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Potassium Binders for Hyperkalemia in Chronic Kidney Disease—Diet, Renin-Angiotensin-Aldosterone System Inhibitor Therapy, and Hemodialysis

  • Biff F. Palmer
    Correspondence
    Correspondence: Address to Biff F. Palmer, MD, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390.
    Affiliations
    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
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Open AccessPublished:October 23, 2019DOI:https://doi.org/10.1016/j.mayocp.2019.05.019

      Abstract

      Hyperkalemia is a potentially life-threatening complication of chronic kidney disease (CKD). The management of CKD requires balancing the benefits of specific treatments, which may exacerbate the potential for hyperkalemia, with the risks of hyperkalemia itself. Renin-angiotensin-aldosterone system (RAAS) inhibitors, which slow CKD progression and improve cardiovascular outcomes, are often discontinued if hyperkalemia develops. Patients with hyperkalemia are frequently advised to restrict dietary potassium (K+), depriving these patients of many heart-healthy foods. Patients receiving hemodialysis are particularly susceptible to hyperkalemia during long interdialytic intervals, and managing this risk without causing hypokalemia can be challenging. Recently, 2 K+-binding agents were approved for the treatment of hyperkalemia: sodium zirconium cyclosilicate and patiromer. These agents offer alternatives to sodium polystyrene sulfonate, which is associated with serious gastrointestinal adverse effects. For this review, PubMed was searched for English-language articles published in 2014-2018 using the terms patiromer, sodium zirconium cyclosilicate, sodium polystyrene sulfonate, hyperkalemia, renin-angiotensin-aldosterone, diet, and dialysis. In randomized controlled studies of patients with hyperkalemia, sodium zirconium cyclosilicate and patiromer effectively reduced serum K+ and were generally well tolerated. Furthermore, patients in these studies could maintain RAAS inhibitor therapy and, in some studies, were not required to limit dietary K+. There may also be a role for these agents in preventing hyperkalemia in patients receiving hemodialysis. Thus, K+-binding agents may allow patients with CKD at risk for hyperkalemia to optimize RAAS inhibitor therapy, receive benefits of a K+-rich diet, and experience improved hemodialysis outcomes. Additional long-term studies are necessary to confirm these effects.

      Abbreviations and Acronyms:

      CKD (chronic kidney disease), CV (cardiovascular), EF (ejection fraction), FDA (Food and Drug Administration), HF (heart failure), K+ (potassium), MRA (mineralocorticoid receptor antagonist), NYHA (New York Heart Association), RAAS (renin-angiotensin-aldosterone system), RCT (randomized controlled trial), SPS (sodium polystyrene sulfonate), SZC (sodium zirconium cyclosilicate)
      Article Highlights
      • Hyperkalemia (serum potassium [K+] >5.0 or >5.5 mEq/L) is a potentially life-threatening complication of chronic kidney disease (CKD). Risk factors for hyperkalemia in patients with CKD include use of drugs that inhibit the renin-angiotensin-aldosterone system (RAAS); advanced renal impairment; comorbidities such as diabetes, hypertension, and heart failure; and consumption of a K+-enriched diet.
      • Management of hyperkalemia in patients with CKD can be challenging because specific CKD treatments may exacerbate the potential for hyperkalemia. The recent approval of 2 new K+-binding drugs (sodium zirconium cyclosilicate [formerly ZS-9] and patiromer) provides new options for managing hyperkalemia. These drugs have the potential to ease K+ dietary restrictions in CKD and attenuate the increase in K+ during the interdialytic period.
      • Potassium-binding drugs reduce serum K+ levels via ion exchange mechanisms in the gastrointestinal tract. Sodium zirconium cyclosilicate is a nonpolymer compound that exchanges K+ for sodium and hydrogen ions. In contrast, patiromer is a polymer that exchanges K+ for calcium ions.
      • Sodium zirconium cyclosilicate significantly lowers serum K+ concentrations 1 hour after administration in patients with hyperkalemia and has been found to maintain serum K+ in patients with CKD and those receiving RAAS inhibitors for up to 1 year. Sodium zirconium cyclosilicate is associated with dose-related mild to moderate edema that can be managed with dose reductions or with diuretic therapy.
      • Patiromer significantly reduces serum K+ concentrations and facilitates use of RAAS inhibitors in patients with CKD and/or heart failure who either have or are at risk of hyperkalemia. Gastrointestinal adverse effects (constipation, diarrhea, nausea, abdominal discomfort, and flatulence) are the most common adverse effects associated with patiromer.
      Chronic kidney disease (CKD) is a common condition, occurring in 10.4% to 13.4% of individuals worldwide.
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • et al.
      Global prevalence of chronic kidney disease - a systematic review and meta-analysis.
      • Mills K.T.
      • Xu Y.
      • Zhang W.
      • et al.
      A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010.
      Hyperkalemia, defined as an elevated serum potassium (K+) concentration (>5.0 or >5.5 mEq/L; to convert values to mmol/L, multiply by 1.0), is a potentially life-threatening complication of CKD
      • Palmer B.F.
      • Clegg D.J.
      Treatment of abnormalities of potassium homeostasis in CKD.
      that affects an estimated 14% to 20% of all patients with CKD
      • Gilligan S.
      • Raphael K.L.
      Hyperkalemia and hypokalemia in CKD: prevalence, risk factors, and clinical outcomes.
      ; recent evidence suggests that K+ fluctuation to either hyperkalemic or hypokalemic levels may be associated with increased mortality or poor cardiovascular (CV) outcomes.
      • Luo J.
      • Brunelli S.M.
      • Jensen D.E.
      • Yang A.
      Association between serum potassium and outcomes in patients with reduced kidney function.
      • Thomsen R.W.
      • Nicolaisen S.K.
      • Hasvold P.
      • et al.
      Elevated potassium levels in patients with chronic kidney disease: occurrence, risk factors and clinical outcomes—a Danish population-based cohort study.
      • 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 [published online ahead of print August 6, 2018].
      • Cheungpasitporn W.
      • Thongprayoon C.
      • Kittanamongkolchai W.
      • Sakhuja A.
      • Mao M.A.
      • Erickson S.B.
      Impact of admission serum potassium on mortality in patients with chronic kidney disease and cardiovascular disease.
      Use of renin-angiotensin-aldosterone system (RAAS) inhibitor therapy, a mainstay in the treatment of CKD, can lead to the development of hyperkalemia.
      • Chang A.R.
      • Sang Y.
      • Leddy J.
      • et al.
      Antihypertensive medications and the prevalence of hyperkalemia in a large health system.
      Kidney Disease: Improving Global Outcomes
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      • Xie X.
      • Liu Y.
      • Perkovic V.
      • et al.
      Renin-angiotensin system inhibitors and kidney and cardiovascular outcomes in patients with CKD: a Bayesian network meta-analysis of randomized clinical trials.
      • Hu J.R.
      • Coresh J.
      The public health dimension of chronic kidney disease: what we have learnt over the past decade.
      Other risk factors for hyperkalemia in patients with CKD include advanced renal impairment,
      • Gilligan S.
      • Raphael K.L.
      Hyperkalemia and hypokalemia in CKD: prevalence, risk factors, and clinical outcomes.
      comorbidities (eg, diabetes, hypertension, and heart failure [HF]), and a K+-enriched diet.
      • Palmer B.F.
      • Clegg D.J.
      Treatment of abnormalities of potassium homeostasis in CKD.
      • 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.
      • Einhorn L.M.
      • Zhan M.
      • Hsu V.D.
      • et al.
      The frequency of hyperkalemia and its significance in chronic kidney disease.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      The key risk predictors for hyperkalemia development in CKD are an estimated glomerular filtration rate of less than 45 mL/min per 1.73 m2 and a baseline serum K+ level of greater than 4.5 mEq/L prior to starting RAAS inhibitor therapy.
      • Lazich I.
      • Bakris G.L.
      Prediction and management of hyperkalemia across the spectrum of chronic kidney disease.
      Another condition associated with an increased risk of hyperkalemia is type 4 renal tubular acidosis, which often occurs in patients with diabetes and overt nephropathy and may lead to impaired urinary excretion of K+.
      • Palmer B.F.
      • Clegg D.J.
      Electrolyte and acid-base disturbances in patients with diabetes mellitus.
      Disturbances in K+ distribution caused by tissue injury, normal anion gap metabolic acidosis, and increased tonicity may also be present in some patients with hyperkalemia.
      • Palmer B.F.
      • Clegg D.J.
      Physiology and pathophysiology of potassium homeostasis.
      Hyperkalemia in patients with CKD can be managed by down-titrating or discontinuing RAAS inhibitor therapy or limiting dietary K+.
      • Chang A.R.
      • Sang Y.
      • Leddy J.
      • et al.
      Antihypertensive medications and the prevalence of hyperkalemia in a large health system.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      • Palmer B.F.
      • Clegg D.J.
      Achieving the benefits of a high-potassium, paleolithic diet, without the toxicity.
      These strategies are problematic because they deprive patients with CKD of therapies (Table 1)
      Kidney Disease: Improving Global Outcomes
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      • 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.
      American Diabetes Association
      10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2019.
      and nutrient-rich foods from which they could otherwise benefit.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      • Palmer B.F.
      • Clegg D.J.
      Achieving the benefits of a high-potassium, paleolithic diet, without the toxicity.
      Additionally, the relationship between dietary K+ and serum K+ is unclear, with studies finding only slight reductions in serum K+ as a result of limiting dietary K+.
      • Clegg D.J.
      • Hill Gallant K.M.
      Plant-based diets in CKD.
      • St-Jules D.E.
      • Goldfarb D.S.
      • Sevick M.A.
      Nutrient non-equivalence: does restricting high-potassium plant foods help to prevent hyperkalemia in hemodialysis patients.
      • Noori N.
      • Kalantar-Zadeh K.
      • Kovesdy C.P.
      • et al.
      Dietary potassium intake and mortality in long-term hemodialysis patients.
      Initial management of hyperkalemia may also include the use of loop diuretics, either alone or in combination with thiazide diuretics, which enhance urinary excretion of K+ by increasing flow and sodium delivery to the distal nephron.
      • Kovesdy C.P.
      Management of hyperkalaemia in chronic kidney disease.
      However, diuretic therapy is less effective in patients with advanced CKD or end-stage renal disease.
      • Kovesdy C.P.
      Management of hyperkalaemia in chronic kidney disease.
      In patients receiving hemodialysis, who are at a particularly high risk for hyperkalemia after a long interdialytic interval,
      • Georgianos P.I.
      • Sarafidis P.A.
      • Sinha A.D.
      • Agarwal R.
      Adverse effects of conventional thrice-weekly hemodialysis: is it time to avoid 3-day interdialytic intervals?.
      • Yusuf A.A.
      • Hu Y.
      • Singh B.
      • Menoyo J.A.
      • Wetmore J.B.
      Serum potassium levels and mortality in hemodialysis patients: a retrospective cohort study.
      hyperkalemia is associated with an increased risk of major CV events and mortality.
      • Luo J.
      • Brunelli S.M.
      • Jensen D.E.
      • Yang A.
      Association between serum potassium and outcomes in patients with reduced kidney function.
      • 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.
      • Yusuf A.A.
      • Hu Y.
      • Singh B.
      • Menoyo J.A.
      • Wetmore J.B.
      Serum potassium levels and mortality in hemodialysis patients: a retrospective cohort study.
      • Karaboyas A.
      • Zee J.
      • Brunelli S.M.
      • et al.
      Dialysate potassium, serum potassium, mortality, and arrhythmia events in hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS).
      • Nakhoul G.N.
      • Huang H.
      • Arrigain S.
      • et al.
      Serum potassium, end-stage renal disease and mortality in chronic kidney disease.
      Thus, minimizing the risk of development of hyperkalemia while also properly managing CKD can be challenging.
      Table 1Guideline Recommendations for RAAS Inhibitor Therapy for CKD and Common Comorbidities in Adults
      ACCF/AHA = American College of Cardiology Foundation/American Heart Association; ACEi = angiotensin-converting enzyme inhibitor; ACR = albumin to creatinine ratio; ADA = American Diabetes Association; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; CKD = chronic kidney disease; EF = ejection fraction; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; JNC = Joint National Committee; KDIGO = Kidney Disease: Improving Global Outcomes; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; RAAS = renin-angiotensin-aldosterone system; UAE = urinary albumin excretion.
      DiseaseRecommendationSource
      CKDARB or ACEi to prevent CKD progression in adults with or without diabetes mellitus who have CKD and UAE >300 mg/dKDIGO 2012 Clinical Practice Guidelines
      Kidney Disease: Improving Global Outcomes
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      ARB or ACEi to prevent CKD progression in adults with diabetes mellitus who have CKD and UAE 30-300 mg/d
      ACEi or ARB to improve kidney outcomes in patients with hypertension and CKDJNC 8 Guidelines
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      HFACEi or ARB to prevent symptomatic HF in patients with reduced EF and a history of MI, and ACEi in patients with reduced EF and no MIACCF/AHA 2013 Guidelines
      • 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.
      ACEi to reduce morbidity and mortality in patients with HFrEF (LVEF ≤40%), or an ARB in ACEi-intolerant patients
      In patients with chronic symptomatic HFrEF NYHA class II or III who are tolerant of an ACEi or ARB, replacement therapy with an ARNI is recommended to further reduce morbidity and mortality.21
      MRA to reduce morbidity and mortality in patients with NYHA class II-IV HF and LVEF ≤35%, and after acute MI in patients with LVEF ≤40% in whom symptoms of HF develop or who have a history of diabetes mellitus
      DiabetesACEi or ARB for first-line treatment of hypertension in patients with diabetes mellitus and urinary ACR ≥300 mg/g creatinine or 30-299 mg/g creatinine
      SI conversion factor: To convert ACR from mg/g creatinine to mg/mmol, multiply by 0.113.
      ADA 2019 Guidelines
      American Diabetes Association
      10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2019.
      a ACCF/AHA = American College of Cardiology Foundation/American Heart Association; ACEi = angiotensin-converting enzyme inhibitor; ACR = albumin to creatinine ratio; ADA = American Diabetes Association; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; CKD = chronic kidney disease; EF = ejection fraction; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; JNC = Joint National Committee; KDIGO = Kidney Disease: Improving Global Outcomes; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; RAAS = renin-angiotensin-aldosterone system; UAE = urinary albumin excretion.
      b In patients with chronic symptomatic HFrEF NYHA class II or III who are tolerant of an ACEi or ARB, replacement therapy with an ARNI is recommended to further reduce morbidity and mortality.
      • 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.
      c SI conversion factor: To convert ACR from mg/g creatinine to mg/mmol, multiply by 0.113.
      Until recently, the long-term pharmacological management of hyperkalemia has relied on sodium polystyrene sulfonate (SPS), a resin that exchanges K+ for sodium in the colon. However, SPS is poorly tolerated and can cause serious gastrointestinal adverse effects,
      • Palmer B.F.
      • Clegg D.J.
      Treatment of abnormalities of potassium homeostasis in CKD.
      • 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.
      which often lead to poor adherence. In a study of approximately 4500 patients initiating therapy with SPS, only 49.8% continued treatment for more than 7 days and less than 10% continued for more than 60 days.
      • Betts K.
      • Woolley J.M.
      • Chu L.
      • Mu F.
      • Tang W.
      • Wu E.
      Real-world treatment discontinuation of sodium polystyrene sulfonate.
      Recently, 2 new K+-binding drugs were approved by the US Food and Drug Administration (FDA) for the treatment of hyperkalemia: sodium zirconium cyclosilicate (SZC; formerly ZS-9), a nonpolymer compound that exchanges K+ for sodium and hydrogen ions in the gastrointestinal tract,
      • Hoy S.M.
      Sodium zirconium cyclosilicate: a review in hyperkalaemia.
      and patiromer, a polymer that exchanges K+ for calcium ions in the gastrointestinal tract
      • Epstein M.
      • Pitt B.
      Recent advances in pharmacological treatments of hyperkalemia: focus on patiromer.
      (Table 2).
      Both SZC and patiromer remove bound K+ via the feces. This article discusses evidence from clinically designed studies and data derived from actual (“real-world”) clinical practice patterns regarding the use of K+-binding agents, with a particular focus on the 3 challenging aspects of CKD management in patients with hyperkalemia: diet, RAAS inhibitor therapy, and hemodialysis.
      Table 2Available Potassium-Binding Agents to Treat Hyperkalemia
      VariableSodium zirconium cyclosilicate
      Patiromer
      Sodium polystyrene sulfonate
      Date of FDA approvalMay 2018October 2015June 1958
      Date of EMA approvalMarch 2018July 2017NA
      Chemical propertiesNonpolymer; nonabsorbed zirconium silicateCross-linked polymer; patiromer sorbitex calciumResin/polymer; sodium salt of polystyrene sulfonic acid
      Sodium content80 mg/gNone∼100 mg/g
      Mechanism of actionPreferentially captures K+ in exchange for hydrogen and sodiumExchanges calcium for K+; also binds magnesiumSodium-K+ exchange resin/polymer; nonspecifically binds K+, magnesium, and calcium
      Onset of action1 Hour7 HoursHours to days
      DoseInitial: 10 g TID for up to 48 hours

      Maintenance: 10 g QD (adjust dose at weekly intervals in 5-g increments to obtain the desired serum K+ range)

      Usual maintenance dose: 5 g QoD to 15 g QD
      Initial: 8.4 g QD; increase dose as necessary at ≥1-wk intervals in increments of 8.4 g15 g (4 level teaspoons) 1-4 times daily
      PreparationCombine powder with ≥45 mL (≥3 tablespoons) of water, stir well, and drink immediatelyCombine powder with 90 mL of water, stir thoroughly to form a cloudy mixture (powder will not dissolve), and drink immediatelyCombine with a small quantity of water, or for greater palatability, syrup; may also give by endogastric tube or as an enema
      AdministrationCan be taken with or without foodDo not heat or add to heated foods or liquidsOral suspension or enema
      Appearance and textureFree-flowing, odorless, insoluble white powder for oral suspensionOff-white to light brown powder composed of spherical beadsCream to light brown finely ground powder
      Storage15°-30°C (59°-86°F)Refrigerate at 2°-8°C (35°-46°F); if stored at room temperature, use within 3 mo (avoid exposure to temperatures >40°C)25°C (77°F; excursions to 15°-30°C permitted)
      Site of K+ bindingGI tractGI tractGI tract or colon when administered by enema
      Adverse effectsEdema (mild to moderate); hypokalemiaHypomagnesemia; hypokalemia; constipation, diarrhea, nausea, abdominal discomfort, flatulenceIntestinal necrosis; electrolyte disturbances (including hypokalemia); nausea, vomiting, constipation, diarrhea; fluid overload in patients sensitive to high sodium intake; risk of aspiration
      Drug interactionsOral medications that exhibit pH-dependent solubility should be administered ≥2 h before or 2 h afterTake other orally administered drugs ≥3 h before or 3 h afterTake other orally administered drugs ≥3 h before or 3 h after; cation-donating antacids may reduce potassium exchange and increase risk of systemic alkalosis; concomitant use of sorbitol may contribute to risk of intestinal necrosis and is not recommended
      EMA = European Medicines Agency; FDA = Food and Drug Administration; GI = gastrointestinal; K+ = potassium; NA = not applicable (product use predates formation of the EMA); QD = once daily; QoD = every other day; TID = thrice daily.

      Methods

      To capture recent literature for review, a search of PubMed was conducted for articles published in English between 2014 and 2018 and included the following terms: patiromer, sodium zirconium cyclosilicate, sodium polystyrene sulfonate, hyperkalemia, renin-angiotensin-aldosterone, diet, and dialysis. Citation lists of articles identified by the search were also used to identify additional literature. Completed and ongoing trials were searched and verified on ClinicalTrials.gov in December 2018 using the same search terms. The articles in this review were included on the basis of content relevance and quality.

      Hyperkalemia and Challenges for CKD Management

      The risk factors for hyperkalemia in patients with CKD include a K+-enriched diet, RAAS inhibitor therapy, and interdialytic interval of hemodialysis. The observation that these hyperkalemia risk factors also provide patient benefits poses unique management challenges for clinicians.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      • Palmer B.F.
      • Clegg D.J.
      Achieving the benefits of a high-potassium, paleolithic diet, without the toxicity.
      • Pun P.H.
      • Middleton J.P.
      Dialysate potassium, dialysate magnesium, and hemodialysis risk.
      This section discusses the clinical implications of addressing the effects of hyperkalemia management on diet, RAAS inhibitor therapy, and hemodialysis and reviews research with new K+-binding agents that may permit management of hyperkalemia despite the presence of these hyperkalemia risk factors.

      Effect on Diet

      A K+-rich diet (primarily achieved by high consumption of fruits and vegetables) can lower blood pressure and may prevent CV events. A diet high in fruits and vegetables is normally recommended in people with normal kidney function as part of a healthy lifestyle.
      • Aaron K.J.
      • Sanders P.W.
      Role of dietary salt and potassium intake in cardiovascular health and disease: a review of the evidence.
      • 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, in patients at risk for hyperkalemia—such as those who have late stages of CKD—high dietary K+ presents a clinical challenge.
      • Palmer B.F.
      • Clegg D.J.
      Achieving the benefits of a high-potassium, paleolithic diet, without the toxicity.
      • 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.
      Dietary K+ restriction (<3 g/d) is recommended in patients at risk for hyperkalemia but should be individualized because it can lead to patients not receiving the benefits of a heart-healthy diet
      • Cupisti A.
      • Kovesdy C.P.
      • D'Alessandro C.
      • Kalantar-Zadeh K.
      Dietary approach to recurrent or chronic hyperkalaemia in patients with decreased kidney function.
      • Kalantar-Zadeh K.
      • Fouque D.
      Nutritional management of chronic kidney disease.
      • Rastogi A.
      • Arman F.
      • Alipourfetrati S.
      New agents in treatment of hyperkalemia: an opportunity to optimize use of RAAS inhibitors for blood pressure control and organ protection in patients with chronic kidney disease.
      (Table 3).
      • Kalantar-Zadeh K.
      • Fouque D.
      Nutritional management of chronic kidney disease.
      US Department of Health and Human ServicesUS Department of Agriculture
      Appendix B: Food sources of selected nutrients.
      US Department of Agriculture
      USDA Food Composition Databases.
      Appropriate dietary counseling is important in patients with CKD with or at risk of hyperkalemia but can be challenging in clinical practice without dedicated resources.
      • Cupisti A.
      • Kovesdy C.P.
      • D'Alessandro C.
      • Kalantar-Zadeh K.
      Dietary approach to recurrent or chronic hyperkalaemia in patients with decreased kidney function.
      This includes an awareness of K+-based additives that are often found in processed foods, as well as salt substitutes containing K+ instead of sodium, which are recommended in patients with hypertension but may increase the risk of hyperkalemia in patients with reduced renal function or in those receiving RAAS inhibitor therapy.
      • Cupisti A.
      • Kovesdy C.P.
      • D'Alessandro C.
      • Kalantar-Zadeh K.
      Dietary approach to recurrent or chronic hyperkalaemia in patients with decreased kidney function.
      Table 3Dietary Potassium Recommendations
      CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; K+ = potassium.
      General dietary K+ recommendations in adults with CKD
      • Kalantar-Zadeh K.
      • Fouque D.
      Nutritional management of chronic kidney disease.
      NutrienteGFR ≥60 mL/min/1.73 m2 with increased CKD riskeGFR 30 to <60 mL/min/1.73 m2eGFR <30 mL/min/1.73 m2Dialysis
      K+ (g/d)4.74.7<3<3
      Approximate K+ content of selected heart-healthy foods
      US Department of Health and Human ServicesUS Department of Agriculture
      Appendix B: Food sources of selected nutrients.
      US Department of Agriculture
      USDA Food Composition Databases.
      Food groupApproximate K+ content (serving)
      Values listed are an estimation based on the reference source.
      Grains
       Brown rice, cooked0.174 g (1 cup)
       Whole-wheat pasta, cooked0.102 g (1 cup)
       Whole-wheat bread0.081 g (1 slice)
      Vegetables
       Tomatoes; red, ripe, cooked0.523 g (1 cup)
       Cooked spinach0.838 g (1 cup)
       Avocado; raw, California1.17 g (1 cup, pureed)
       Cooked beet greens1.31 g (1 cup)
      Fruits and fruit juices
       Bananas0.422 g (1, medium size)
       Cantaloupe0.368 g (one-quarter, medium size)
       Orange juice0.473 g (1 cup)
      Low-fat or fat-free dairy
       Yogurt; plain, nonfat0.579 g (8 oz)
       1%-2% Milk0.366 g (1 cup)
      Lean meats, poultry, fish
       Pork loin; roasted0.371 g (3 oz)
       Chicken; dark or light meat, roasted0.190-0.200 g (3 oz)
       Cod; Pacific, cooked0.439 g (3 oz)
      a CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; K+ = potassium.
      b Values listed are an estimation based on the reference source.
      The degree of benefit achieved by reducing dietary K+ is unclear. In one study of patients undergoing hemodialysis, a diet enriched with fruits and vegetables had a weak correlation (r=0.14; P<.05) with predialysis serum K+.
      • Noori N.
      • Kalantar-Zadeh K.
      • Kovesdy C.P.
      • et al.
      Dietary potassium intake and mortality in long-term hemodialysis patients.
      In another study of patients receiving hemodialysis, there were no correlations observed between serum K+ concentrations and dietary K+ intake (r=0.06; P=.50) or K+ density (r=−0.003; P=.97).
      • St-Jules D.E.
      • Goldfarb D.S.
      • Sevick M.A.
      Nutrient non-equivalence: does restricting high-potassium plant foods help to prevent hyperkalemia in hemodialysis patients.
      In a 24-month prospective controlled trial of patients who have stage 3 or 4 CKD, a K+-restricted group did have significantly lower serum K+ concentrations than a control group (4.6±0.5 mEq/L vs 4.8±0.4 mEq/L; P=.03) at the end of the study, but this difference was relatively small.
      • Cheungpasitporn W.
      • Thongprayoon C.
      • Kittanamongkolchai W.
      • Sakhuja A.
      • Mao M.A.
      • Erickson S.B.
      Impact of admission serum potassium on mortality in patients with chronic kidney disease and cardiovascular disease.
      In a recent meta-analysis, increased intake of total dietary fiber (including fruits and vegetables) in the general population was associated with reductions in body weight, systolic blood pressure, and cholesterol, as well as reduced mortality, highlighting the potential benefits of a diet enriched in fruits and vegetables.
      • Reynolds A.
      • Mann J.
      • Cummings J.
      • Winter N.
      • Mete E.
      • Te Morenga L.
      Carbohydrate quality and human health: a series of systematic reviews and meta-analyses.
      Furthermore, ingestion of a K+-rich diet is hypothesized to facilitate renal excretion of K+ in patients with normal renal function by enhancing K+ transport in the distal convoluted tubule, and thus preventing hyperkalemia development.
      • Palmer B.F.
      • Clegg D.J.
      Cardiovascular benefits of a diet enriched in fruits and vegetables.
      Taken together, the lost nutritional benefit of a high-K+ diet, the difficulty in maintaining a K+-restricted diet, and the modest effects of restricting dietary K+ can make this aspect of CKD management highly challenging.
      A potential use of new K+ binders is to ease dietary K+ restrictions in patients with CKD.
      • Palmer B.F.
      • Clegg D.J.
      Achieving the benefits of a high-potassium, paleolithic diet, without the toxicity.
      • Palmer B.F.
      • Clegg D.J.
      Cardiovascular benefits of a diet enriched in fruits and vegetables.
      • Kovesdy C.P.
      Updates in hyperkalemia: outcomes and therapeutic strategies.
      • Zannad F.
      • Rossignol P.
      • Stough W.G.
      • et al.
      New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: considerations for trial design and regulatory approval.
      In patients with advanced CKD or end-stage renal disease, resuming a plant-based diet may lead to increased fecal excretion of K+ through increases in stool bulk from dietary fiber.
      • Palmer B.F.
      • Clegg D.J.
      Cardiovascular benefits of a diet enriched in fruits and vegetables.
      Thus far, studies of SZC and patiromer do not systematically control for diet: some required patients to follow a K+-restricted diet,
      • 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.
      • 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.
      • 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.
      whereas others did not.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • 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.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      Furthermore, many of these studies were of short duration. In theory, these K+-binding agents may allow patients with CKD to be less restrictive in their diet while still minimizing the risk of hyperkalemia.
      • Palmer B.F.
      • Clegg D.J.
      Achieving the benefits of a high-potassium, paleolithic diet, without the toxicity.
      However, future studies are necessary to determine the long-term effects of K+ binders (eg, on K+ control, CV events, and mortality) in the context of a high-K+ (and heart-healthy) diet vs a K+-restricted diet.

      Effect on RAAS Inhibitor Therapy Optimization

      The use of RAAS inhibitor therapy, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists (MRAs) is well established in patients with CKD.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      Treatment with RAAS inhibitors is associated with slowed progression of CKD and improved outcomes in patients with common CKD comorbidities (eg, hypertension, HF, and diabetes).
      Kidney Disease: Improving Global Outcomes
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      • 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.
      American Diabetes Association
      10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2019.
      Furthermore, RAAS inhibition is beneficial in both the early stages of CKD, during which they reduce hypertension, proteinuria, and glomerulosclerosis, and later stages of CKD, during which they help to preserve residual renal function in patients receiving hemodialysis.
      • Zhang F.
      • Liu H.
      • Liu D.
      • et al.
      Effects of RAAS inhibitors in patients with kidney disease.
      Although optimization of RAAS inhibitor therapy is important to achieve the greatest CV and renal benefits obtainable, use of RAAS inhibitors can increase the risk of hyperkalemia in patients with CKD.
      • Palmer B.F.
      • Clegg D.J.
      Treatment of abnormalities of potassium homeostasis in CKD.
      Among patients with CKD, RAAS inhibitor–associated hyperkalemia has been estimated to occur in 5% to 10% of patients, compared with less than 2% of patients without CKD.
      • 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.
      • Dunn J.D.
      • Benton W.W.
      • Orozco-Torrentera E.
      • Adamson R.T.
      The burden of hyperkalemia in patients with cardiovascular and renal disease.
      A common management strategy for hyperkalemia is the down-titration or discontinuation of RAAS inhibitor therapy.
      • Chang A.R.
      • Sang Y.
      • Leddy J.
      • et al.
      Antihypertensive medications and the prevalence of hyperkalemia in a large health system.
      • 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.
      Accordingly, there is marked inconsistency between guideline recommendations and real-world use of RAAS inhibitors, and the patients who would benefit most from RAAS inhibitor therapy (ie, patients with CKD, HF, or diabetes) are either not receiving it or receiving it in suboptimal doses.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      In a large retrospective US database analysis, moderate to severe hyperkalemia events resulted in down-titration or discontinuation of RAAS inhibitor therapy in approximately 50% of patients receiving maximal doses and in discontinuation in about 30% of patients receiving submaximal doses.
      • 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.
      Patients receiving submaximal doses or those who discontinued RAAS inhibitor therapy had worse outcomes, including higher incidence of CV events and more rapid progression of kidney disease and increased mortality compared with patients receiving maximal doses of RAAS inhibitors.
      • 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.
      These results highlight the challenge faced by clinicians when prescribing RAAS inhibitor therapy in patients with CKD—balancing the risk of hyperkalemia with potential cardiorenal morbidity and mortality benefits.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      Given the integral role of RAAS inhibitor therapy in reducing CV risk and slowing the progression of CKD, the use of new K+ binders to lower serum K+ and thereby maintain optimal RAAS inhibitor therapy is expected to improve long-term clinical outcomes in patients with CKD.
      • Chang A.R.
      • Sang Y.
      • Leddy J.
      • et al.
      Antihypertensive medications and the prevalence of hyperkalemia in a large health system.
      • Epstein M.
      Hyperkalemia constitutes a constraint for implementing renin-angiotensin-aldosterone inhibition: the widening gap between mandated treatment guidelines and the real-world clinical arena.
      • Zannad F.
      • Rossignol P.
      • Stough W.G.
      • et al.
      New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: considerations for trial design and regulatory approval.
      Although studies evaluating SZC and patiromer included patients receiving RAAS inhibitor therapy and appeared to permit continued use without hyperkalemia,
      • 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.
      • 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.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • Weir M.R.
      • Bushinsky D.A.
      • Benton W.W.
      • et al.
      Effect of patiromer on hyperkalemia recurrence in older chronic kidney disease patients taking RAAS inhibitors.
      the direct effects of these agents on the optimization of RAAS inhibitor dose have not been clearly delineated. Although evidence is emerging on the sustained benefits of K+ binders,
      • 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.
      additional studies are necessary to evaluate these effects long term. As described in greater detail later in this article, Zannad et al
      • Zannad F.
      • Rossignol P.
      • Stough W.G.
      • et al.
      New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: considerations for trial design and regulatory approval.
      offer the following potential clinical efficacy end points for investigating K+ binder and RAAS inhibitor use in CKD: the proportion of patients receiving RAAS inhibitor therapy at follow-up and end points related to improved RAAS inhibitor use (eg, renal or cardiac outcomes).

      Effect on Hemodialysis

      Maintenance of serum K+ within the normal range during the intradialytic and interdialytic intervals is a goal of hemodialysis, yet hyperkalemia is common in patients receiving hemodialysis.
      • Pun P.H.
      • Middleton J.P.
      Dialysate potassium, dialysate magnesium, and hemodialysis risk.
      These patients are at risk of hyperkalemia because K+ accumulates during the interdialytic period, and alternately, patients are at risk of hypokalemia because K+ is removed by the dialysis procedure during the intradialytic period. Achieving appropriate dialysate K+ concentrations is critical because dialysis-induced K+ lowering may provoke arrhythmias and cardiac death.
      • Pun P.H.
      • Middleton J.P.
      Dialysate potassium, dialysate magnesium, and hemodialysis risk.
      In addition to the potential mortality risk from hyperkalemia, patients receiving hemodialysis may have an increased risk of mortality due to other factors, such as fluid overload,
      • Siriopol D.
      • Siriopol M.
      • Stuard S.
      • et al.
      An analysis of the impact of fluid overload and fluid depletion for all-cause and cardiovascular mortality [published online ahead of print January 8, 2019].
      rapid fluid shifts with high ultrafiltration rates,
      • Flythe J.E.
      • Kimmel S.E.
      • Brunelli S.M.
      Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality.
      hemodialysis-associated hypotension,
      • Shoji T.
      • Tsubakihara Y.
      • Fujii M.
      • Imai E.
      Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patients.
      increased muscle sympathetic nerve activity,
      • Kaur J.
      • Young B.E.
      • Fadel P.J.
      Sympathetic overactivity in chronic kidney disease: consequences and mechanisms.
      and acid-base disturbances.
      • Qian Q.
      Acid-base alterations in ESRD and effects of hemodialysis.
      The risk of hyperkalemia may be increased with the thrice-weekly administration of hemodialysis, which includes a long 3-day interdialytic interval (including the weekend) before the first dialysis session of the week.
      • Georgianos P.I.
      • Sarafidis P.A.
      • Sinha A.D.
      • Agarwal R.
      Adverse effects of conventional thrice-weekly hemodialysis: is it time to avoid 3-day interdialytic intervals?.
      • Yusuf A.A.
      • Hu Y.
      • Singh B.
      • Menoyo J.A.
      • Wetmore J.B.
      Serum potassium levels and mortality in hemodialysis patients: a retrospective cohort study.
      A retrospective US database study found that the frequency of hyperkalemia was 2-fold greater the day after the long vs the short interdialytic interval.
      • Yusuf A.A.
      • Hu Y.
      • Singh B.
      • Menoyo J.A.
      • Wetmore J.B.
      Serum potassium levels and mortality in hemodialysis patients: a retrospective cohort study.
      The long interdialytic interval was associated with greater predialytic risk for sudden cardiac death, with evidence suggesting fluctuations in K+ as a contributor.
      • Joki N.
      • Tokumoto M.
      • Takahashi N.
      • Nishimura M.
      Current perspectives on sudden cardiac death in hemodialysis patients.
      • Bleyer A.J.
      • Hartman J.
      • Brannon P.C.
      • Reeves-Daniel A.
      • Satko S.G.
      • Russell G.
      Characteristics of sudden death in hemodialysis patients.
      A retrospective analysis of 80 cases of sudden death in patients receiving hemodialysis reported that the risk of sudden death was 3-fold greater 12 hours before hemodialysis after a long interdialytic interval compared with the expected rate of death.
      • Bleyer A.J.
      • Hartman J.
      • Brannon P.C.
      • Reeves-Daniel A.
      • Satko S.G.
      • Russell G.
      Characteristics of sudden death in hemodialysis patients.
      In contrast, the risk of sudden death occurring in the 12-hour period prior to initiating dialysis treatment was only 1.7-fold greater than expected. Thus, when clinically feasible, it is recommended that all interdialytic intervals be 48 hours or less to reduce the risk of hyperkalemia.
      • Yusuf A.A.
      • Hu Y.
      • Singh B.
      • Menoyo J.A.
      • Wetmore J.B.
      Serum potassium levels and mortality in hemodialysis patients: a retrospective cohort study.
      Potassium concentration before, during, and after dialysis is of clinical significance. High predialysis serum K+ concentration is a risk factor for sudden death and all-cause mortality.
      • Yusuf A.A.
      • Hu Y.
      • Singh B.
      • Menoyo J.A.
      • Wetmore J.B.
      Serum potassium levels and mortality in hemodialysis patients: a retrospective cohort study.
      • Kovesdy C.P.
      • Regidor D.L.
      • Mehrotra R.
      • et al.
      Serum and dialysate potassium concentrations and survival in hemodialysis patients.
      • Genovesi S.
      • Valsecchi M.G.
      • Rossi E.
      • et al.
      Sudden death and associated factors in a historical cohort of chronic haemodialysis patients.
      Use of dialysate with low K+ concentration (<2 mEq/L) has been reported to increase the risk of sudden cardiac death
      • Yusuf A.A.
      • Hu Y.
      • Singh B.
      • Menoyo J.A.
      • Wetmore J.B.
      Serum potassium levels and mortality in hemodialysis patients: a retrospective cohort study.
      • Pun P.H.
      • Middleton J.P.
      Dialysate potassium, dialysate magnesium, and hemodialysis risk.
      and cause adverse electrocardiographic changes during and after hemodialysis.
      • Santoro A.
      • Mancini E.
      • London G.
      • et al.
      Patients with complex arrhythmias during and after haemodialysis suffer from different regimens of potassium removal.
      • Buemi M.
      • Aloisi E.
      • Coppolino G.
      • et al.
      The effect of two different protocols of potassium haemodiafiltration on QT dispersion.
      Recent data suggest that bradyarrhythmia due to hyperkalemia may cause sudden cardiac death before hemodialysis.
      • Joki N.
      • Tokumoto M.
      • Takahashi N.
      • Nishimura M.
      Current perspectives on sudden cardiac death in hemodialysis patients.
      Furthermore, rapid prolongation of the QT interval due to a shift in K+ and other electrolytes may be the likely cause of ventricular arrhythmia and sudden cardiac death after hemodialysis. Additional studies are needed to better understand the effects of serum and dialysate K+ concentrations on clinical outcomes in patients receiving hemodialysis.
      The use of nondialytic measures to improve K+ homeostasis would decrease the need to expose patients to dialysate with low K+ concentrations. These measures include, but are not limited to, use of K+ binders to stabilize K+ concentrations during the interdialytic period. However, there is a risk of polypharmacy with addition of K+-binder therapy, particularly in patients undergoing hemodialysis, which is known to increase the risk of hospitalization.
      • Flythe J.E.
      • Katsanos S.L.
      • Hu Y.
      • Kshirsagar A.V.
      • Falk R.J.
      • Moore C.R.
      Predictors of 30-day hospital readmission among maintenance hemodialysis patients: a hospital's perspective.
      Ongoing and planned clinical trials will provide insight into whether a K+-binding agent can decrease the incidence of predialysis hyperkalemia, lessen the blood to dialysate K+ gradient, and decrease the rate of decline in serum K+ concentration during dialysis. If successful, this strategy has the potential to reduce the incidence of arrhythmias and sudden cardiac death during and after dialysis.
      The ongoing randomized phase 3 DIALIZE study (A Study to Test Whether ZS [Sodium Zirconium Cyclosilicate] Can Reduce the Incidence of Increased Blood Potassium Levels Among Dialized Patients; ClinicalTrials.gov Identifier: NCT03303521) is evaluating the efficacy of SZC in maintaining normal serum K+ concentration after the long interdialytic interval in patients receiving hemodialysis without the need for rescue therapy. Adults receiving hemodialysis thrice weekly for at least 3 months with a predialysis serum K+ level greater than 5.4 mEq/L after the long interdialytic interval and greater than 5.0 mEq/L after the short interdialytic interval will be evaluated.
      The TWOPLUS-HD trial (A Pilot Trial of Twice-weekly Versus Thrice-weekly Hemodialysis in Patients With Incident End-stage Kidney Disease; ClinicalTrials.gov Identifier: NCT03740048) will investigate whether a dialysis-sparing effect may be achieved with the addition of patiromer to a hemodialysis treatment plan. In this randomized pilot study, patients with an indication to initiate hemodialysis will be randomized to thrice-weekly dialysis or twice-weekly dialysis plus pharmacotherapy for 6 weeks followed by thrice-weekly dialysis. The pharmacotherapy for patients randomized to the twice-weekly regimen will consist of a loop diuretic and sodium bicarbonate, and if patients experience hyperkalemia during the first 6 weeks, they will then receive patiromer.

      Clinical Efficacy and Safety of K+ Binders for the Treatment of Hyperkalemia in CKD

      Sodium polystyrene sulfonate was approved by the FDA in 1958 for the treatment of hyperkalemia
      • Georgianos P.I.
      • Agarwal R.
      Revisiting RAAS blockade in CKD with newer potassium-binding drugs.
      ; however, because the FDA did not require significant clinical data for approval prior to 1962, rigorous randomized controlled trial (RCT) efficacy and safety data for SPS in hyperkalemia are lacking.
      • Georgianos P.I.
      • Agarwal R.
      Revisiting RAAS blockade in CKD with newer potassium-binding drugs.
      • 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.
      In contrast, SZC and patiromer have been evaluated in phase 2 and phase 3 RCTs and have had consistent K+-lowering efficacy and favorable safety profiles.
      • 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.
      • 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.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • 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.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      Both agents are approved by the FDA and the European Medicines Agency for the treatment of hyperkalemia. The chemical properties, dosage regimens, and other characteristics of SPS, patiromer, and SZC are shown in Table 2. Sodium zirconium cyclosilicate is a nonpolymer compound that has a rapid onset of action (within 1 hour) when given at 10 g thrice daily for up to 48 hours in the acute setting (Table 2). The typical initial maintenance dose is 10 g once daily titrated to achieve the desired K+ concentration. The usual maintenance dose ranges from 5 g every other day to 15 g daily.
      Patiromer is an insoluble cross-linked polymer, has an onset of action of 7 hours, and is typically given at a dose of 8.4 g once daily (Table 2). When used as maintenance therapy, it is recommended that the dose of patiromer be increased in 8.4-g increments at intervals of 1 week or more.
      In the remainder of this section, the results of key clinical studies (registration studies) of SPS, SZC, and patiromer in patients with hyperkalemia will be described. Apart from one small prospective study in patients receiving hemodialysis,
      • Bushinsky D.A.
      • Rossignol P.
      • Spiegel D.M.
      • et al.
      Patiromer decreases serum potassium and phosphate levels in patients on hemodialysis.
      the studies described in this section included predialysis patients with CKD receiving RAAS inhibitor therapy (Tables 4 and 5).
      • 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.
      • 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.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • 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.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.

      Zannad F, Hsu B-G, Maeda Y, et al. Sodium zirconium cyclosilicate for hyperkalemia: results of the randomized, placebo-controlled, multi-dose HARMONIZE-GLOBAL study. Poster presented at: ASN Kidney Week; October 25, 2018; San Diego, CA. Abstract TH-PO1158.

      Some study protocols specified K+-controlled diets or advised restricted diets,
      • 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.
      • 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.
      • Bushinsky D.A.
      • Rossignol P.
      • Spiegel D.M.
      • et al.
      Patiromer decreases serum potassium and phosphate levels in patients on hemodialysis.
      while others had no such dietary restrictions.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      Table 4Key Clinical Studies of SZC in Patients with Hyperkalemia
      CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HARMONIZE = Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance study; HARMONIZE-GL = HARMONIZE Global; K+ = potassium; NA = not applicable; QD = once daily; RAASi = renin-angiotensin-aldosterone system inhibitor; SZC = sodium zirconium cyclosilicate; TID = thrice daily.
      ,
      SI conversion factors: To convert potassium values to mmol/L, multiply by 1.0.
      Study designPatient populationStudy treatmentPrimary efficacy end point results
      Safety was also assessed. In clinical studies, edema (generally mild to moderate in severity) was the most commonly reported adverse reaction with SZC. SZC should not be used in patients with severe constipation, bowel obstruction, or impaction, including bowel motility disorders that occur postoperatively; it may be ineffective or worsen gastrointestinal conditions.35
      Phase 2, 4-d, randomized, double-blind, placebo-controlled, dose-escalating
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      eGFR 30-60 mL/min/1.73 m2 and serum K+ 5.0-6.0 mEq/L (n=90); RAASi: n=56SZC 0.3, 3, or 10 g TID or placebo for 48 h (minimum of 6 doses over 2 d or maximum of 12 doses over 4 d)Rate of serum K+ decline in first 48 h (SZC 10 g):

      −0.11±0.46 mEq/L decrease in serum K+ at 1 h vs +0.12±0.36 mEq/L with placebo (P=.04)

      –0.92±0.52 mEq/L at 38 h vs –0.26±0.4 mEq/L with placebo (P<.001)
      Phase 3, 2-wk, randomized, double-blind, placebo-controlled, dose-ranging
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      Correction phase: serum K+ 5.0-6.5 mEq/L (n=754); CKD: n=463; RAASi: n=502Correction phase: SZC 1.25, 2.5, 5, or 10 g TID or placebo for 48 hCorrection phase: between-group difference in exponential rate of serum K+ change/h in first 48 h: –0.11% for SZC 1.25 g, −0.16% for SZC 2.5 g, −0.21% for SZC 5 g, and –0.30% for SZC 10 g vs –0.09% for placebo (P<.001 for all except SZC 1.25 g)
      Maintenance phase: serum K+ 3.5-4.9 mEq/L at 48 h of the initial (correction) phase (n=543)Maintenance phase: SZC dose from initial phase (administered QD) or placebo for 12 dMaintenance phase: between-group difference in mean serum K+ during 12-d treatment period: SZC 5 g and 10 g were significantly superior to placebo in maintaining normokalemia (P=.008 and P<.001, respectively)
      Maintenance phase efficacy was a secondary end point in this study.78
      HARMONIZE: phase 3, 4-wk, randomized, double-blind, placebo-controlled
      • 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.
      Open-label phase: serum K+ ≥5.1 mEq/L (n=258); CKD: n=169; RAASi: n=180Open-label phase: SZC 10 g TID for 48 hNA
      Randomized phase: serum K+ 3.5-5 mEq/L at 48 h of the initial (open-label) phase (n=237); CKD: n=152; RAASi: n=163Randomized phase: SZC 5, 10, or 15 g QD or placebo for 28 dMean serum K+ in each dosing group vs placebo during days 8-29 of the randomized phase: 4.8 mEq/L for SZC 5 g, 4.5 mEq/L for SZC 10 g, and 4.4 mEq/L for SZC 15 g vs 5.1 mEq/L for placebo (P<.001 for all)
      Phase 3, 12-mo, open-label, single-arm
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      Correction phase: serum K+ ≥5.1 mEq/L (n=751)Correction phase: SZC 10 g TID for 24-72 hCorrection phase: proportion of patients with serum K+ 3.5-5.0 mEq/L: 78%
      Maintenance phase: serum K+ 3.5-5.0 mEq/L (n=746); CKD: n=483; RAASi: n=483Maintenance phase: SZC titrated to serum K+ 3.5-5.0 mEq/L (maximum 15 g QD, minimum 5 g every other day)Maintenance phase: proportion of patients with serum K+ ≤5.1 during 3-12 mo: 88%
      HARMONIZE-GL: phase 3, 4-wk, randomized, double-blind, placebo-controlled

      Zannad F, Hsu B-G, Maeda Y, et al. Sodium zirconium cyclosilicate for hyperkalemia: results of the randomized, placebo-controlled, multi-dose HARMONIZE-GLOBAL study. Poster presented at: ASN Kidney Week; October 25, 2018; San Diego, CA. Abstract TH-PO1158.

      Correction phase: serum K+ ≥5.1 mEq/L (n=267); CKD: n=209; RAASi: n=205Correction phase: SZC 10 g TID for 48 hNA
      Maintenance phase: serum K+ 3.5-5.0 mEq/L (n=248); CKD: n=199; RAASi: n=195Maintenance (randomized) phase: SZC 5 or 10 g QD or placebo for 28 dBack-transformed least squares mean serum K+ on days 8-29 of the maintenance phase: 4.81 mEq/L for SZC 5 g and 4.38 mEq/L for SZC 10 g vs 5.32 mEq/L for placebo (P<.001 for both)
      a CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HARMONIZE = Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance study; HARMONIZE-GL = HARMONIZE Global; K+ = potassium; NA = not applicable; QD = once daily; RAASi = renin-angiotensin-aldosterone system inhibitor; SZC = sodium zirconium cyclosilicate; TID = thrice daily.
      b SI conversion factors: To convert potassium values to mmol/L, multiply by 1.0.
      c Safety was also assessed. In clinical studies, edema (generally mild to moderate in severity) was the most commonly reported adverse reaction with SZC. SZC should not be used in patients with severe constipation, bowel obstruction, or impaction, including bowel motility disorders that occur postoperatively; it may be ineffective or worsen gastrointestinal conditions.
      d Maintenance phase efficacy was a secondary end point in this study.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      Table 5Key Clinical Studies of Patiromer in Patients with Hyperkalemia
      AMETHYST-DN = Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy; BID = twice daily; eGFR = estimated glomerular filtration rate; HF = heart failure; K+ = potassium; MRA = mineralocorticoid receptor antagonist; 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; RAASi = renin-angiotensin-aldosterone system inhibitor.
      ,
      SI conversion factors: To convert potassium values to mmol/L, multiply by 1.0.
      Study: designPatient populationStudy treatmentPrimary efficacy end point results
      Safety was also assessed. Patiromer may bind to magnesium ions in the colon, which can lead to hypomagnesemia. In clinical studies, 5.3% of patients treated with patiromer experienced hypomagnesemia as an adverse event. Patiromer should not be used in patients with severe constipation, bowel obstruction or impaction, including bowel motility disorders that occur postoperatively; it may be ineffective or worsen gastrointestinal conditions.37
      PEARL-HF: phase 2, 4-wk, double-blind, placebo-controlled, randomized
      • 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.
      HF, an indication to start MRA therapy, serum K+ 4.3-5.1 mEq/L, and either (1) eGFR <60 mL/min/1.73 m2 and ≥1 HF therapy (RAASi or β-blocker) or (2) hyperkalemia resulting in RAASi or β-blocker discontinuation in the past 6 mo (n=120)Patiromer 15 g BID or placebo (plus spironolactone 25 mg/d, titrated to 50 mg/d at week 2 if serum K+ >3.5 to ≤5.1 mEq/L)Mean change in serum K+ from baseline to week 4: patiromer −0.22 mEq/L vs placebo +0.23 mEq/L (P<.001)
      AMETHYST-DN: phase 2, 52-wk, open-label, randomized, dose-ranging
      • 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.
      Type 2 diabetes, eGFR 15 to <60 mL/min/1.73 m2, serum K+ >5.0 to <6.0 mEq/L, and RAASi therapy (n=306)Patiromer 4.2, 8.4, or 12.6 g BID for serum K+ >5.0 to <6.0 mEq/L; patiromer 8.4, 12.6, or 16.8 g BID for serum K+ >5.5 to <6.0 mEq/LMean change in serum K+ from baseline to week 4:

      Mild hyperkalemia: –0.35 to –0.55 mEq/L (P<.001 vs baseline for all dose groups)

      Moderate hyperkalemia: –0.87 to –0.92 mEq/L (P<.001 vs baseline for all dose groups)
      OPAL-HK: phase 3, 4-wk, single-group, single-blind initial treatment phase plus an 8-wk placebo-controlled, single-blind, randomized withdrawal phase
      • 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.
      Initial treatment phase: eGFR 15 to <60 mL/min/1.73 m2, serum K+ 5.1 to <6.5 mEq/L, and stable dose of ≥1 RAASi for ≥28 d (n=243)Treatment phase: patiromer 4.2 g BID for serum K+ 5.1 to <5.5 mEq/L; patiromer 8.4 g BID for serum K+ 5.5 to <6.5 mEq/LTreatment phase (mean change in serum K+ from baseline to week 4): –1.01 mEq/L (P<.001 vs baseline)
      Withdrawal phase: serum K+ ≥5.5 mEq/L at initial treatment baseline, serum K+ 3.8 to <5.1 mEq/L at end of initial treatment while receiving patiromer, and RAASi therapy (n=107)Withdrawal phase: patiromer at previous week 4 dose or placeboWithdrawal phase (difference for patiromer vs placebo in median change in serum K+ at week 4 or earliest visit at which serum K+ was <3.8 mEq/L or ≥5.5 mEq/L): patiromer 0 mEq/L vs placebo +0.72 mEq/L (P<.001)
      a AMETHYST-DN = Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy; BID = twice daily; eGFR = estimated glomerular filtration rate; HF = heart failure; K+ = potassium; MRA = mineralocorticoid receptor antagonist; 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; RAASi = renin-angiotensin-aldosterone system inhibitor.
      b SI conversion factors: To convert potassium values to mmol/L, multiply by 1.0.
      c Safety was also assessed. Patiromer may bind to magnesium ions in the colon, which can lead to hypomagnesemia. In clinical studies, 5.3% of patients treated with patiromer experienced hypomagnesemia as an adverse event. Patiromer should not be used in patients with severe constipation, bowel obstruction or impaction, including bowel motility disorders that occur postoperatively; it may be ineffective or worsen gastrointestinal conditions.

      Sodium Polystyrene Sulfonate

      In a 2015 RCT in which 33 patients with CKD (nondialysis-dependent) and serum K+ concentrations of 5.0 to 5.9 mEq/L received double-blind treatment with oral sorbitol-free SPS or placebo for 7 days, SPS was superior to placebo in reducing serum K+ (between-group difference, 1.04 mEq/L; P<.001) without a significant difference in gastrointestinal adverse events between the groups.
      • Lepage L.
      • Dufour A.C.
      • Doiron J.
      • et al.
      Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD.
      Angiotensin receptor blocker and angiotensin-converting enzyme inhibitor doses remained stable, and patients had received routine counseling to follow a low-K+ diet and were asked not to modify their diets during the study.
      • Lepage L.
      • Dufour A.C.
      • Doiron J.
      • et al.
      Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD.
      However, the small number of patients and short duration of this RCT are not sufficient to support long-term use of SPS in patients with hyperkalemia.
      • Georgianos P.I.
      • Agarwal R.
      Revisiting RAAS blockade in CKD with newer potassium-binding drugs.
      • 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.

      Sodium Zirconium Cyclosilicate

      Phase 2 and phase 3 studies have investigated the efficacy and safety of SZC for the treatment of hyperkalemia in a wide range of patients, including a high proportion of patients with CKD receiving RAAS inhibitor therapy (Table 4).
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.

      Zannad F, Hsu B-G, Maeda Y, et al. Sodium zirconium cyclosilicate for hyperkalemia: results of the randomized, placebo-controlled, multi-dose HARMONIZE-GLOBAL study. Poster presented at: ASN Kidney Week; October 25, 2018; San Diego, CA. Abstract TH-PO1158.

      In these studies, patients received doses of SZC ranging from 0.3 to 10 g thrice daily for a short period (ie, 24-72 hours) to normalize serum K+ concentrations (the correction phase), then continued SZC up to 15 g once daily for a period (ie, ∼2 weeks to 12 months) to maintain normokalemia; no dietary restrictions were imposed, and patients were not provided with any protocol-directed dietary advice.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      More than 50% of patients received RAAS inhibitor therapy in the trials,
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      which was kept at a constant dose in 2 studies.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      Sodium zirconium cyclosilicate was associated with rapid lowering of serum K+ concentrations, with significant reductions vs baseline observed 1 hour after the first 10-g dose.
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      Consistent reductions in serum K+ with SZC were observed in patients receiving RAAS inhibitor therapy,
      • Ash S.R.
      • Singh B.
      • Lavin P.T.
      • Stavros F.
      • Rasmussen H.S.
      A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.
      • 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.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      as well as in a subgroup of patients with severe hyperkalemia (serum K+ concentration ≥6 mEq/L).
      • Kosiborod M.
      • Peacock W.F.
      • Packham D.K.
      Sodium zirconium cyclosilicate for urgent therapy of severe hyperkalemia [letter].
      Reductions in serum K+ were maintained with continued daily doses of SZC in 2- to 4-week phase 3 studies,
      • 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.
      • Packham D.K.
      • Rasmussen H.S.
      • Lavin P.T.
      • et al.
      Sodium zirconium cyclosilicate in hyperkalemia.
      including in patients receiving RAAS inhibitor therapy.
      • 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.
      The long-term efficacy of SZC has been studied for up to 1 year in an open-label study
      • Spinowitz B.S.
      • Fishbane S.
      • Pergola P.E.
      • et al.
      ZS-005 Study Investigators
      Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study.
      that included patients with CKD and patients receiving RAAS inhibitors.
      • McCullough P.
      • Pergola P.
      • Fishbane S.
      • et al.
      Efficacy and safety of sodium zirconium cyclosilicate to treat hyperkalemia among patients taking renin-angiotensin-aldosterone system inhibitors in a 12-month, open-label, phase 3 study: a post hoc subgroup analysis.
      • Roger S.
      • Lavin P.
      • Lerma E.
      • et al.
      Safety and efficacy of sodium zirconium cyclosilicate for long-term treatment of hyperkalaemia in patients with chronic kidney disease: results from an open-label, phase 3 study.
      Sodium zirconium cyclosilicate was generally well tolerated in phase 2 and phase 3 trials, with an incidence of gastrointestinal adverse events similar to that of placebo, and a dose-related increase in the incidence of mild to moderate edema in patients during maintenance dosing resolved spontaneously or with diuretic therapy (edema was more common in patients treated with SZC 15 g—the highest dose of SZC in clinical trials).
      • Hoy S.M.
      Sodium zirconium cyclosilicate: a review in hyperkalaemia.
      • 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.
      • Anker S.D.
      • Kosiborod M.
      • Zannad F.
      • et al.
      Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial.
      Hypokalemia that resolved with dose reductions or discontinuation of SZC was also reported in clinical trials.
      Ongoing trials are also investigating the effect of SZC in optimizing RAAS inhibitor therapy and in rapid reduction and normalization of serum K+ in an emergency setting. The PRIORITIZE HF study (Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure; ClinicalTrials.gov Identifier: NCT03532009) is investigating the optimization of RAAS inhibitor therapy with SZC in patients with HF with reduced ejection fraction (EF; New York Heart Association [NYHA] functional class II-IV disease). The primary objective is to evaluate the efficacy and safety of using SZC to initiate and intensify RAAS inhibitor therapy, including MRAs. The ENERGIZE study (A Study to Evaluate a Potassium Normalization Treatment Regimen Including Sodium Zirconium Cyclosilicate [ZS] Among Patients With S-K ≥5.8; ClinicalTrials.gov Identifier: NCT03337477) is investigating the effect of SZC added to a K+-normalization treatment regimen in patients with serum K+ concentrations of 5.8 mEq/L or greater. The primary outcome is mean absolute change in serum K+ concentration from baseline until 4 hours after the start of dosing with SZC added to insulin and glucose vs that with placebo added to insulin and glucose.

      Patiromer

      The efficacy and safety of patiromer in patients with CKD and/or HF receiving RAAS inhibitor therapy was established in several key clinical studies (registration studies) that are described in Table 5.
      • 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.
      • 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.
      • 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 either had hyperkalemia (counseled to follow a low-K+ diet)
      • 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.
      • 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.
      or were at risk for development of hyperkalemia (eg, had CKD, HF, history of hyperkalemia leading to discontinuation of RAAS inhibitors).
      • 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.
      In these studies, patiromer significantly reduced serum K+ concentrations
      • 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.
      • 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.
      • 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.
      and facilitated continuation and up-titration of RAAS inhibitor therapy.
      • 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.
      • 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.
      In the 4-week PEARL-HF study (Evaluation of Patiromer in Heart Failure Patients; ClinicalTrials.gov Identifier: NCT00868439), significantly more patients treated with patiromer were able to increase their spironolactone dose from 25 to 50 mg/d vs those receiving placebo (91% vs 74%; P=.019) without experiencing hyperkalemia.
      • 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.
      All patients in this trial had NYHA class I to III HF (mean EF, 40%-41%); 11 patients (15%) had HF with preserved EF (≥50%).
      • 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.
      In the 12-week OPAL-HK (A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia; ClinicalTrials.gov Identifier: NCT01810939) study, 94% of patients in the patiromer group were able to continue RAAS inhibitor therapy, whereas discontinuation of RAAS inhibitors was required in 56% of patients receiving placebo because of recurrence of hyperkalemia.
      • 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.
      Approximately 42% of patients (102 of 243) in this trial had NYHA class I to III HF (EF not reported).
      • 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 prespecified subgroup analyses, 100% of patiromer recipients with HF and 100% of patiromer recipients aged 65 years or older continued RAAS inhibitor therapy while maintaining K+ control.
      • Weir M.R.
      • Bushinsky D.A.
      • Benton W.W.
      • et al.
      Effect of patiromer on hyperkalemia recurrence in older chronic kidney disease patients taking RAAS inhibitors.
      • Pitt B.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors.
      A post hoc analysis of OPAL-HK found that the efficacy and safety of patiromer were not compromised by background diuretic therapy, which is often required in patients with CKD.
      • Weir M.R.
      • Mayo M.R.
      • Garza D.
      • et al.
      Effectiveness of patiromer in the treatment of hyperkalemia in chronic kidney disease patients with hypertension on diuretics.
      In the AMETHYST-DN study (Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy; ClinicalTrials.gov Identifier: NCT01371747), serum K+ concentrations were reduced with patiromer through week 4 of treatment, and K+ was maintained in a normal range over 52 weeks.
      • 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.
      Approximately 35% of patients (105 of 304) in this trial had NYHA class I to II HF (EF not reported).
      • 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.
      Reductions in serum K+ in patients with HF (despite maintenance of RAAS inhibitor therapy) were consistent with those observed in patients without HF at week 4.
      • 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.
      More recently, a patiromer dose-titration strategy to prevent hyperkalemia was evaluated in patients with NYHA class II to III HF (mean EF, 39%; ∼8% of patients [5 of 63] had an EF >50%).
      • Pitt B.
      • Bushinsky D.A.
      • Kitzman D.W.
      • et al.
      Patiromer-204 Investigators
      Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease.
      Starting at a dose of 16.8 g/d, rather than the 25.2-g/d fixed-dose strategy used in the PEARL-HF study, was found to be potentially beneficial.
      • Pitt B.
      • Bushinsky D.A.
      • Kitzman D.W.
      • et al.
      Patiromer-204 Investigators
      Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease.
      A small phase 2 study of patiromer in patients with hyperkalemia receiving hemodialysis has also been conducted.
      • Bushinsky D.A.
      • Rossignol P.
      • Spiegel D.M.
      • et al.
      Patiromer decreases serum potassium and phosphate levels in patients on hemodialysis.
      In this study, patients were placed on a K+-controlled diet for the entire study period (both pretreatment and treatment phases) and had reduced serum K+ concentrations with patiromer treatment vs the pretreatment phase. Overall, patiromer has been generally well tolerated among patients in clinical trials, with the most common adverse events being gastrointestinal disorders.
      • Pitt B.
      • Garza D.
      The tolerability and safety profile of patiromer: a novel polymer-based potassium binder for the treatment of hyperkalemia.
      Ongoing trials of patiromer are investigating effects in patients with CKD and resistant hypertension and in patients receiving dialysis, including children. The AMBER trial (Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease; ClinicalTrials.gov Identifier: NCT03071263) is investigating the concomitant use of patiromer and spironolactone in patients with resistant hypertension and CKD to determine whether this strategy prevents hyperkalemia and allows for long-term use of spironolactone for the management of hypertension.
      • Agarwal R.
      • Rossignol P.
      • Garza D.
      • et al.
      Patiromer to enable spironolactone use in the treatment of patients with resistant hypertension and chronic kidney disease: rationale and design of the AMBER study.
      The primary end point of the AMBER study is the proportion of patients continuing to take spironolactone at week 12. Secondary end points include changes in blood pressure and albuminuria (a marker of CV and renal outcomes). As noted previously, the TWOPLUS-HD trial will investigate whether a dialysis-sparing effect may be achieved with the addition of patiromer to a hemodialysis treatment plan. Patients initiating hemodialysis will be randomized to thrice-weekly dialysis or twice-weekly dialysis plus pharmacotherapy for 6 weeks followed by thrice-weekly dialysis. Patients randomized to receive pharmacotherapy who have development of hyperkalemia during the first 6 weeks will receive patiromer. Patient recruitment is currently under way for the EMERALD study (Pharmacodynamic & Safety of Patiromer in Children & Adolescents [2-<18 Yrs] With Chronic Kidney Disease and Hyperkalemia; ClinicalTrials.gov Identifier: NCT03087058), which is designed to evaluate the efficacy and safety of patiromer in children (aged 2 to <18 years) with CKD and hyperkalemia. As part of this study, the effect of different patiromer doses on the change in serum K+ concentrations from baseline to day 14 in this patient population will be explored.

      Real-World Experience With K+ Binders

      Multiple recent real-world evidence studies (ie, prospective or retrospective database analyses) support the burden of hyperkalemia,
      • Thomsen R.W.
      • Nicolaisen S.K.
      • Hasvold P.
      • et al.
      Elevated potassium levels in patients with chronic kidney disease: occurrence, risk factors and clinical outcomes—a Danish population-based cohort study.
      • 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 [published online ahead of print August 6, 2018].
      • Fitch K.
      • Woolley J.M.
      • Engel T.
      • Blumen H.
      The clinical and economic burden of hyperkalemia on Medicare and commercial payers.
      • Bandak G.
      • Sang Y.
      • Gasparini A.
      • et al.
      Hyperkalemia after initiating renin-angiotensin system blockade: the Stockholm Creatinine Measurements (SCREAM) project.
      • Nilsson E.
      • Gasparini A.
      • Ārnlöv J.
      • et al.
      Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system.
      • Betts K.A.
      • Woolley J.M.
      • Mu F.
      • Xiang C.
      • Tang W.
      • Wu E.Q.
      The cost of hyperkalemia in the United States.
      • Trevisan M.
      • de Deco P.
      • Xu H.
      • et al.
      Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists.
      • Thomsen R.W.
      • Nicolaisen S.K.
      • Hasvold P.
      • et al.
      Elevated potassium levels in patients with congestive heart failure: occurrence, risk factors, and clinical outcomes; a Danish population-based cohort study.
      • Betts K.A.
      • Woolley J.M.
      • Mu F.
      • McDonald E.
      • Tang W.
      • Wu E.Q.
      The prevalence of hyperkalemia in the United States.
      • Karaboyas A.
      • Xu H.
      • Morgenstern H.
      • et al.
      DOPPS data suggest a possible survival benefit of renin angiotensin-aldosterone system inhibitors and other antihypertensive medications for hemodialysis patients.
      • Furuland H.
      • McEwan P.
      • Evans M.
      • et al.
      Serum potassium as a predictor of adverse clinical outcomes in patients with chronic kidney disease: new risk equations using the UK Clinical Practice Research Datalink.
      • Hughes-Austin J.M.
      • Rifkin D.E.
      • Beben T.
      • et al.
      The relation of serum potassium concentration with cardiovascular events and mortality in community-living individuals.
      and actual-use data on the agents used to treat hyperkalemia are accruing.
      • Hagan A.E.
      • Farrington C.A.
      • Wall G.C.
      • Belz M.M.
      Sodium polystyrene sulfonate for the treatment of acute hyperkalemia: a retrospective study.
      • Hunt T.V.
      • DeMott J.M.
      • Ackerbauer K.A.
      • Whittier W.L.
      • Peksa G.D.
      Single-dose sodium polystyrene sulfonate for hyperkalemia in chronic kidney disease or end-stage renal disease.
      Available real-world data indicate that SPS is associated with a high incidence of severe gastrointestinal adverse events, including reports of colonic necrosis and gastrointestinal injury, particularly when combined with sorbitol and in patients with CKD.
      • 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.
      • Georgianos P.I.
      • Agarwal R.
      Revisiting RAAS blockade in CKD with newer potassium-binding drugs.
      • Hagan A.E.
      • Farrington C.A.
      • Wall G.C.
      • Belz M.M.
      Sodium polystyrene sulfonate for the treatment of acute hyperkalemia: a retrospective study.
      • Hunt T.V.
      • DeMott J.M.
      • Ackerbauer K.A.
      • Whittier W.L.
      • Peksa G.D.
      Single-dose sodium polystyrene sulfonate for hyperkalemia in chronic kidney disease or end-stage renal disease.
      In retrospective observational analyses of low-dose sorbitol-free SPS use in 26 patients with CKD and 14 patients with CKD as well as heart disease, significant and sustained reductions in serum K+ were observed without significant safety concerns, with continued/optimal RAAS inhibitor therapy in those with CKD and heart disease (3 of 14 patients did not reach the target dose of RAAS inhibitor therapy).
      • Chernin G.
      • Gal-Oz A.
      • Ben-Assa E.
      • et al.
      Secondary prevention of hyperkalemia with sodium polystyrene sulfonate in cardiac and kidney patients on renin-angiotensin-aldosterone system inhibition therapy.
      • Georgianos P.I.
      • Liampas I.
      • Kyriakou A.
      • et al.
      Evaluation of the tolerability and efficacy of sodium polystyrene sulfonate for long-term management of hyperkalemia in patients with chronic kidney disease.
      This real-world experience adds to the minimal RCT evidence available for SPS.
      • Georgianos P.I.
      • Liampas I.
      • Kyriakou A.
      • et al.
      Evaluation of the tolerability and efficacy of sodium polystyrene sulfonate for long-term management of hyperkalemia in patients with chronic kidney disease.
      Retrospective observational studies have begun to examine patiromer in patients receiving hemodialysis,
      • Pitt B.
      • Garza D.
      The tolerability and safety profile of patiromer: a novel polymer-based potassium binder for the treatment of hyperkalemia.
      including a study of early adopters of patiromer in US dialysis centers.

      Chatoth DK, Spiegel DM, Weir MR, et al. Outcomes in ESRD patients on hemodialysis taking patiromer for hyperkalemia. Presented at: ASN Kidney Week; November 2, 2017; New Orleans, LA. Abstract TH-PO779.

      A recent retrospective analysis of 527 patients undergoing hemodialysis who received patiromer for hyperkalemia found that treatment with patiromer was associated with a mean reduction in serum K+ of 0.5 mEq/L.
      • Kovesdy C.P.
      • Rowan C.G.
      • Conrad A.
      • et al.
      Real-world evaluation of patiromer for the treatment of hyperkalemia in hemodialysis patients.
      In this study, the proportion of patients with severe hyperkalemia (serum K+ ≥6.0 mEq/L) decreased from 64% at baseline to 23% after initiation of patiromer.
      • Kovesdy C.P.
      • Rowan C.G.
      • Conrad A.
      • et al.
      Real-world evaluation of patiromer for the treatment of hyperkalemia in hemodialysis patients.
      However, long-term real-world experience is needed to confirm the safety of patiromer and SZC if used as maintenance therapy.
      • Georgianos P.I.
      • Agarwal R.
      Revisiting RAAS blockade in CKD with newer potassium-binding drugs.
      • Pitt B.
      • Garza D.
      The tolerability and safety profile of patiromer: a novel polymer-based potassium binder for the treatment of hyperkalemia.

      Conclusion

      Sodium zirconium cyclosilicate and patiromer have been found to be effective and tolerable in clinical trials and are viable alternatives to SPS for the management of hyperkalemia in patients with CKD. These agents also offer improved taste, texture, and appearance compared with SPS. Both SZC and patiromer effectively lower serum K+ concentrations in patients with CKD with hyperkalemia. Sodium zirconium cyclosilicate has a rapid onset of action (1 hour) that makes it well suited to restore normokalemia in outpatients with severe hyperkalemia (K+ ≥6.0 mEq/L). Clinical data suggest that SZC and patiromer can maintain serum K+ concentrations without limits on RAAS inhibitors, including MRAs, or dietary restrictions in some patients, although additional studies are needed. Furthermore, use of SZC and patiromer to limit predialysis hyperkalemia may be useful in lowering the blood to dialysate K+ gradient and may decrease the rate and extent of the decrease in serum K+ concentration during dialysis. If successful, this strategy has the potential to reduce the incidence of arrhythmias and sudden cardiac death in patients receiving dialysis. Clinical studies are either ongoing or being planned to confirm these hypotheses.

      Acknowledgments

      Joanne Dalton, Mollie Marko, and Blair Jarvis on behalf of inScience Communications, Springer Healthcare, and Sarah Greig, PhD, of inScience Communications. Springer Healthcare provided medical writing support, which was funded by AstraZeneca.

      Supplemental Online Material

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