins A.J.
      • Pitt B.
      • Reaven N.
      • et al.
      Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes.
      with permission.
      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
      • Palmer B.F.
      • Clegg D.J.
      Physiology and pathophysiology of potassium homeostasis: core curriculum 2019.
      ,
      • Mathialahan T.
      • Maclennan K.A.
      • Sandle L.N.
      • Verbeke C.
      • Sandle G.I.
      Enhanced large intestinal potassium permeability in end-stage renal disease.
      which may favor intracellular K+ storage,
      • Sterns R.H.
      • Feig P.U.
      • Pring M.
      • Guzzo J.
      • Singer I.
      Disposition of intravenous potassium in anuric man: a kinetic analysis.
      or by increasing insulin-mediated intracellular K+ uptake in splanchnic and peripheral muscle tissues.
      • Alvestrand A.
      • Wahren J.
      • Smith D.
      • DeFronzo R.A.
      Insulin-mediated potassium uptake is normal in uremic and healthy subjects.
      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
      • Berti C.
      • Zsolnay V.
      • Shannon T.R.
      • Fill M.
      • Gillespie D.
      Sarcoplasmic reticulum Ca2+, Mg2+, K+, and Cl concentrations adjust quickly as heart rate changes.
      ,
      • Stillitano F.
      • Lonardo G.
      • Zicha S.
      • et al.
      Molecular basis of funny current (If) in normal and failing human heart.
      and environmental
      • Wang X.
      • Fitts R.H.
      Ventricular action potential adaptation to regular exercise: role of β-adrenergic and KATP channel function.
      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,
      • Martin H.E.
      • Wertman M.
      Serum potassium, magnesium, and calcium levels in diabetic acidosis.
      it would be interesting to examine whether metabolic acidosis affects the association between serum K+ and mortality risk in patients with CKD.

      Epidemiology of Hyperkalemia

      Hyperkalemia Incidence

      Hyperkalemia is rare in the general population.
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      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
      • Fleet J.L.
      • Shariff S.Z.
      • Gandhi S.
      • Weir M.A.
      • Jain A.K.
      • Garg A.X.
      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.
      and 4.9% (>5.0 mEq/L) in Ireland.
      • Conway R.
      • Creagh D.
      • Byrne D.G.
      • O'Riordan D.
      • Silke B.
      Serum potassium levels as an outcome determinant in acute medical admissions.
      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
      • Nilsson E.
      • Gasparini A.
      • Ärnlöv J.
      • et al.
      Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system.
      and another in the United States,
      • Chang A.R.
      • Sang Y.
      • Leddy J.
      • et al.
      Antihypertensive medications and the prevalence of hyperkalemia in a large health system.
      observed higher rates of hyperkalemia (7%
      • Nilsson E.
      • Gasparini A.
      • Ärnlöv J.
      • et al.
      Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system.
      and 11% [>5.0 mEq/L] and 2% [>5.5 mEq/L],
      • Chang A.R.
      • Sang Y.
      • Leddy J.
      • et al.
      Antihypertensive medications and the prevalence of hyperkalemia in a large health system.
      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.
      • Collins A.J.
      • Pitt B.
      • Reaven N.
      • et al.
      Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes.
      ,
      • Krogager M.L.
      • Eggers-Kaas L.
      • Aasbjerg K.
      • et al.
      Short-term mortality risk of serum potassium levels in acute heart failure following myocardial infarction.
      ,
      • Krogager M.L.
      • Torp-Pedersen C.
      • Mortensen R.N.
      • et al.
      Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data.
      Additional risk factors include RAASi usage, advanced age,
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      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.
      • Palmer B.F.
      • Clegg D.J.
      Physiology and pathophysiology of potassium homeostasis: core curriculum 2019.
      ,
      • Palmer B.F.
      Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system.
      The risk of hyperkalemia progressively increases as eGFR decreases.
      • Gasparini A.
      • Evans M.
      • Barany P.
      • et al.
      Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project.
      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.
      • Palmer B.F.
      • Clegg D.J.
      Hyperkalemia across the continuum of kidney function.
      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.
      • Bandak G.
      • Sang Y.
      • Gasparini A.
      • et al.
      Hyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) project.
      ,
      • Trevisan M.
      • de Deco P.
      • Xu H.
      • et al.
      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.
      • Adelborg K.
      • Nicolaisen S.K.
      • Hasvold P.
      • Palaka E.
      • Pedersen L.
      • Thomsen R.W.
      Predictors for repeated hyperkalemia and potassium trajectories in high-risk patients – a population-based cohort study.
      Hyperkalemia risk is slightly higher in men than in women after initiation of RAASi therapy
      • Bandak G.
      • Sang Y.
      • Gasparini A.
      • et al.
      Hyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) project.
      and differs among racial groups, in whom ethnicity, diet, and socioeconomic factors may contribute.
      • Kim T.
      • Rhee C.M.
      • Streja E.
      • et al.
      Racial and ethnic differences in mortality associated with serum potassium in a large hemodialysis cohort.
      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
      Kidney Disease Outcomes Quality Initiative
      K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.
      ; 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.
      • Clase C.M.
      • Carrero J.-J.
      • Ellison D.H.
      • et al.
      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.
      • Palmer B.F.
      • Clegg D.J.
      Achieving the benefits of a high-potassium, paleolithic diet, without the toxicity.
      Restriction of dietary K+ as a general approach to preventing hyperkalemia may therefore deprive patients of these benefits.
      • Clase C.M.
      • Carrero J.-J.
      • Ellison D.H.
      • et al.
      Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.

      RAASi Therapy—Benefits and Hyperkalemia Risk

      Renin-angiotensin-aldosterone system inhibitors are recommended for patients with hypertension,
      • Mancia G.
      • Fagard R.
      • Narkiewicz K.
      • et al.
      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).
      HF,
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      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.
      ,
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      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.
      stable coronary artery disease,
      • Montalescot G.
      • Sechtem U.
      • et al.
      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].
      CKD, diabetic kidney disease (DKD),
      Kidney Disease: Improving Global Outcomes Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      and diabetes.
      • Rydén L.
      • Grant P.J.
      • Anker S.D.
      • et al.
      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).
      ,
      American Diabetes Association
      9. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes–2018.
      They improve survival in patients with CKD,
      • Molnar M.Z.
      • Kalantar-Zadeh K.
      • Lott E.H.
      • et al.
      Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker use, and mortality in patients with chronic kidney disease.
      HF,
      • Tai C.
      • Gan T.
      • Zou L.
      • et al.
      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.
      ,
      • Zannad F.
      • McMurray J.J.
      • Krum H.
      • et al.
      EMPHASIS-HF Study Group
      Eplerenone in patients with systolic heart failure and mild symptoms.
      and post-MI status
      • Xu Y.
      • Qiu Z.
      • Yang R.
      • Wu Y.
      • Cheng X.
      Efficacy of mineralocorticoid receptor antagonists in postmyocardial infarction patients with or without left ventricular dysfunction: a meta-analysis of randomized controlled trials.
      and also provide kidney benefits in patients with non-DKD
      • Jafar T.H.
      • Schmid C.H.
      • Landa M.
      • et al.
      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].
      and DKD.
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • et al.
      RENAAL Study Investigators
      Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
      ,
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • et al.
      Collaborative Study Group
      Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
      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.
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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.
      Treatment gaps exist between guideline recommendations and RAASi use in clinical practice in patients with increased hyperkalemia risk.
      • Trevisan M.
      • de Deco P.
      • Xu H.
      • et al.
      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].
      ,
      • Rassi A.N.
      • Cavender M.A.
      • Fonarow G.C.
      • et al.
      Temporal trends and predictors in the use of aldosterone antagonists post-acute myocardial infarction.
      ,
      • Epstein M.
      • Reaven N.L.
      • Funk S.E.
      • McGaughey K.J.
      • Oestreicher N.
      • Knispel J.
      Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors.
      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.
      • Epstein M.
      • Reaven N.L.
      • Funk S.E.
      • McGaughey K.J.
      • Oestreicher N.
      • Knispel J.
      Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors.
      In one study, 74% of patients who discontinued mineralocorticoid receptor antagonists (MRAs) because of hyperkalemia did not reinitiate therapy during the subsequent year.
      • Trevisan M.
      • de Deco P.
      • Xu H.
      • et al.
      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].
      Many patients who have had acute MI are not prescribed MRAs at hospital discharge because of hyperkalemia risk.
      • Rassi A.N.
      • Cavender M.A.
      • Fonarow G.C.
      • et al.
      Temporal trends and predictors in the use of aldosterone antagonists post-acute myocardial infarction.
      Additionally, patients with HF are often prescribed subtherapeutic MRA doses despite guideline recommendations.
      • Savarese G.
      • Carrero J.-J.
      • Pitt B.
      • et al.
      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.
      Although hyperkalemia represents a significant barrier to effective use of RAASis,
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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.
      ,
      • De Nicola L.
      • Di Lullo L.
      • Paoletti E.
      • Cupisti A.
      • Bianchi S.
      Chronic hyperkalemia in non-dialysis CKD: controversial issues in nephrology practice.
      ,
      • Tamargo J.
      • Caballero R.
      • Delpón E.
      New therapeutic approaches for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors.
      RAASi therapy is associated with improved survival in patients with HF, particularly in those at risk for hyperkalemia.
      • Beusekamp J.C.
      • Tromp J.
      • van der Wal H.H.
      • et al.
      Potassium and the use of renin-angiotensin-aldosterone system inhibitors in heart failure with reduced ejection fraction: data from BIOSTAT-CHF.
      ,
      • Rossignol P.
      • Dobre D.
      • McMurray J.J.V.
      • et al.
      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.
      • Qiao Y.
      • Shin J.-I.
      • Chen T.K.
      • et al.
      Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate.
      • Epstein M.
      • Alvarez P.J.
      • Reaven N.L.
      • et al.
      Evaluation of clinical outcomes and costs based on prescribed dose level of renin-angiotensin-aldosterone system inhibitors.
      • Rossignol P.
      • Lainscak M.
      • Crespo-Leiro M.G.
      • et al.
      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.
      • Qiao Y.
      • Shin J.-I.
      • Chen T.K.
      • et al.
      Association between renin-angiotensin system blockade discontinuation and all-cause mortality among persons with low estimated glomerular filtration rate.
      In addition, a recent consensus report
      • Seferovic P.M.
      • Ponikowski P.
      • Anker S.D.
      • et al.
      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.
      and a position paper
      • Butler J.
      • Khan M.S.
      • Anker S.D.
      Novel potassium binders as enabling therapy in heart failure.
      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 thumbnail gr3
      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.

      Classification of Hyperkalemia

      Although the precise K+ concentration thresholds for mild, moderate, and severe hyperkalemia vary among current guidelines,
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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.
      ,
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      Canadian Cardiovascular Society Heart Failure Guidelines Panels
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      National Kidney Foundation
      Best practices in managing hyperkalemia in chronic kidney disease. National Kidney Foundation website.
      UK Renal Association
      Clinical practice guidelines: treatment of acute hyperkalaemia in adults.
      a serum K+ level of 5.5 mEq/L or greater is widely accepted as the threshold for hyperkalemia.
      UK Renal Association
      Clinical practice guidelines: treatment of acute hyperkalaemia in adults.
      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,
      • Krogager M.L.
      • Eggers-Kaas L.
      • Aasbjerg K.
      • et al.
      Short-term mortality risk of serum potassium levels in acute heart failure following myocardial infarction.
      ,
      • Aldahl M.
      • Jensen A.-S.C.
      • Davidsen L.
      • et al.
      Associations of serum potassium levels with mortality in chronic heart failure patients.
      hypertension,
      • Krogager M.L.
      • Torp-Pedersen C.
      • Mortensen R.N.
      • et al.
      Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data.
      or CKD.
      • Gasparini A.
      • Evans M.
      • Barany P.
      • et al.
      Plasma potassium ranges associated with mortality across stages of chronic kidney disease: the Stockholm CREAtinine Measurements (SCREAM) project.
      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,
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
      which is caused by the release of K+ from platelets during coagulation.
      • Ranjitkar P.
      • Greene D.N.
      • Baird G.S.
      • Hoofnagle A.N.
      • Mathias P.C.
      Establishing evidence-based thresholds and laboratory practices to reduce inappropriate treatment of pseudohyperkalemia.
      The methods used for K+ determination are not standardized, with wide variations in reference ranges.
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      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
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      Potassium homeostasis in health and disease: a scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension.
      ,
      • Palmer B.F.
      • Clegg D.J.
      Physiology and pathophysiology of potassium homeostasis: core curriculum 2019.
      ,
      • Don B.R.
      • Sebastian A.
      • Cheitlin M.
      • Christiansen M.
      • Schambelan M.
      Pseudohyperkalemia caused by fist clenching during phlebotomy.
      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.
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      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.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      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.
      ,
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      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.
      For example, the 2012 KDIGO guidelines advocate serum K+ measurement within 1 week of starting or dose escalation of RAASis in patients with CKD.
      Kidney Disease: Improving Global Outcomes Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      Repetitive consecutive measurements facilitate determination of whether hyperkalemia is a chronic or transient event
      National Kidney Foundation
      Best practices in managing hyperkalemia in chronic kidney disease. National Kidney Foundation website.
      ; however, there is no consensus on the number of tests required to document chronic hyperkalemia risk.
      • De Nicola L.
      • Di Lullo L.
      • Paoletti E.
      • Cupisti A.
      • Bianchi S.
      Chronic hyperkalemia in non-dialysis CKD: controversial issues in nephrology practice.
      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.
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      Canadian Cardiovascular Society Heart Failure Guidelines Panels
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      ,
      • Clase C.M.
      • Carrero J.-J.
      • Ellison D.H.
      • et al.
      Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
      The most commonly observed changes in ECG are peaked T waves and prolonged QRS complexes.
      • Clase C.M.
      • Carrero J.-J.
      • Ellison D.H.
      • et al.
      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,
      • Peacock W.F.
      • Rafique Z.
      • Clark C.L.
      • et al.
      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
      • Galloway C.D.
      • Valys A.V.
      • Shreibati J.B.
      • et al.
      Development and validation of a deep-learning model to screen for hyperkalemia from the electrocardiogram.
      ; 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.
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
      ,
      National Kidney Foundation
      Best practices in managing hyperkalemia in chronic kidney disease. National Kidney Foundation website.
      ,
      • Kovesdy C.P.
      • Appel L.J.
      • Grams M.E.
      • et al.
      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.
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
      ,
      • Kovesdy C.P.
      Management of hyperkalaemia in chronic kidney disease.
      If no effect is observed within 5 to 10 minutes, another dose of calcium gluconate may be given.
      • Lindner G.
      • Burdmann E.A.
      • Clase C.M.
      • et al.
      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.
      • Kovesdy C.P.
      Management of hyperkalaemia in chronic kidney disease.
      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,
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      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.
      • Palmer B.F.
      • Clegg D.J.
      Diagnosis and treatment of hyperkalemia.
      Dialysis increases K+ elimination from the body and may be used as an adjunctive therapy in acute hyperkalemia after instituting other approaches.
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      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.
      • Peacock W.F.
      • Rafique Z.
      • Clark C.L.
      • et al.
      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,
      • Peacock W.F.
      • Rafique Z.
      • Clark C.L.
      • et al.
      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,
      • Clase C.M.
      • Carrero J.-J.
      • Ellison D.H.
      • et al.
      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.
      • Clase C.M.
      • Carrero J.-J.
      • Ellison D.H.
      • et al.
      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).
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
      ,
      • Palmer B.F.
      Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system.
      ,
      • Clase C.M.
      • Carrero J.-J.
      • Ellison D.H.
      • et al.
      Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disese: Improving Global Outcomes (KDIGO) Controversies Conference.
      Diuretics promote urinary excretion of K+ in patients with CKD or DKD by stimulating the flow and delivery of K+ to the renal collecting ducts.
      • Palmer B.F.
      • Clegg D.J.
      Diagnosis and treatment of hyperkalemia.
      Fludrocortisone can also increase K+ excretion but is associated with an increased risk of fluid retention, hypertension, and vascular injury.
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
      ,
      • Pochineni V.
      • Rondon-Berrios H.
      Electrolyte and acid-base disorders in the renal transplant recipient.
      These long-term treatment options have limitations.
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      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).
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      Canadian Cardiovascular Society Heart Failure Guidelines Panels
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      ,
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      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
      ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; GFR = glomerular filtration rate; HK= hyperkalemia; K+ = potassium; MRA = mineralocorticoid receptor antagonist; NS = not specified; RAASi = renin-angiotensin-aldosterone system inhibitor.
      SocietySerum K+ (mEq/L)Recommendations for RAASi therapy
      American College of Cardiology/American Heart Association/ Heart Failure Society of America
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      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.
      >5.0Use ACEis and ARBs with caution

      MRAs are not recommended
      Canadian Cardiovascular Society
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      Canadian Cardiovascular Society Heart Failure Guidelines Panels
      The Canadian Cardiovascular Society heart failure companion: bridging guidelines to your practice.
      Mild HK (K+ 5.0-5.5)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) HKReinitiate 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
      European Society of Cardiology
      • Rosano G.M.C.
      • Tamargo J.
      • Kjeldsen K.P.
      • et al.
      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.
      4.5-5.0
      Serum or plasma K+.
      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 ≤6.5If 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
      >6.5Discontinue 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
      Kidney Disease: Improving Global Outcomes Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      NSAssess GFR and measure serum K+ within 1 week of starting RAASi or following any dose escalation
      National Institute for Health and Care Excellence
      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.
      >5.0Do not initiate RAASi therapy in patients with CKD
      ≥6.0Discontinue RAASi therapy once other drugs known to increase the risk of hyperkalemia have been stopped
      a ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; GFR = glomerular filtration rate; HK= hyperkalemia; K+ = potassium; MRA = mineralocorticoid receptor antagonist; NS = not specified; RAASi = renin-angiotensin-aldosterone system inhibitor.
      b Serum or plasma K+.

      Potassium Binders

      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.
      Until recently, SPS (Kayexalate)
      ,
      • Beccari M.V.
      • Meaney C.J.
      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)
      and sodium zirconium cyclosilicate (SZC; Lokelma [formerly ZS-9]),
      are now approved in the United States and the European Union. The characteristics of these 3 K+-binding agents are summarized in Table 2.
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      ,
      • De Nicola L.
      • Di Lullo L.
      • Paoletti E.
      • Cupisti A.
      • Bianchi S.
      Chronic hyperkalemia in non-dialysis CKD: controversial issues in nephrology practice.
      ,
      • Tamargo J.
      • Caballero R.
      • Delpón E.
      New therapeutic approaches for the treatment of hyperkalemia in patients treated with renin-angiotensin-aldosterone system inhibitors.
      ,
      • Beccari M.V.
      • Meaney C.J.
      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].
      • Georgianos P.I.
      • Agarwal R.
      Revisiting RAAS blockade in CKD with newer potassium-binding drugs.
      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).
      • Lepage L.
      • Dufour A.-C.
      • Doiron J.
      • et al.
      Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD.
      • Rafique Z.
      • Liu M.
      • Staggers K.A.
      • Minard C.G.
      • Peacock W.F.
      Patiromer for treatment of hyperkalemia in the emergency department: a pilot study.
      • Pitt B.
      • Anker S.D.
      • Bushinsky D.A.
      • Kitzman D.W.
      • Zannad F.
      • Huang I.-Z.
      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.
      • Bakris G.L.
      • Pitt B.
      • Weir M.R.
      • 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 [published correction appears in JAMA. 2015;314(7):731].
      • Agarwal R.
      • Rossignol P.
      • Romero A.
      • et al.
      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.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      OPAL-HK Investigators
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      • Peacock W.F.
      • Rafique Z.
      • Vishnevskiy K.
      • et al.
      Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      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].
      • Roger S.D.
      • Spinowitz B.S.
      • Lerma E.V.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for treatment of hyperkalemia: an 11-month open-label extension of HARMONIZE.
      • Zannad F.
      • Hsu B.-G.
      • Maeda Y.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate in individuals with hyperkalemia: a 12-month phase 3 study.
      • 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.
      The newer K+-binding agents are also more palatable than SPS, facilitating adherence and efficacy and potentially leading to improved outcomes.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      ,
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      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].
      ,
      • Zannad F.
      • Hsu B.-G.
      • Maeda Y.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study.
      ,
      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.
      ,
      National Institute for Health and Care Excellence
      Patiromer for treating hyperkalaemia. National Institute for Health and Care Excellence website.
      Table 2Selected Characteristics of K+-Binding Agents for Hyperkalemia
      CharacteristicSPSPatiromerSZC
      Approval date1958US, 2015; EU, 2017US, 2018; EU, 2018
      Mechanism of actionK+ binding in exchange for Na+ in GI tract (↑ fecal excretion)K+ binding in exchange for Ca2+ in GI tract (↑ fecal excretion)K+ binding in exchange for H+ and Na+ in GI tract (↑ fecal excretion)
      Site of actionColonColonSmall and large intestines
      Selectivity for K+Nonselective; also binds Ca2+ and Mg2+Nonselective; also binds Na+ and Mg2+Highly selective; also binds NH4+
      Onset of actionVariable; several hours7 h1 h
      Na+ content1500 mg per 15-mg doseNone400 mg per 5-g dose
      Ca2+ contentNone1.6 g per 8.4-g doseNone
      Sorbitol content20,000 mg per 15-g dose4000 mg per 8.4-g doseNo sorbitol content
      Dosing15 g 1-4 times (oral); 30-50 g 1-2 times (rectal)8.4 g QD (oral), titrate up to 16.8 g or 25.2 g QD10 g TID (oral) for initial correction of hyperkalemia (for ≤48 h), then 5 g QOD to 15 g QD for maintenance
      Serious AEsCases of fatal GI injury reportedNone reportedNone reported
      Most common AEsGI disorders (constipation, diarrhea, nausea, vomiting, gastric irritation), hypomagnesemia, hypokalemia, hypocalcemia, systemic alkalosisGI disorders (abdominal discomfort, constipation, diarrhea, nausea, flatulence), hypomagnesemiaGI disorders (constipation, diarrhea, nausea, vomiting), mild to moderate edema
      AE = adverse event; Ca2+ = calcium; EU = European Union; GI = gastrointestinal; H+ = hydrogen ion; K+ = potassium; Mg2+ = magnesium; Na+ = sodium; NH4+ = ammonium; QD = once daily; QOD = every other day; SPS = sodium polystyrene sulfonate; SZC = sodium zirconium cyclosilicate; TID = three times daily; US = United States; ↑ = increased.
      Data from references 12, 59, 60, and 79 to 81.
      Table 3Summary of Key Clinical Studies of K+-Binding Agents
      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.
      Study name; design (duration)Patient populationStudy treatmentPrimary efficacy outcomes
      SPS
       Phase 4, randomized, double-blind, placebo-controlled (7 d)
      • Lepage L.
      • Dufour A.-C.
      • Doiron J.
      • et al.
      Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD.
      Outpatients with CKD and mild hyperkalemia (K+ 5.0-5.9 mEq/L); N=33SPS 30 g or placebo QD
      • Mean change in serum K+:
        • −1.25 mEq/L with SPS
        • −0.21 mEq/L with placebo
      • Mean difference (95% CI) vs placebo:
        • −1.04 mEq/L (−1.37 to 0.71 mEq/L); P<.001
      Patiromer
       Phase 4, randomized, open-label, single-blind (10 h)
      • Rafique Z.
      • Liu M.
      • Staggers K.A.
      • Minard C.G.
      • Peacock W.F.
      Patiromer for treatment of hyperkalemia in the emergency department: a pilot study.
      Emergency department patients with ESRD and serum K+ ≥6.0 mEq/L; N=43Single dose of patiromer 25.2 g + SOC or SOC alone
      • Adjusted mean serum K+ at 6 h:
        • 5.81 mEq/L with patiromer + SOC
        • 6.32 mEq/L with SOC alone; P=.155 vs SOC alone
      • Adjusted mean serum K+ at 2 h:
        • 5.90 mEq/L with patiromer + SOC
        • 6.51 mEq/L with SOC alone; P=.009 vs SOC alone
       PEARL-HF; phase 2, randomized, double-blind, placebo-controlled (28 d)
      • Pitt B.
      • Anker S.D.
      • Bushinsky D.A.
      • Kitzman D.W.
      • Zannad F.
      • Huang I.-Z.
      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.
      Patients with chronic HF with (1) history of hyperkalemia leading to RAASi and/or β-blocker withdrawal or (2) CKD; N=105Patiromer 15 g or placebo BID (+ spironolactone 25 mg/d
      Spironolactone dosage increased to 50 mg/d after 2 weeks in patients with serum K+ >3.5 to ≤5.1 mEq/L.
      )
      • LS mean change in serum K+:
        • −0.22 mEq/L with patiromer
        • +0.23 mEq/L with placebo
      • LS mean difference vs placebo:
        • −0.45 mEq/L; P<.001
       AMETHYST-DN; phase 2, randomized, open-label (28 d)
      • Bakris G.L.
      • Pitt B.
      • Weir M.R.
      • 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 [published correction appears in JAMA. 2015;314(7):731].
      Outpatients with DKD and mild (K+ 5.0-5.5 mEq/L) or moderate (K+ 5.5-6.0 mEq/L) hyperkalemia; N=306Mild hyperkalemia: patiromer 4.2, 8.4, or 12.6 g BID
      Patiromer was titrated to achieve and maintain serum K+ ≤5.0 mEq/L.
      • Mild hyperkalemia:
        • LS mean change in serum K+:
          • −0.35 mEq/L with patiromer 4.2 g
          • −0.51 mEq/L with patiromer 8.4 g
          • −0.55 mEq/L with patiromer 12.6 g
      Moderate hyperkalemia: patiromer 8.4, 12.6, or 16.8 g BID
      Patiromer was titrated to achieve and maintain serum K+ ≤5.0 mEq/L.
      • Moderate hyperkalemia:
        • LS mean change in serum K+:
          • −0.87 mEq/L with patiromer 8.4 g
          • −0.97 mEq/L with patiromer 12.6 g
          • −0.92 mEq/L with patiromer 16.8 g
       AMBER; phase 2, randomized, double-blind, placebo-controlled (12 wk)
      • Agarwal R.
      • Rossignol P.
      • Romero A.
      • et al.
      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.
      Patients with CKD, K+ 4.3-5.1 mEq/L, and resistant hypertension; N=295Patiromer 8.4 g or placebo QD (+ open-label spironolactone 25 mg/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.
      )
      • Patients remaining on spironolactone:
        • 86% with patiromer
        • 66% with placebo
      • Difference vs placebo:
        • 19.5%; P<.0001
      • More patients in placebo vs patiromer with serum K+ ≥5.5 mEq/L:
        • P<.001
       OPAL-HK; phase 3, 2 stages: (1) treatment, single-group, single-blind (4 wk) and (2) with-drawal, randomized, single-blind, placebo-controlled (8 wk)
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      OPAL-HK Investigators
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      Patients with CKD on RAASi therapy with mild (K+ 5.1-5.5 mEq/L) or moderate to severe (K+ 5.5-6.5 mEq/L) hyperkalemia; N=237Treatment stage: patiromer 4.2 g (mild hyper-kalemia) or 8.4 g (moderate to severe hyper-kalemia) BID
      • Treatment stage:
        • Mean change in serum K+ at wk 4:
          • Overall: −1.01 mEq/L (P<.001 vs baseline)
        • Mild hyperkalemia: −0.65 mEq/L
        • Moderate to severe hyperkalemia: −1.23 mEq/L
      Withdrawal stage: patiromer (at same dosage) or placebo (K+ 3.8-5.1 mEq/L)
      • Withdrawal stage:
        • Median change in K+ to wk 4:
          • 0 mEq/L with patiromer
          • +0.72 mEq/L with placebo
          • P<.001 vs placebo
      SZC
       ENERGIZE; phase 2, randomized, double-blind, placebo-controlled (24 h)
      • Peacock W.F.
      • Rafique Z.
      • Vishnevskiy K.
      • et al.
      Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
      Emergency department patients with serum K+ ≥5.8 mEq/L; N=70SZC 10 g (≤3 doses in 10 h) or placebo (+ insulin + glucose)
      • LS mean change in serum K+ at 4 h:
        • −0.41 mEq/L with SZC
        • −0.27 mEq/L with placebo
      • LS mean difference vs placebo:
        • −0.13 mEq/L (95% CI −0.44 to 0.17 mEq/L)
       Phase 3, 2-stage, randomized, double-blind, placebo-controlled (14 d)
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      Patients with hyperkalemia (K+ 5.0-6.5 mEq/L); N=754Correction phase:

      SZC 1.25, 2.5, 5, or 10 g or placebo TID for 48 h
      • Correction phase:
        • Exponential rate of change in mean serum K+ at 48 h:
          • −0.11% with SZC 1.25 g
          • −0.16% with SZC 2.5 g
          • −0.21% with SZC 5 g
          • −0.30% with SZC 10 g
          • −0.09% with placebo
          • P<.001 vs placebo for 3 highest doses
      Maintenance phase:

      SZC (same dose) or placebo QD (K+ 3.5-4.9 mEq/L) for 14 d
      • Maintenance phase:
        • Exponential rate of change in mean serum K+:
          • +0.14% per hour with SZC 10 g +1.04% per hour with placebo
          • P<.001
          • +0.09% per hour with SZC 5 g +0.47% per hour with placebo
          • P=.008
       HARMONIZE; phase 3, 2-stage, randomized, double-blind, placebo-controlled (28 d)
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      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].
      Outpatients with hyper-kalemia (K+ ≥5.1 mEq/L); N=258Initial phase (open-label):

      SZC 10 g TID for 48 h
      • Initial phase (open-label):
        • Mean change in serum K+ over 48 h:
          • −1.1 mEq/L; P<.001 vs baseline
      Maintenance phase (double-blind):

      SZC 5, 10, or 15 g or placebo QD for 28 d (K+ 3.5-5.0 mEq/L)
      • Maintenance phase (double-blind):
        • Mean serum K+ during days 8-29:
          • 4.8 mEq/L with SZC 5 g QD
          • 4.5 mEq/L with SZC 10 g QD
          • 4.4 mEq/L with SZC 15 g QD
          • 5.1 mEq/L with placebo
          • P<.001 vs placebo for each dose
       HARMONIZE-OLE; phase 3, open-label (11 mo)
      • Roger S.D.
      • Spinowitz B.S.
      • Lerma E.V.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for treatment of hyperkalemia: an 11-month open-label extension of HARMONIZE.
      Patients from HARMONIZE with K+ 3.5-6.2 mEq/L; N=123SZC 10 g QD, titrated in 5-g amounts to maintain K+ 3.5-5.0 mEq/L (min, 5 g QD; max, 15 g QD)93% of patients achieved mean serum K+ ≤5.1 mEq/L across days 8-337
       HARMONIZE-Global; phase 3, randomized, double-blind, placebo-controlled (28 d)
      • Zannad F.
      • Hsu B.-G.
      • Maeda Y.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study.
      Outpatients with hyperkalemia (K+ ≥5.1 mEq/L); N=267Correction phase (open-label):

      SZC 10 g TID for 48 h
      • Correction phase (open-label):
        • Mean change in serum K+ over 48 h:
          • −1.28 mEq/L; P<.001 vs baseline
      Maintenance phase (double-blind):

      SZC 5 or 10 g or placebo QD for 28 d (K+ 3.5-5.0 mEq/L)
      • Maintenance phase (double-blind):
        • Mean serum K+ during days 8-29:
          • 4.8 mEq/L with SZC 5 g QD
          • 4.4 mEq/L with SZC 10 g QD
          • 5.3 mEq/L with placebo
          • P<.001 vs placebo for each dose
       ZS-005; phase 3, 2-stage, open-label (12 mo)
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate in individuals with hyperkalemia: a 12-month phase 3 study.
      Outpatients with hyperkalemia (K+ ≥5.1 mEq/L); N=751Correction phase:

      SZC 10 g TID for 24-72 h
      • Correction phase:
        • 78% of patients had serum K+ 3.5-5.0 mEq/L at 72 h
      Maintenance phase:

      SZC 5 g QD
      SZC was titrated to maintain serum K+ 3.5-5.0 mEq/L.
      • Maintenance phase:
        • 88% of patients had serum K+ <5.1 mEq/L over 3-12 mo
       DIALIZE; phase 3b, randomized, double-blind, placebo-controlled (4 wk)
      • 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.
      Patients with ESRD on hemodialysis with 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.
      • Bounthavong M.
      • Butler J.
      • Dolan C.M.
      • et al.
      Cost-effectiveness analysis of patiromer and spironolactone therapy in heart failure patients with hyperkalemia [published correction appears in Pharmacoeconomics. 2019;37(8):1071].

      Sodium Polystyrene Sulfonate

      Sodium polystyrene sulfonate is a polymeric cation-exchange resin that binds K+ ions in exchange for sodium ions in the distal colon.
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      ,
      It is nonselective for K+, with affinity for calcium and magnesium ions. Sodium polystyrene sulfonate may be administered either orally or rectally,
      although the oral suspension has poor palatability.
      • Zann V.
      • McDermott J.
      • Jacobs J.W.
      • et al.
      Palatability and physical properties of potassium-binding resin RDX7675: comparison with sodium polystyrene sulfonate.
      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).
      • Lepage L.
      • Dufour A.-C.
      • Doiron J.
      • et al.
      Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD.
      Its short-term efficacy is also inconsistent,
      • Rafique Z.
      • Weir M.R.
      • Onuigbo M.
      • et al.
      Expert panel recommendations for the identification and management of hyperkalemia and role of patiromer in patients with chronic kidney disease and heart failure.
      and the onset of action is variable (hours to days).
      Its use varies widely among countries, ranging from 42% of patients in France to less than 1% in the United Kingdom, Spain, and Japan.
      • Jadoul M.
      • Karaboyas A.
      • Goodkin D.A.
      • et al.
      Potassium-binding resins: associations with serum chemistries and interdialytic weight gain in hemodialysis patients.
      Sodium polystyrene sulfonate has been associated with adverse events (AEs), including intestinal ischemia and colonic necrosis,
      • Parks M.
      • Grady D.
      Sodium polystyrene sulfonate for hyperkalemia [published online ahead of print June 10, 2019].
      ,
      • Laureati P.
      • Xu Y.
      • Trevisan M.
      • et al.
      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].
      a doubling in the risk of hospitalization for serious gastrointestinal AEs,
      • Noel J.A.
      • Bota S.E.
      • Petrcich W.
      • et al.
      Risk of hospitalization for serious adverse gastrointestinal events associated with sodium polystyrene sulfonate use in patients of advanced age.
      and a reported overall mortality rate of 33% for patients with serious gastrointestinal injury.
      • Harel Z.
      • Harel S.
      • Shah P.S.
      • Wald R.
      • Perl J.
      • Bell C.M.
      Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review.
      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).
      • Laureati P.
      • Xu Y.
      • Trevisan M.
      • et al.
      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].
      ,
      • Noel J.A.
      • Bota S.E.
      • Petrcich W.
      • et al.
      Risk of hospitalization for serious adverse gastrointestinal events associated with sodium polystyrene sulfonate use in patients of advanced age.
      Because of its potential to cause constipation, SPS was often previously coadministered with the laxative sorbitol.
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      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).
      US Food and Drug Administration
      Kayexalate (sodium polystyrene sulfonate, USP) powder approval letter (2009). US Food and Drug Administration website.
      Coadministration of SPS with sorbitol is currently not recommended,
      although gastrointestinal injury has been reported in patients receiving SPS without sorbitol.
      • Laureati P.
      • Xu Y.
      • Trevisan M.
      • et al.
      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].
      • Noel J.A.
      • Bota S.E.
      • Petrcich W.
      • et al.
      Risk of hospitalization for serious adverse gastrointestinal events associated with sodium polystyrene sulfonate use in patients of advanced age.
      • Harel Z.
      • Harel S.
      • Shah P.S.
      • Wald R.
      • Perl J.
      • Bell C.M.
      Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review.
      The nonselective binding properties of SPS may also lead to hypocalcemia and hypomagnesemia,
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      and because orally administered SPS potentially binds to other oral medications, their administration should be separated by 3 or more hours.
      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.
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      ,

      Patiromer Sorbitex Calcium

      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.
      • Rafique Z.
      • Liu M.
      • Staggers K.A.
      • Minard C.G.
      • Peacock W.F.
      Patiromer for treatment of hyperkalemia in the emergency department: a pilot study.
      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
      • Pitt B.
      • Anker S.D.
      • Bushinsky D.A.
      • Kitzman D.W.
      • Zannad F.
      • Huang I.-Z.
      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.
      ,
      • Bakris G.L.
      • Pitt B.
      • Weir M.R.
      • 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 [published correction appears in JAMA. 2015;314(7):731].
      ,
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      OPAL-HK Investigators
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      and effectively maintained normokalemia (K+ levels of 3.8 to 5.1 mEq/L) for a further 4 weeks.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      OPAL-HK Investigators
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      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.
      • Agarwal R.
      • Rossignol P.
      • Romero A.
      • et al.
      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.
      • Pitt B.
      • Bakris G.L.
      • Weir M.R.
      • 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.
      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.
      • Kovesdy C.P.
      • Rowan C.G.
      • Conrad A.
      • et al.
      Real-world evaluation of patiromer for the treatment of hyperkalemia in hemodialysis patients.
      Oral patiromer contains a calcium-sorbitol counterion that exchanges calcium for K+ as it passes through the colon.
      Similar to SPS, patiromer is a polymer that is nonselective for K+ and may also bind magnesium and small amounts of sodium.
      ,
      • Epstein M.
      • Pitt B.
      Recent advances in pharmacological treatments of hyperkalemia: focus on patiromer.
      The time to onset of action with patiromer is approximately 7 hours.
      • Bushinsky D.A.
      • Williams G.H.
      • Pitt B.
      • et al.
      Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia.
      Patiromer administration should also be separated from other oral medications by 3 or more hours because of the potential for binding with patiromer.
      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).
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      ,
      ,
      • Georgianos P.I.
      • Agarwal R.
      Revisiting RAAS blockade in CKD with newer potassium-binding drugs.
      Because patiromer exchanges calcium for K+ in the colon, theoretically it may also increase the risk of hypercalcemia.
      • Chaitman M.
      • Dixit D.
      • Bridgeman M.B.
      Potassium-binding agents for the clinical management of hyperkalemia.
      Although rare, cases of patiromer-induced hypercalcemia have been reported,
      • Bhattarai S.
      • Pupillo S.
      • Man Singh Dangol G.
      • Sarac E.
      Patiromer acetate induced hypercalcemia: an unreported adverse effect.
      ,
      • Wiederkehr M.R.
      • Mehta A.N.
      • Emmett M.
      Case report: patiromer-induced hypercalcemia.
      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).
      • Peacock W.F.
      • Rafique Z.
      • Vishnevskiy K.
      • et al.
      Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      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].
      • Roger S.D.
      • Spinowitz B.S.
      • Lerma E.V.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for treatment of hyperkalemia: an 11-month open-label extension of HARMONIZE.
      • Zannad F.
      • Hsu B.-G.
      • Maeda Y.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate in individuals with hyperkalemia: a 12-month phase 3 study.
      • 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.
      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.
      • Peacock W.F.
      • Rafique Z.
      • Vishnevskiy K.
      • et al.
      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.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      ,
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      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].
      ,
      • Zannad F.
      • Hsu B.-G.
      • Maeda Y.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study.
      Significant reductions in serum K+ levels were observed within 1 hour of a single SZC 10-g dose in the overall patient populations
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      ,
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      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].
      ,
      • Zannad F.
      • Hsu B.-G.
      • Maeda Y.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study.
      and in those with severe hyperkalemia (≥6.0 mEq/L).
      • Kosiborod M.
      • Peacock W.F.
      • Packham D.K.
      Sodium zirconium cyclosilicate for urgent therapy of severe hyperkalemia [letter].
      The efficacy and safety of SZC over 12 months have also been documented.
      • Roger S.D.
      • Spinowitz B.S.
      • Lerma E.V.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate for treatment of hyperkalemia: an 11-month open-label extension of HARMONIZE.
      ,
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate in individuals with hyperkalemia: a 12-month phase 3 study.
      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.
      • 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.
      Sustained increases in serum bicarbonate have been observed with SZC,
      • de Francisco A.
      • Rasmussen H.
      • Lavin P.
      • et al.
      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.
      Sodium zirconium cyclosilicate binds monovalent cations (K+) as opposed to divalent cations (eg, calcium and magnesium).
      • Stavros F.
      • Yang A.
      • Leon A.
      • Nuttall M.
      • Rasmussen H.S.
      Characterization of structure and function of ZS-9, a K+ selective ion trap.
      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.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      ,
      • Kosiborod M.
      • Rasmussen H.S.
      • Lavin P.
      • et al.
      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].
      ,
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate in individuals with hyperkalemia: a 12-month phase 3 study.
      Because SZC was only recently launched in US and other markets, postmarketing safety data are currently very limited.

      Hyperkalemia Education

      The National Kidney Foundation recommends improvements in patient awareness of hyperkalemia.
      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.

      Supplemental Online Material

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