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Zheng Z, Su Y, Schmidt-Rohr K. Vinyl and methyl-ester groups in the insoluble polymer drug patiromer identified and quantified by solid-state NMR. J Pharm Biomed Anal 2024; 246:116228. [PMID: 38781726 DOI: 10.1016/j.jpba.2024.116228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024]
Abstract
Patiromer (Veltassa®) is a crosslinked, insoluble co-polymer drug used as a nonabsorbent potassium binder, approved for treatment of hyperkalemia. Quantitative solid-state 13C nuclear magnetic resonance (NMR) analysis with comprehensive peak assignment, component quantification, and calculation of mole and weight fractions of monomer units was performed on three doses of patiromer. The workflow is documented in detail. Spectrally edited solid-state 13C NMR spectra of patiromer show =CHn peaks of matching intensity at 116 and 141 ppm, characteristic of -CH=CH2 vinyl groups. Similar spectral features can be observed in earlier studies but were previously ignored. In this study, the vinyl signals are well-resolved in a 2-s direct polarization (DP) spectrum without and with dipolar dephasing, which confirms that these sp2-hybridized carbons are bonded to hydrogen and partially mobile, consistent with vinyl side groups from incompletely reacted divinyl crosslinkers. The vinyl groups account for 1.6% of all carbon, 3% of the monomer units, and nearly 1/3 of the crosslinkers. Furthermore, an unexpected OCH3 moiety accounting for ∼1.2% of all carbons was identified by spectral editing; its chemical shift of 54 ppm is more consistent with a methyl ester than with a methyl ether. It can originate from incomplete hydrolysis of ∼6% of methyl-2-fluoroacrylate, the main monomer of patiromer. Characteristic cross peaks in two-dimensional 1H-13C heteronuclear correlation NMR confirm the presence of the vinyl and OCH3 groups. Trace amounts of xanthan gum are also detected. The quantitative 13C NMR spectrum of patiromer has been matched in a simulation using a model with five monomer units.
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Affiliation(s)
- Zhaoxi Zheng
- Department of Chemistry, Brandeis University, Waltham, MA 02453, USA
| | - Yongchao Su
- Analytical Research and Development, Merck & Co. Inc., Rahway, NJ 07065, USA; Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., Rahway, NJ 07065, USA
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2
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Rydell A, Thackrey C, Molki M, Mullins BP. Effectiveness of Patiromer Versus Sodium Zirconium Cyclosilicate for the Management of Acute Hyperkalemia. Ann Pharmacother 2024; 58:790-795. [PMID: 37953506 DOI: 10.1177/10600280231209968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Patiromer and sodium zirconium cyclosilicate (SZC) are 2 oral potassium binders approved for chronic hyperkalemia. It is unknown if one is more effective at reducing serum potassium than the other in acute hyperkalemia. OBJECTIVE The objective of this study was to determine if there was a difference between patiromer and SZC in the reduction of serum potassium in patients with acute hyperkalemia. METHODS This was a single-center, retrospective, observational study. Patients with a nonhemolyzed serum potassium level of 5.5 mEq/L or greater and received at least one dose of patiromer or SZC were included. The primary outcome was to determine the difference in effectiveness between patiromer and SZC in lowering of serum potassium 6 to 24 hours after administration. Secondary outcomes included description of total dosage received in 24 hours and incidence of electrolyte changes. RESULTS A total of 200 patients were included in this study, with 100 patients in each group. Serum potassium was significantly reduced by both patiromer (-1.2 mEq/L, 95% confidence interval [CI]: -2.3 to -0.2) and SZC (-0.8 mEq/L, 95% CI: -1.0 to -0.7), but there was no difference between the 2 medications in the amount of potassium reduction (P = 0.464). No clinically significant differences in electrolyte changes were seen. CONCLUSIONS AND RELEVANCE This study represents the first head-to-head comparison of patiromer and SZC in the setting of acute hyperkalemia. No difference in effectiveness between patiromer and SZC in reducing serum potassium was seen. Both agents can be considered in acute hyperkalemia management.
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Affiliation(s)
- Alison Rydell
- Pharmacy Department, Carle Foundation Hospital, Urbana, IL, USA
| | | | - Maryam Molki
- Pharmacy Department, St. Luke's Hospital, Chesterfield, MO, USA
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Abrignani MG, Gronda E, Marini M, Gori M, Iacoviello M, Temporelli PL, Benvenuto M, Binaghi G, Cesaro A, Maloberti A, Tinti MD, Riccio C, Colivicchi F, Grimaldi M, Gabrielli D, Oliva F, on behalf of the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Working Groups on Cardiological Chronicity, Cardiorenal, Metabolic, Heart Failure. Hyperkalaemia in Cardiological Patients: New Solutions for an Old Problem. Cardiovasc Drugs Ther 2024. [DOI: 10.1007/s10557-024-07551-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/09/2024] [Indexed: 01/16/2025]
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Kettritz R, Loffing J. Potassium homeostasis - Physiology and pharmacology in a clinical context. Pharmacol Ther 2023; 249:108489. [PMID: 37454737 DOI: 10.1016/j.pharmthera.2023.108489] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 07/18/2023]
Abstract
Membrane voltage controls the function of excitable cells and is mainly a consequence of the ratio between the extra- and intracellular potassium concentration. Potassium homeostasis is safeguarded by balancing the extra-/intracellular distribution and systemic elimination of potassium to the dietary potassium intake. These processes adjust the plasma potassium concentration between 3.5 and 4.5 mmol/L. Several genetic and acquired diseases but also pharmacological interventions cause dyskalemias that are associated with increased morbidity and mortality. The thresholds at which serum K+ not only associates but also causes increased mortality are hotly debated. We discuss physiologic, pathophysiologic, and pharmacologic aspects of potassium regulation and provide informative case vignettes. Our aim is to help clinicians, epidemiologists, and pharmacologists to understand the complexity of the potassium homeostasis in health and disease and to initiate appropriate treatment strategies in dyskalemic patients.
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Affiliation(s)
- Ralph Kettritz
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin Berlin, Germany.
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Sampani E, Theodorakopoulou M, Iatridi F, Sarafidis P. Hyperkalemia in chronic kidney disease: a focus on potassium lowering pharmacotherapy. Expert Opin Pharmacother 2023; 24:1775-1789. [PMID: 37545002 DOI: 10.1080/14656566.2023.2245756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/08/2023]
Abstract
INTRODUCTION Hyperkalemia is one of the most common electrolyte disorders in chronic kidney disease (CKD) and is associated with serious adverse outcomes. Hyperkalemia risk is even greater when CKD patients also have additional predisposing conditions such as diabetes or heart failure. Renin-angiotensin-aldosterone-system blockers are first-line treatments for cardio- and nephroprotection, but their use is often limited due to K+ elevation, resulting in high rates of discontinuation. AREAS COVERED This article provides an overview of factors interfering with K+ homeostasis and discusses recent data on newer therapeutic agents used for the treatment of hyperkalemia. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to April 2023. EXPERT OPINION Major clinical trials have tested new and promising kidney protective therapies such as sodium/glucose-cotransporter-2 inhibitors and mineralocorticoid-receptor-antagonists, with promising results. Until recently, the only treatment option for hyperkalemia was the cation-exchanging resin sodium-polystyrene-sulfonate. However, despite its common use, the efficacy and safety data of this drug in the long-term management of hyperkalemia are scarce. During the last decade, two novel orally administered K+-exchanging compounds (patiromer and sodium-zirconium-cyclosilicate) have been approved for the treatment of adults with hyperkalemia, as they both effectively reduce elevated serum K+ and maintain chronically K+ balance within the normal range with an excellent tolerability and no serious adverse events.
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Affiliation(s)
- Erasmia Sampani
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marieta Theodorakopoulou
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fotini Iatridi
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Hasara S, Dubey J, Amatea J, Finnigan N. Sodium polystyrene sulfonate versus sodium zirconium cyclosilicate for the treatment of hyperkalemia in the emergency department. Am J Emerg Med 2023; 65:59-64. [PMID: 36586223 DOI: 10.1016/j.ajem.2022.12.043] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Hyperkalemia accounts for over 800,000 emergency department (ED) visits in the United States each year, and has been associated with significant morbidity and mortality likely due to fatal cardiac dysrhythmias. Previous studies have demonstrated reductions in mortality when potassium levels are normalized in the ED. Cation exchange resins, such as sodium polystyrene sulfonate (SPS) and sodium zirconium cyclosilicate (SZC), may be administered as a means of definitively eliminating potassium from the body. This practice is based on physician preference and is not supported by high quality data. Two studies evaluating the use of cation exchange resins versus standard treatment in the ED demonstrated reductions in serum potassium levels within two hours of administration; however, there have been no published studies investigating these agents in a head-to-head comparison. OBJECTIVE The purpose of this study was to evaluate the efficacy and safety of SPS versus SZC in lowering serum potassium in patients presenting to the ED with hyperkalemia. METHODS This was an institutional review board-approved, retrospective cohort study conducted at a single-site ED. All patients who received medications under the "ED Hyperkalemia Treatment" order set between August 26, 2019 and May 13, 2021 were eligible for inclusion. The primary outcome was the change in serum potassium from baseline to first repeat level following SPS or SZC administration in the ED. RESULTS A total of 885 patients were screened with 54 patients in the SPS group and 51 patients in the SZC group included in the final analyses. The mean change in serum potassium from baseline to first repeat level following administration of the cation exchange resin was -1.1 mEq/L for both groups. CONCLUSION Administration of SPS or SZC for the treatment of hyperkalemia in the ED resulted in similar reductions in serum potassium.
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Affiliation(s)
- Shannon Hasara
- Department of Pharmacy, Lakeland Regional Health, 1324 Lakeland Hills Blvd., Lakeland, FL 33805, United States of America.
| | - Jesse Dubey
- Department of Emergency Medicine, Lakeland Regional Health, 1324 Lakeland Hills Blvd., Lakeland, FL 33805, United States of America
| | - John Amatea
- Department of Emergency Medicine, Lakeland Regional Health, 1324 Lakeland Hills Blvd., Lakeland, FL 33805, United States of America
| | - Nancy Finnigan
- Department of Nephrology, Lakeland Regional Health, 1324 Lakeland Hills Blvd., Lakeland, FL 33805, United States of America
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Colbert G, Sannapaneni S, Lerma EV. Clinical Efficacy, Safety, Tolerability, and Real-World Data of Patiromer for the Treatment of Hyperkalemia. Drug Healthc Patient Saf 2022; 14:87-96. [PMID: 35860695 PMCID: PMC9292454 DOI: 10.2147/dhps.s338579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 07/12/2022] [Indexed: 11/30/2022] Open
Abstract
Hyperkalemia remains one of the most difficult consequences of disease state and treatment for patients with chronic kidney disease, heart failure, and diabetes. Controlling hyperkalemia can be difficult, but has become easier with the introduction of novel oral potassium binders. Patiromer was approved in 2015 for the treatment of hyperkalemia by the FDA in the United States. Several pivotal trials proved its efficacy, safety, and improved tolerability compared with previous hyperkalemia treatments. Additionally, many real-world publications and trials have given deeper insights into the capabilities of patiromer. We discuss improved disease state outcomes with combining patiromer with RAASi. This paper will also highlight new trials forthcoming that are highly anticipated to expand the possibilities in using patiromer to improve outcomes and populations.
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Affiliation(s)
- Gates Colbert
- Department of Internal Medicine, Division of Nephrology, Texas A&M College of Medicine, Dallas, TX, USA
- Correspondence: Gates Colbert, 3417 Gaston Ave, Suite 875, Dallas, TX, 75246, Tel +972-388-5970, Fax +972-388-5971, Email
| | - Shilpa Sannapaneni
- Department of Internal Medicine, Division of Nephrology, Texas A&M College of Medicine, Dallas, TX, USA
| | - Edgar V Lerma
- Department of Internal Medicine, Division of Nephrology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA
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Nguyen PT, Kataria VK, Sam TR, Hooper K, Mehta AN. Comparison of Patiromer to Sodium Polystyrene Sulfonate in Acute Hyperkalemia. Hosp Pharm 2022; 57:359-364. [PMID: 35615481 PMCID: PMC9125127 DOI: 10.1177/00185787211037552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
Background: Patiromer and sodium polystyrene sulfonate (SPS) are cation-exchangers approved for the treatment of chronic hyperkalemia. Data regarding their efficacy acutely is lacking. Despite this, both drugs are frequently used in the emergent setting. Objective: The purpose of this study was to compare the potassium reduction of patiromer to SPS within 6 to 24 hours following a single dose. Methods: This retrospective quality improvement project included hyperkalemic patients receiving 1 dose of patiromer or SPS and had a second potassium level drawn in 6 to 24 hours. Doses of 8.4 g of patiromer and 15 g of SPS were considered "low dose" while 16.8 g of patiromer and 30 g of SPS were considered "high dose." The presence of a dose-response relationship was assessed through a linear regression analysis. Results: Mean (SD) potassium reduction was higher in SPS than patiromer [0.76 (0.63) mEq/L vs 0.32 (0.65) mEq/L, (P = .001)]. A dose response relationship was not demonstrated in low versus high dose groups [-0.21 (0.14), P = .13] and CKD, ESRD, and renal transplant patients when compared to patients with normal renal function [0.11 (0.17), P = .51, -0.07 (0.19), P = -0.07 (0.19), P = .73, and -0.10 (0.22), P = .65]. Conclusions: This study suggests a clinically significant reduction in potassium with SPS compared to patiromer. Although SPS was successful in demonstrating this outcome, due to well-documented adverse reactions in the literature and a time to onset of 6 hours, it cannot be recommended for use in acute hyperkalemia either.
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Affiliation(s)
| | | | - Teena R. Sam
- Baylor University Medical Center, Dallas, TX, USA
| | - Katie Hooper
- Baylor University Medical Center, Dallas, TX, USA
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9
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Abstract
IMPORTANCE Hyperkalemia is a common electrolyte disorder in hospitalized patients; however, the clinical usefulness of administering patiromer for reduction of serum potassium levels in this setting is unknown. OBJECTIVE To evaluate the outcomes associated with patiromer as monotherapy in patients with acute hyperkalemia in an acute care setting. DESIGN, SETTING, AND PARTICIPANTS This cohort study used electronic health record data from adult patients treated with patiromer for acute hyperkalemia in emergency departments, inpatient units, and intensive care units at an urban, academic medical center in the Bronx, New York, between January 30, 2018, and December 30, 2019. Data analysis was conducted between June 2020 and February 2021. EXPOSURES A single dose of oral patiromer (8.4 g, 16.8 g, or 25.2 g). MAIN OUTCOMES AND MEASURE The primary outcome was the mean absolute reduction in serum potassium level from baseline at 3 distinct time intervals after patiromer administration: 0 to 6 hours, greater than 6 to 12 hours, and greater than 12 to 24 hours. Key secondary outcomes were the incidence of hypokalemia and potassium reduction stratified by baseline potassium level and care setting. RESULTS Among 881 encounters of patiromer treatment, the mean (SD) age of patients was 67.4 (14.4) years; 463 encounters (52.6%) were for male patients, and most (338 [38.4%]) were for patients who identified as non-Hispanic Black. The mean (SD) baseline serum potassium level was 5.60 (0.35) mEq/L (to convert to mmol/L, multiply by 1.0), and within the first 6 hours after patiromer administration, the mean (SD) potassium reduction was 0.50 (0.56) mEq/L (P < .001). Both absolute and relative potassium reduction from baseline varied across baseline hyperkalemia severity but not by care setting. The lowest dose of patiromer (8.4 g) was used in 721 encounters (81.8%), and in 725 encounters (82.3%), no further doses of a potassium binder were required. Hypokalemia was noted in 2 encounters (0.2%) at 24 hours after patiromer administration. CONCLUSIONS AND RELEVANCE In this cohort study of patients with acute, non-life-threatening hyperkalemia, a single dose of patiromer was associated with a significant decrease in serum potassium levels and a low incidence of hypokalemia. These findings suggest that patiromer monotherapy may be useful in an institutional setting for managing elevated potassium levels and minimizing the risk of hypokalemia associated with other potassium control measures.
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Affiliation(s)
- Katherine E. Di Palo
- Center for Pharmacotherapy Research and Quality, Department of Pharmacy, Montefiore Medical Center, Bronx, New York
- Division of Hospital Medicine, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
| | - Mark J. Sinnett
- Center for Pharmacotherapy Research and Quality, Department of Pharmacy, Montefiore Medical Center, Bronx, New York
| | - Pavel Goriacko
- Center for Pharmacotherapy Research and Quality, Department of Pharmacy, Montefiore Medical Center, Bronx, New York
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
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Jaques DA, Stucker F, Ernandez T, Alves C, Martin PY, De Seigneux S, Saudan P. OUP accepted manuscript. Clin Kidney J 2022; 15:1908-1914. [PMID: 36158152 PMCID: PMC9494516 DOI: 10.1093/ckj/sfac129] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Indexed: 12/05/2022] Open
Abstract
Background Hyperkalaemia is frequent in haemodialysis (HD) patients and associated with increased cardiovascular mortality. Despite routine clinical use, evidence regarding the efficacy of potassium (K+) binders in HD is scant. We wished to compare the efficacy of patiromer (PAT) and sodium polystyrene sulfonate (SPS) on K+ levels in this setting. Methods We screened patients in three HD centres with pre-HD K+ value between 5.0 and 6.4 mmol/L, after an initial 2-week washout period for those previously on K+ binders. We included patients in an unblinded two-arm crossover trial comparing SPS 15 g before each meal on non-dialysis days with PAT 16.8 g once daily on non-dialysis days with randomized attribution order and a 2-week intermediate washout period. The primary outcome was the mean weekly K+ value. Results We included 51 patients and analysed 48 with mean age of 66.4 ± 19.4 years, 72.9% men and 43.4% diabetics. Mean weekly K+ values were 5.00 ± 0.54 mmol/L, 4.55 ± 0.75 mmol/L and 5.17 ± 0.64 mmol/L under PAT (P = .003), SPS (P < .001) and washout, respectively. In direct comparison, K+ values and prevalence of hyperkalaemia were lower under SPS as compared with PAT (P < .001). While the incidence of gastrointestinal side effects was similar between treatments, SPS showed lower subjective tolerability score (6.0 ± 2.4 and 6.9 ± 1.9) and compliance (10.8 ± 20.4% and 2.4 ± 7.3% missed doses) as compared with PAT (P < .001 for both). Conclusion Both PAT and SPS are effective in decreasing K+ levels in chronic HD patients. However, at the tested doses, SPS was significantly more effective in doing so as compared with PAT, despite lower tolerability and compliance. Larger randomized controlled trials should be conducted in order to confirm our findings and determine whether they would impact clinical outcomes.
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Affiliation(s)
| | - Fabien Stucker
- Division of Nephrology, Hôpital de la Providence, Neuchâtel, Switzerland
| | - Thomas Ernandez
- Division of Nephrology, Hôpital de la Tour, Geneva, Switzerland
| | - Cyrielle Alves
- Division of Nephrology, Geneva University Hospitals, Geneva, Switzerland
| | - Pierre-Yves Martin
- Division of Nephrology, Geneva University Hospitals, Geneva, Switzerland
| | - Sophie De Seigneux
- Division of Nephrology, Geneva University Hospitals, Geneva, Switzerland
| | - Patrick Saudan
- Division of Nephrology, Geneva University Hospitals, Geneva, Switzerland
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11
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Rizk JG, Lazo JG, Quan D, Gabardi S, Rizk Y, Streja E, Kovesdy CP, Kalantar-Zadeh K. Mechanisms and management of drug-induced hyperkalemia in kidney transplant patients. Rev Endocr Metab Disord 2021; 22:1157-1170. [PMID: 34292479 DOI: 10.1007/s11154-021-09677-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/16/2021] [Indexed: 10/20/2022]
Abstract
Hyperkalemia is a common and potentially life-threatening complication following kidney transplantation that can be caused by a composite of factors such as medications, delayed graft function, and possibly potassium intake. Managing hyperkalemia after kidney transplantation is associated with increased morbidity and healthcare costs, and can be a cause of multiple hospital admissions and barriers to patient discharge. Medications used routinely after kidney transplantation are considered the most frequent culprit for post-transplant hyperkalemia in recipients with a well-functioning graft. These include calcineurin inhibitors (CNIs), pneumocystis pneumonia (PCP) prophylactic agents, and antihypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers). CNIs can cause hyperkalemic renal tubular acidosis. When hyperkalemia develops following transplantation, the potential offending medication may be discontinued, switched to another agent, or dose-reduced. Belatacept and mTOR inhibitors offer an alternative to calcineurin inhibitors in the event of hyperkalemia, however should be prescribed in the appropriate patient. While trimethoprim/sulfamethoxazole (TMP/SMX) remains the gold standard for prevention of PCP, alternative agents (e.g. dapsone, atovaquone) have been studied and can be recommend in place of TMP/SMX. Antihypertensives that act on the Renin-Angiotensin-Aldosterone System are generally avoided early after transplant but may be indicated later in the transplant course for patients with comorbidities. In cases of mild to moderate hyperkalemia, medical management can be used to normalize serum potassium levels and allow the transplant team additional time to evaluate the function of the graft. In the immediate post-operative setting following kidney transplantation, a rapidly rising potassium refractory to medical therapy can be an indication for dialysis. Patiromer and sodium zirconium cyclosilicate (ZS-9) may play an important role in the management of chronic hyperkalemia in kidney transplant patients, although additional long-term studies are necessary to confirm these effects.
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Affiliation(s)
- John G Rizk
- Arizona State University, Edson College, Phoenix, AZ, USA.
| | - Jose G Lazo
- UCSF Medical Center, University of California San Francisco, San Francisco, CA, USA
| | - David Quan
- UCSF Medical Center, University of California San Francisco, San Francisco, CA, USA
| | - Steven Gabardi
- Department of Transplant Surgery, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Youssef Rizk
- Department of Internal Medicine, Division of Family Medicine, Lebanese American University Medical Center - St. John's Hospital, Beirut, Lebanon
| | - Elani Streja
- Department of Medicine, Division of Nephrology, Hypertension and Kidney Transplantation, School of Medicine, University of California, CA, Irvine, Orange, USA
| | - Csaba P Kovesdy
- Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Kamyar Kalantar-Zadeh
- Department of Medicine, Division of Nephrology, Hypertension and Kidney Transplantation, School of Medicine, University of California, CA, Irvine, Orange, USA
- Department of Epidemiology, University of California, UCLA Fielding School of Public Health, Los Angeles, CA, USA
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Li S, Yakabe K, Zai K, Liu Y, Kishimura A, Hase K, Kim YG, Mori T, Katayama Y. Specific adsorption of a β-lactam antibiotic in vivo by an anion-exchange resin for protection of the intestinal microbiota. Biomater Sci 2021; 9:7219-7227. [PMID: 34581317 DOI: 10.1039/d1bm00958c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The fraction of antibiotics that are excreted from the intestine during administration leads to disruption of commensal bacteria as well as resulting in dysbiosis and various diseases. To protect the gut microbiota during treatment with antibiotics, use of activated carbon (AC) has recently been reported as a method to adsorb antibiotics. However, the antibiotic adsorption by AC is nonspecific and may also result in the adsorption of essential biological molecules. In this work, we reported that an anion exchange resin (AER) has better specificity than AC for adsorbing the β-lactam antibiotic cefoperazone (CEF). Because CEF has a negatively charged carboxylate group and a conjugated system, the AER was used to adsorb CEF through electrostatic and π-π interactions. The AER was specific for CEF over biological molecules such as bile acids and vitamins in the intestine. The AER protected Escherichia coli from CEF in vitro. Furthermore, oral administration of the AER reduced the fecal free CEF concentration, and protected the gut microbiota from CEF-induced dysbiosis.
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Affiliation(s)
- Shunyi Li
- Graduate School of Systems Life Sciences, Kyushu University, Fukuoka, 819-0395, Japan.
| | - Kyosuke Yakabe
- Division of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, 105-8512, Japan.,Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, 105-8512, Japan.
| | - Khadijah Zai
- Department of Pharmaceutics, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, 55281, Indonesia
| | - Yiwei Liu
- Department of Applied Chemistry, Faculty of Engineering, Kyushu University, Fukuoka, 819-0395, Japan
| | - Akihiro Kishimura
- Graduate School of Systems Life Sciences, Kyushu University, Fukuoka, 819-0395, Japan. .,Department of Applied Chemistry, Faculty of Engineering, Kyushu University, Fukuoka, 819-0395, Japan.,Center for Future Chemistry, Kyushu University, Fukuoka, 819-0395, Japan.,International Research Center for Molecular Systems, Kyushu University, Fukuoka, 819-0395, Japan
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, 105-8512, Japan.,Division of Mucosal Barrierology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Yun-Gi Kim
- Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, 105-8512, Japan.
| | - Takeshi Mori
- Graduate School of Systems Life Sciences, Kyushu University, Fukuoka, 819-0395, Japan. .,Department of Applied Chemistry, Faculty of Engineering, Kyushu University, Fukuoka, 819-0395, Japan.,Center for Future Chemistry, Kyushu University, Fukuoka, 819-0395, Japan
| | - Yoshiki Katayama
- Graduate School of Systems Life Sciences, Kyushu University, Fukuoka, 819-0395, Japan. .,Department of Applied Chemistry, Faculty of Engineering, Kyushu University, Fukuoka, 819-0395, Japan.,Center for Future Chemistry, Kyushu University, Fukuoka, 819-0395, Japan.,International Research Center for Molecular Systems, Kyushu University, Fukuoka, 819-0395, Japan.,Centre for Advanced Medicine Innovation, Kyushu University, Fukuoka, 812-8582, Japan.,Department of Biomedical Engineering, Chung Yuan Christian University, Taiwan, 32023, Republic of China
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13
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Rafique Z, Peacock F, Armstead T, Bischof JJ, Hudson J, Weir MR, Neuenschwander J. Hyperkalemia management in the emergency department: An expert panel consensus. J Am Coll Emerg Physicians Open 2021; 2:e12572. [PMID: 34632453 PMCID: PMC8485984 DOI: 10.1002/emp2.12572] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/18/2021] [Accepted: 09/16/2021] [Indexed: 01/11/2023] Open
Abstract
Hyperkalemia is a common electrolyte abnormality identified in the emergency department (ED) and potentially fatal. However, there is no consensus over the potassium threshold that warrants intervention or its treatment algorithm. Commonly used medications are at best temporizing measures, and the roles of binders are unclear in the emergent setting. As the prevalence of comorbid conditions altering potassium homeostasis rises, hyperkalemia becomes more common, and hence there is a need to standardize management. A panel was assembled to synthesize the available evidence and identify gaps in knowledge in hyperkalemia treatment in the ED. The panel was composed of 7 medical practitioners, including 5 physicians, a nurse, and a clinical pharmacist with collective expertise in the areas of emergency medicine, nephrology, and hospital medicine. This panel was sponsored by the American College of Emergency Physicians with a goal to create a consensus document for managing acute hyperkalemia. The panel evaluated the evidence on calcium for myocyte stabilization and potassium shifting and excretion. This article summarizes information on available therapies for hyperkalemia and proposes a hyperkalemia treatment algorithm for the ED practitioner based on the currently available literature and highlights diagnostic pitfalls and evidence gaps.
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Affiliation(s)
- Zubaid Rafique
- Baylor College of MedicineDepartment of Emergency MedicineBen Taub General HospitalHoustonTexasUSA
| | - Frank Peacock
- Baylor College of MedicineDepartment of Emergency MedicineBen Taub General HospitalHoustonTexasUSA
| | | | - Jason J. Bischof
- The Ohio State UniversityDepartment of Emergency MedicineColumbusOhioUSA
| | - Joanna Hudson
- The University of Tennessee Health Science CenterDepartments of Clinical Pharmacy and Translational Science & Medicine (Nephrology)MemphisTennesseeUSA
| | - Matthew R. Weir
- Division of NephrologyDepartment of MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - James Neuenschwander
- The Ohio State UniversityDepartment of Emergency MedicineColumbusOhioUSA
- Genesis Healthcare SystemDepartment of Emergency MedicineZanesvilleOhioUSA
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14
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Shibata S, Uchida S. Hyperkalemia in patients undergoing hemodialysis: its pathophysiology and management. Ther Apher Dial 2021; 26:3-14. [PMID: 34378859 PMCID: PMC9291487 DOI: 10.1111/1744-9987.13721] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/01/2021] [Accepted: 08/09/2021] [Indexed: 11/28/2022]
Abstract
Potassium is a major intracellular cation in the body, regulating membrane potential of excitable cells, such as cardiomyocytes and skeletal muscle cells. Because the kidney plays a critical role in controlling potassium balance, the elevation in serum potassium levels is one of the most common complications in patients with maintenance hemodialysis (MHD). In addition to reduced renal potassium excretion, the alteration in body potassium distribution owing to comorbid conditions may also contribute to dyskalemia. Besides potassium elimination through hemodialysis in MHD patients, accumulating data indicate the potential importance of extra‐renal elimination involving the gastrointestinal system, which can be affected by the inhibitors of the renin‐angiotensin‐aldosterone system. In this article, the literature on potassium physiology in MHD patients is reviewed with an emphasis on the changes from individuals with normal kidney function. This article also summarizes the findings of recent studies on dietary control, dialysate prescription, and pharmacological therapy.
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Affiliation(s)
- Shigeru Shibata
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Shunya Uchida
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.,Department of Health Care, Teikyo Heisei University, Tokyo, Japan
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15
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Rastogi A, Hanna RM, Mkrttchyan A, Khalid M, Yaqoob S, Shaffer K, Dhawan P, Nobakht N, Kamgar M, Goshtaseb R, Sarmosyan K, Gnarini M, Wassef O, Lerma E. Sodium zirconium cyclosilicate for the management of chronic hyperkalemia in kidney disease, a novel agent. Expert Rev Clin Pharmacol 2021; 14:1055-1064. [PMID: 34227913 DOI: 10.1080/17512433.2021.1932460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Hyperkalemia is a common finding in patients with advanced kidney disease for multiple reasons. Renin-Angiotensin-Aldosterone-System Inhibitors (RAASi) that are indicated for slowing down progression of kidney disease are often associated with hyperkalemia which becomes a limiting factor in their use and titration to the maximum dose. Having a safe, effective, tolerable, and affordable potassium binder can help optimize RAAS inhibition in the setting of kidney disease. AREAS COVERED Although sodium polystyrene sulfonate has been a mainstay of acute management of hyperkalemia for decades, evidence regarding its efficacy is limited, and its chronic use is not routinely recommended for concerns regarding toxicity. The concern of gastrointestinal (GI) adverse effects with sodium polystyrene sulfonate has spurred the development of alternatives. Sodium zirconium cyclosilicate (SZC) is a promising agent that selectively binds potassium in the gut and eliminates it, while being safe for chronic use based on 1 year of data. Even though we do not have head-to-head studies among the three currently available binders, SZC stands out in rapidity of onset and efficacy. EXPERT OPINION In this review, we summarize the general management of hyperkalemia, including new agents. We review the pre-clinical and clinical data relating to sodium zirconium cyclosilicate.
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Affiliation(s)
- Anjay Rastogi
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | - Ramy M Hanna
- Department of Medicine, Division of Nephrology, University of California Irvine Medical Center, USA
| | - Anita Mkrttchyan
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | - Maham Khalid
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | - Sinan Yaqoob
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | - Kelly Shaffer
- Department of Medicine, UCLA CORE Kidney Health Program Collaborator, USA
| | - Puneet Dhawan
- Division of Cardiothoracic Surgery at David Geffen School of Medicine, UCLA, USA
| | - Niloofar Nobakht
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | - Mohammad Kamgar
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | - Ray Goshtaseb
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | - Kristine Sarmosyan
- CORE Kidney Health Program at David Geffen School of Medicine, UCLA, USA.,Department of Medicine, Division of Nephrology, UCLA-Health, USA
| | | | - Olivia Wassef
- Department of Medicine, UCLA CORE Kidney Health Program Collaborator, USA
| | - Edgar Lerma
- Division of Nephrology, University of Illinois at Chicago, Chicago, USA
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16
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Singh J, Kichloo A, Vipparla N, Aljadah M, Albosta M, Jamal S, Ananthaneni S, Parajuli S. Hyperkalemia: Major but still understudied complication among heart transplant recipients. World J Transplant 2021; 11:203-211. [PMID: 34164295 PMCID: PMC8218349 DOI: 10.5500/wjt.v11.i6.203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/17/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Hyperkalemia is a recognized and potentially life-threatening complication of heart transplantation. In the complex biosystem created by transplantation, recipients are susceptible to multiple mechanisms for hyperkalemia which are discussed in detail in this manuscript. Hyperkalemia in heart transplantation could occur pre-transplant, during the transplant period, or post-transplant. Pre-transplant causes of hyperkalemia include hypothermia, donor heart preservation solutions, conventional cardioplegia, normokalemic cardioplegia, continuous warm reperfusion technique, and ex-vivo heart perfusion. Intra-transplant causes of hyperkalemia include anesthetic medications used during the procedure, heparinization, blood transfusions, and a low output state. Finally, post-transplant causes of hyperkalemia include hemostasis and drug-induced hyperkalemia. Hyperkalemia has been studied in kidney and liver transplant recipients, but there is limited data on the incidence, causes, management, and prevention in heart transplant recipients. Hyperkalemia is associated with an increased risk of hospital mortality and readmission in these patients. This review describes the current literature pertaining to the causes, pathophysiology, and treatment of hyperkalemia in patients undergoing heart transplantation and focuses primarily on post-heart transplantation.
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Affiliation(s)
- Jagmeet Singh
- Department of Nephrology, Guthrie Robert Packer Hospital, Sayre, PA 18840, United States
| | - Asim Kichloo
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI 48602, United States
| | - Navya Vipparla
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI 48602, United States
| | - Michael Aljadah
- Department of Internal Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Michael Albosta
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI 48602, United States
| | - Shakeel Jamal
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI 48602, United States
| | - Sindhura Ananthaneni
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI 48602, United States
| | - Sandesh Parajuli
- Department of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States
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17
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Abstract
Hyperkalaemia has become an increasingly prevalent finding in patients with heart failure (HF), especially with renin–angiotensin–aldosterone system (RAAS) inhibitors and angiotensin–neprilysin inhibitors being the cornerstone of medical therapy. Patients living with HF often have other comorbidities, such as diabetes and chronic kidney disease, which predispose to hyperkalaemia. Until now, we have not had any reliable or tolerable therapies for the treatment of hyperkalaemia to facilitate implementation or achievement of target doses of RAAS inhibition. Patiromer sorbitex calcium and sodium zirconium cyclosilicate are two novel potassium-binding resins that have shown promise in the management of patients predisposed to developing recurrent hyperkalaemia, and their use may allow for further optimisation of guideline directed medical therapy.
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Affiliation(s)
- Umar Ismail
- Section of Cardiology, Max Rady College of Medicine, University of Manitoba Winnipeg, Manitoba, Canada
| | - Kiran Sidhu
- Section of Cardiology, Max Rady College of Medicine, University of Manitoba Winnipeg, Manitoba, Canada
| | - Shelley Zieroth
- Section of Cardiology, Max Rady College of Medicine, University of Manitoba Winnipeg, Manitoba, Canada
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18
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Increased colonic K + excretion through inhibition of the H,K-ATPase type 2 helps reduce plasma K + level in a murine model of nephronic reduction. Sci Rep 2021; 11:1833. [PMID: 33469051 PMCID: PMC7815745 DOI: 10.1038/s41598-021-81388-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 12/21/2020] [Indexed: 11/09/2022] Open
Abstract
Hyperkalemia is frequently observed in patients at the end-stage of chronic kidney disease (CKD), and has possible harmful consequences on cardiac function. Many strategies are currently used to manage hyperkalemia, one consisting of increasing fecal K+ excretion through the administration of cation-exchange resins. In this study, we explored another more specific method of increasing intestinal K+ secretion by inhibiting the H,K-ATPase type 2 (HKA2), which is the main colonic K+ reabsorptive pathway. We hypothetised that the absence of this pump could impede the increase of plasma K+ levels following nephronic reduction (N5/6) by favoring fecal K+ secretion. In N5/6 WT and HKA2KO mice under normal K+ intake, the plasma K+ level remained within the normal range, however, a load of K+ induced strong hyperkalemia in N5/6 WT mice (9.1 ± 0.5 mM), which was significantly less pronounced in N5/6 HKA2KO mice (7.9 ± 0.4 mM, p < 0.01). This was correlated to a higher capacity of HKA2KO mice to excrete K+ in their feces. The absence of HKA2 also increased fecal Na+ excretion by inhibiting its colonic ENaC-dependent absorption. We also showed that angiotensin-converting-enzyme inhibitor like enalapril, used to treat hypertension during CKD, induced a less severe hyperkalemia in N5/6 HKA2KO than in N5/6 WT mice. This study therefore provides the proof of concept that the targeted inhibition of HKA2 could be a specific therapeutic maneuver to reduce plasma K+ levels in CKD patients.
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19
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Wu YH, Chou JW, Lai HC, Su GS, Cheng KS, Chen TW. Adverse Gastrointestinal Effects with Kayexalate or Kalimate: A Comprehensive Review. Clin Exp Gastroenterol 2021; 14:1-18. [PMID: 33469334 PMCID: PMC7810591 DOI: 10.2147/ceg.s278812] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/24/2020] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Patients with hyperkalemia are commonly treated with Kayexalate or Kalimate. Both drugs are associated with some fatal gastrointestinal (GI) adverse events (AEs). AIM To assess the clinical characteristics and outcomes of GI AEs induced by Kayexalate or Kalimate from published case reports. METHODS We conducted a systematic review of case reports of Kayexalate or Kalimate-induced GI AEs, from PubMed, Medline, Cochrane Library, Clinical Key, and Google Scholar databases (1948 to March 31, 2020). We analyzed the clinical characteristics, GI AEs, and risk factors of enrolled patients. RESULTS We identified 41 published articles describing 135 cases of GI AEs induced by Kayexalate (103 cases) or Kalimate (32 cases). The mean age of all patients was 55.5 years. Most patients were male (54.8%). As high as 55.6% preparations were administered with sorbitol whereas 44.4% preparations had no sorbitol. The average time causing GI AEs was 19.8 days. Colon was the most commonly affected site (76.3%). Drug crystals were histopathologically proven in 95.5% of the patients. Meanwhile, mortality was reported in 20.7%. CONCLUSION Kayexalate or Kalimate, without or with sorbitol combination, may be related to fatal GI damage. Uremia, hypertension, and transplantation are predisposing factors. Clinicians should be careful in prescribing Kayexalate or Kalimate to patients.
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Affiliation(s)
- Yi-Hua Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jen-Wei Chou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University Hospital, Taichung, Taiwan
- Taiwan Society of Inflammatory Bowel Disease, Taipei, Taiwan
- Taiwan Association for the Study of Small Intestinal Diseases, Taoyuan, Taiwan
- Correspondence: Jen-Wei Chou Division of Gastroenterology and Hepatology, Department of Internal Medicine. China Medical University Hospital, No. 2, Yude Road, North District, Taichung40447, TaiwanTel + 886-4-22052121 ext. 2220Fax +886-4-22023119 Email
| | - Hsiang-Chun Lai
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Gin-Shen Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ken-Sheng Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Tsung-Wei Chen
- Department of Pathology, Asia University Hospital, Taichung, Taiwan
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20
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Wong SWS, Zhang G, Norman P, Welihinda H, Wijeratne DT. Polysulfonate Resins in Hyperkalemia: A Systematic Review. Can J Kidney Health Dis 2020; 7:2054358120965838. [PMID: 33240515 PMCID: PMC7675864 DOI: 10.1177/2054358120965838] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/24/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Hyperkalemia is a potentially life-threatening electrolyte abnormality defined as a serum potassium above the lab reference range (usually >5.0-5.5 mEq/L). Polystyrene resins, including sodium polystyrene sulfonate (SPS) and calcium polystyrene sulfonate (CPS), have long been used to treat hyperkalemia. Sodium polystyrene sulfonate/calcium polystyrene sulfonate act by exchanging a cation for potassium within the intestinal lumen. While SPS and CPS have been available since the 1960s, there are rising concerns about the validity of the data supporting its use and about serious adverse gastrointestinal effects. OBJECTIVE The objective of this systematic review was to quantify the efficacy and safety of polystyrene sulfonate resins (SPS/CPS) in the treatment of adults with hyperkalemia. This review focuses on the randomized control trial (RCT), interventional non-RCT, and observational data available on SPS/CPS use. DESIGN Systematic review. SETTING Any country of origin. Both inpatient and outpatient settings. PATIENTS Adults with hyperkalemia treated with polystyrene sulfonate resins. MEASUREMENTS The primary outcome was change in serum potassium. The secondary outcomes included adverse effects of SPS/CPS and prevention of recurrent hyperkalemia. METHODS We conducted a systematic review using Cochrane Library, EMBASE (1947-2019), and Medline (1946-2019) databases. Literature reviews, systematic reviews, case studies, case series, and editorial pieces were excluded. Included studies were assessed for risk of bias. RESULTS Four RCTs, 21 observational studies, and 5 quasi-experimental trials were included. A total of 212 351 patients were included. Two thousand and fifty-eight patients were studied for the primary outcome and 210 293 patients were studied for the secondary outcomes. Study designs were heterogeneous and not amenable to meta-analysis. Most studies included nonhemodialysis outpatients older than 65 years. Of the included studies, 22/25 (88%) demonstrated a reduction of serum potassium >0.5 mEq/L over the study period. The magnitude of reduction in serum potassium of potassium resin compared with placebo or matched controls in the 3 low-risk studies identified was 0.14 to 1.04 mEq/L. However, each study used different dosing regimens. Ten of 22 studies reported the effects of polystyrene resins on serum potassium within 24 hours. A few high-quality observational studies suggest an increased risk of serious adverse gastrointestinal events with a relative risk of 2.10 and a hazard ratio of 1.25 to 1.94; however, the absolute risk remains low. The incidence of adverse gastrointestinal events is 16 to 23 events per 1000 person-years. LIMITATIONS We acknowledge several limitations in this study. Case studies and case series were excluded from the search results. Large case series may have been excluded despite having comparable sample sizes to studies included due to lack of a comparator and calculated estimates. Due to the heterogeneity of the studies, the data were unable to be meta-analyzed and as such the potassium-lowering effect of polystyrene sulfonate resins remains founded on small studies with potential confounders. CONCLUSIONS This systematic review demonstrates a continued lack of high-quality evidence for the use of SPS/CPS in hyperkalemia. Studies investigated highly variable timelines and the most robust evidence for SPS/CPS use is in chronic hyperkalemia. While the absence of high-quality evidence does not exclude the possibility of benefit, prescribers must understand that the use of SPS/CPS in acute hyperkalemia is not supported by high-quality evidence. TRIAL REGISTRATION The protocol for this systematic review was not registered.
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Affiliation(s)
| | - Grace Zhang
- Department of Internal Medicine, Queen’s University, Kingston, ON, Canada
| | | | - Hasitha Welihinda
- School of Medicine, Queen’s University, Kingston, ON, Canada
- Kingston Health Sciences Centre, ON, Canada
| | - Don Thiwanka Wijeratne
- School of Medicine, Queen’s University, Kingston, ON, Canada
- Kingston Health Sciences Centre, ON, Canada
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21
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Takkar C, Nassar T, Qunibi W. An evaluation of sodium zirconium cyclosilicate as a treatment option for hyperkalemia. Expert Opin Pharmacother 2020; 22:19-28. [PMID: 32892634 DOI: 10.1080/14656566.2020.1810234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Hyperkalemia, defined as serum potassium level > 5.0 mEq/l, is associated with serious cardiac dysrhythmias, sudden death and increased mortality risk. It is common in patients with chronic kidney disease (CKD), diabetes (DM) and heart failure (HF), particularly in those treated with the renin-angiotensin-aldosterone system (RAAS) inhibitors or potassium-sparing diuretics. Although these drugs have documented renal and cardiac protective benefits, frequent hyperkalemia associated with their use often dictates administration of suboptimal doses or their discontinuation altogether. Treatment for chronic hyperkalemia in these settings has been challenging; however, the recent introduction of two new potassium-binding resins has revolutionized our approach to treating hyperkalemia. AREAS COVERED We review key clinical data relating to the pharmacokinetics, efficacy and safety of sodium zirconium cyclosilicate (SZC) as a treatment option for hyperkalemia. EXPERT OPINION SZC and Patiromer are promising new agents for lowering serum potassium in hyperkalemic patients, including those with CKD, with and without DM or HF, facilitating the use of the RAAS inhibitors for renal and cardiac protection. Recent randomized clinical trials have shown that SZC effectively lowers serum potassium and maintains normokalemia in most hyperkalemic patients. Clinical trials showed that SZC lowers serum potassium within 1 h, although it is not approved for treating acute hyperkalemia. SZC was well tolerated and associated with minimal adverse effects.
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Affiliation(s)
- Chandan Takkar
- Internal Medicine, Division of Nephrology, University of Texas Health Science Center at San Antonio , San Antonio, USA
| | - Tareq Nassar
- Division of Nephrology, University of Texas Health Science Center at San Antonio, Internal Medicine , San Antonio, USA
| | - Wajeh Qunibi
- Internal Medicine, Division of Nephrology, University of Texas Health Science Centre and Texas Diabetes Institute , San Antonio, USA
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22
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Laureati P, Xu Y, Trevisan M, Schalin L, Mariani I, Bellocco R, Sood MM, Barany P, Sjölander A, Evans M, Carrero JJ. Initiation of sodium polystyrene sulphonate and the risk of gastrointestinal adverse events in advanced chronic kidney disease: a nationwide study. Nephrol Dial Transplant 2020; 35:1518-1526. [PMID: 31377791 PMCID: PMC7473802 DOI: 10.1093/ndt/gfz150] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 06/27/2019] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Despite long-standing clinical use of sodium polystyrene sulphonate (SPS) for hyperkalaemia management in chronic kidney disease (CKD), its safety profile remains poorly investigated. METHODS We undertook an observational analysis of nephrology-referred adults with incident CKD Stage 4+ in Sweden during 2006-16 and with no previous SPS use. We studied patterns of use and adverse events associated to SPS initiation during follow-up. Patterns of SPS use were defined by chronicity of treatment and by prescribed dose. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with SPS initiation (time-varying exposure) for the risk of severe (intestinal ischaemia, thrombosis or ulceration/perforation) and minor (de novo dispensation of laxatives or anti-diarrheal drugs) gastrointestinal (GI) events. RESULTS Of 19 530 SPS-naïve patients with CKD, 3690 initiated SPS during follow-up. A total of 59% took SPS chronically, with an average of three dispensations/year. The majority (85%) were prescribed lower dosages than specified on the product label. During follow-up, 202 severe and 1149 minor GI events were recorded. SPS initiation was associated with a higher incidence of severe adverse events [adjusted HR 1.25 95% CI 1.05-1.49)], particularly in those receiving per label doses [1.54 (1.09-2.17)] and mainly attributed to ulcers and perforations. SPS initiation was also associated with higher incidence of minor GI events [adjusted HR 1.11 (95% CI 1.03-1.19)], regardless of dose, and mainly accounted for by de novo dispensation of laxatives. CONCLUSIONS Initiation of SPS in patients with advanced CKD is associated with a higher risk of severe GI complications as well as the initiation of GI-related medications, particularly when prescribed at per label doses.
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Affiliation(s)
- Paola Laureati
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- University of Milano-Bicocca, Milan, Italy
| | - Yang Xu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Marco Trevisan
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | | | - Illaria Mariani
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- University of Milano-Bicocca, Milan, Italy
| | - Rino Bellocco
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- University of Milano-Bicocca, Milan, Italy
| | - Manish M Sood
- Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Peter Barany
- Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Arvid Sjölander
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Marie Evans
- Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Juan J Carrero
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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23
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Esposito P, Conti NE, Falqui V, Cipriani L, Picciotto D, Costigliolo F, Garibotto G, Saio M, Viazzi F. New Treatment Options for Hyperkalemia in Patients with Chronic Kidney Disease. J Clin Med 2020; 9:2337. [PMID: 32707890 PMCID: PMC7465118 DOI: 10.3390/jcm9082337] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/09/2020] [Accepted: 07/21/2020] [Indexed: 02/07/2023] Open
Abstract
Hyperkalemia may cause life-threatening cardiac and neuromuscular alterations, and it is associated with high mortality rates. Its treatment includes a multifaceted approach, guided by potassium levels and clinical presentation. In general, treatment of hyperkalemia may be directed towards stabilizing cell membrane potential, promoting transcellular potassium shift and lowering total K+ body content. The latter can be obtained by dialysis, or by increasing potassium elimination by urine or the gastrointestinal tract. Until recently, the only therapeutic option for increasing fecal K+ excretion was represented by the cation-exchanging resin sodium polystyrene sulfonate. However, despite its common use, the efficacy of this drug has been poorly studied in controlled studies, and concerns about its safety have been reported. Interestingly, new drugs, namely patiromer and sodium zirconium cyclosilicate, have been developed to treat hyperkalemia by increasing gastrointestinal potassium elimination. These medications have proved their efficacy and safety in large clinical trials, involving subjects at high risk of hyperkalemia, such as patients with heart failure and chronic kidney disease. In this review, we discuss the mechanisms of action and the updated data of patiromer and sodium zirconium cyclosilicate, considering that the availability of these new treatment options offers the possibility of improving the management of both acute and chronic hyperkalemia.
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Affiliation(s)
- Pasquale Esposito
- Clinica Nefrologica, Dialisi, Trapianto, Department of Internal Medicine, University of Genoa and IRCCS Ospedale Policlinico San Martino, Viale Benedetto XV, 16132 Genoa, Italy; (N.E.C.); (V.F.); (L.C.); (D.P.); (F.C.); (G.G.); (M.S.); (F.V.)
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Pellegrinelli M, Marchesi M, Morini O, Lotti M. Bowel perforation complicating sodium polystyrene sulfonate (Kayexalate®) therapy. Chirurgia (Bucur) 2020. [DOI: 10.23736/s0394-9508.19.04942-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Labriola L, Jadoul M. Sodium polystyrene sulfonate: still news after 60 years on the market. Nephrol Dial Transplant 2020; 35:1455-1458. [DOI: 10.1093/ndt/gfaa004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 12/28/2019] [Indexed: 11/13/2022] Open
Affiliation(s)
- Laura Labriola
- Division of Nephrology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Michel Jadoul
- Division of Nephrology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
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26
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Shahar‐Nissan K, Peled O, Krause I. The ice cream challenge: A favourable extemporaneous Kayexalate formulation improves compliance in paediatric patients. Br J Clin Pharmacol 2019; 85:2450-2452. [PMID: 31392771 PMCID: PMC6783585 DOI: 10.1111/bcp.14067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 07/02/2019] [Accepted: 07/05/2019] [Indexed: 11/30/2022] Open
Affiliation(s)
- Keren Shahar‐Nissan
- Department of Pediatrics CSchneider Children's Medical CenterPetah TikvaIsrael
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
| | - Orit Peled
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
- Department of PharmacySchneider Children's Medical CenterPetah TikvaIsrael
| | - Irit Krause
- Department of Pediatrics CSchneider Children's Medical CenterPetah TikvaIsrael
- Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
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Treatment of infant formula with patiromer dose dependently decreases potassium concentration. Pediatr Nephrol 2019; 34:1395-1401. [PMID: 30963285 DOI: 10.1007/s00467-019-04232-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/04/2019] [Accepted: 03/07/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hyperkalemia is a potentially life-threatening complication of chronic kidney disease (CKD). Dietary potassium restriction is challenging in infants despite low-potassium formulas. Decreasing potassium in formula using patiromer, a new calcium-based cation exchange polymer may be one option to accomplish this; however, data confirming efficacy is lacking. METHODS Varying doses of patiromer were added to prepared Similac Advance and Similac PM 60/40. Measurements of potassium, calcium, sodium, magnesium, and phosphorus were obtained at baseline and at 30 min, 60 min, and 24 h following patiromer administration. RESULTS Following pre-treatment with patiromer, the potassium concentration of both formulas decreased. This effect was mild with the lowest dose but increased in a dose-dependent fashion. Treating for 60 min or 24 h did not yield substantially greater effects than treating for 30 min. Calcium levels increased in both formula groups, mostly in a dose-dependent fashion. Changes in magnesium, sodium, and phosphorus were also seen after patiromer pre-treatment. CONCLUSIONS Pre-treatment with patiromer decreases the potassium concentration of infant formula. Calcium levels increased after treatment as expected with the majority of ion exchange occurring in 30 min. Treatment of formula with patiromer shows promise as a unique option for managing hyperkalemia.
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28
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Fractal Deposits of a Hemostatic Hydrophilic Polymer in Mohs Micrographic Surgery Frozen Sections: A Histologic Analysis and Comparison With Sodium Polystyrene Sulfonate (Kayexalate). Am J Dermatopathol 2019; 42:258-260. [PMID: 31295160 DOI: 10.1097/dad.0000000000001465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Hydrophilic polymer with potassium ferrate (HPPF) powder is available as an over-the-counter hemostatic agent used by patients to stop superficial bleeding. In dermatology, it is applied to stop bleeding after superficial shave or punch biopsies or in open wounds after Mohs micrographic surgery. Despite its widespread availability, however, HPPF in histopathologic skin sections is highly unusual. We noted HPPF in skin closely resembles sodium polystyrene sulfonate (SPS) seen in colonic necrosis; SPS is a potassium binder given orally or rectally in hyperkalemic patients with end-stage renal disease. We describe the in vivo and in vitro histologic appearance of HPPF, compare HPPF with SPS, and discuss its potential migration into blood or lymph vessels.
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Ko CY, Liu PY, Chen PW. Successful management of severe acute respiratory distress syndrome caused by sodium polystyrene sulfonate aspiration: A case report. Medicine (Baltimore) 2019; 98:e16574. [PMID: 31348289 PMCID: PMC6708910 DOI: 10.1097/md.0000000000016574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
RATIONALE Sodium polystyrene sulfonate is commonly administered to treat hyperkalemia. Severe pneumonia due to aspiration of this drug is rare and no survival case has thus far been reported. PATIENT CONCERNS A 45-year-old man was hospitalized for acute decompensated heart failure and acute kidney injury with hyperkalemia. He aspirated sodium polystyrene sulfonate while consuming the drug. Severe acute respiratory distress syndrome (ARDS) developed rapidly, and he was transferred to the intensive care unit (ICU). DIAGNOSES Chest radiography results after aspiration showed new consolidation in the left upper lung. He underwent emergency bronchoscopy, which revealed a considerable amount of yellow mud-like material in the trachea and bronchi. Chest radiography results after the bronchoscopic removal of the foreign material revealed rapid resolution of the left upper lung consolidation. INTERVENTIONS In the ICU, mechanical ventilation with low tidal volume and high positive end-expiratory pressure was administered and extracorporeal membrane oxygenation (ECMO) was set up for treating severe ARDS. We arranged an emergency bronchoscopy for diagnosis and removal of polystyrene sulfonate. OUTCOMES ECMO was discontinued after 10 days and the patient was discharged after approximately 2 weeks. LESSONS Aspiration of sodium polystyrene sulfonate is not common but can be lethal. Clinicians should be cautious and appropriately inform patients of the aspiration risk while administering this drug. Mechanical ventilation and bronchoscopy were effective treatments for severe ARDS caused by aspiration of this drug.
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Affiliation(s)
- Cheng-Yu Ko
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine
| | - Ping-Yen Liu
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Wei Chen
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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30
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Si J, Hao N, Zhang M, Cheng S, Liu A, Li L, Ye X. Universal Synthetic Strategy for the Construction of Topological Polystyrenesulfonates: The Importance of Linkage Stability during Sulfonation. ACS Macro Lett 2019; 8:730-736. [PMID: 35619531 DOI: 10.1021/acsmacrolett.9b00260] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Polystyrenesulfonate (PSS), as one of the most important categories of polyelectrolytes, has received increasing attention due to its great potential in the applications of energy- and biomedical-related fields. However, most of the previous studies only focused on linear PSS and its derivatives, but little attention was paid to nonlinear topological PSSs. So far, the synthesis of nonlinear PSSs with well-defined structures is still a challenging task, and the main obstacle lies in the stability issue of functional chemical linkages during the sulfonation process of polystyrene (PS) precursors, such as the carbon-oxygen-containing linkages. Herein, by rationally designing the chemical structure of the functional linkage, we introduce a versatile and efficient strategy for the preparation of topological PSSs. Specifically, by embedding firm triazole linkages (without carbon-oxygen linkages) into the backbone structure of cyclic and hyperbranched PS precursors, the backbone and functional linkages are found to present excellent chemical stability under certain sulfonation conditions, which eventually lead to the successful preparation of cyclic and hyperbranched PSSs. By using two sets of PSS samples with varied molar masses, the scaling relations between the number of repeating units and the sedimentation coefficient are established for both linear and cyclic PSSs. We believe that our proposed synthetic strategy is universal and could be extended to the synthesis of other types of topological PSSs.
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Athyros VG, Sachinidis AG, Zografou I, Simoulidou E, Piperidou A, Stavropoulos N, Karagiannis A. Boosting the Limited Use of Mineralocorticoid Receptor Antagonists Through New Agents for Hyperkalemia. Curr Pharm Des 2019; 24:5542-5547. [DOI: 10.2174/1381612825666190306162339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/26/2019] [Indexed: 11/22/2022]
Abstract
Background:
Hyperkalemia is an important clinical problem that is associated with significant lifethreatening
complications. Several conditions are associated with increased risk for hyperkalemia such as chronic
kidney disease, diabetes mellitus, heart failure, and the use of renin-angiotensin-aldosterone system (RAAS)
inhibitors.
Objective:
The purpose of this review is to present and critically discuss treatment options for the management of
hyperkalemia.
Method:
A comprehensive review of the literature was performed to identify studies assessing the drug-induced
management of hyperkalemia.
Results:
The management of chronic hyperkalemia seems to be challenging and includes a variety of traditional
interventions, such as restriction in the intake of the dietary potassium, loop diuretics or sodium polystyrene sulfonate.
In the last few years, several new agents have emerged as promising options to reduce potassium levels in
hyperkalemic patients. Patiromer and sodium zirconium cyclosilicate 9 (ZS-9) have been examined in hyperkalemic
patients and were found to be efficient and safe. Importantly, the efficacy of these novel drugs might allow
the continuation of the use of RAAS inhibitors, morbidity- and mortality-wise beneficial class of drugs in the
setting of chronic kidney disease and heart failure.
Conclusion:
Data support that the recently emerged patiromer and ZS-9 offer significant hyperkalemia-related
benefits. Larger trials are needed to unveil the impact of these drugs in other patients’ subpopulations, as well.
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Affiliation(s)
- Vasilios G. Athyros
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | | | - Ioanna Zografou
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | - Elisavet Simoulidou
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | - Alexia Piperidou
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | - Nikiforos Stavropoulos
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
| | - Asterios Karagiannis
- Second Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece
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Sasikumar AN, Killilea DW, Kennedy BK, Brem RB. Potassium restriction boosts vacuolar acidity and extends lifespan in yeast. Exp Gerontol 2019; 120:101-106. [PMID: 30742903 DOI: 10.1016/j.exger.2019.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/15/2019] [Accepted: 02/01/2019] [Indexed: 12/23/2022]
Abstract
Lysosome function is compromised during aging and in many disease states. Interventions that promote lysosomal activity and acidification are thus of prime interest as treatments for longevity and health. Intracellular pH can be controlled by the exchange of protons for inorganic ions, and in cells from microbes to man, when potassium is restricted in the growth medium, the cytoplasm becomes acidified. Here we use a yeast model to show that potassium limited-cells exhibit hallmarks of increased acidity in the vacuole, the analog of the lysosome, and live long by a mechanism that requires the vacuolar machinery. The emerging picture is one in which potassium restriction shores up vacuolar acidity and function, conferring health benefits early in life and extending viability into old age. Against the backdrop of well-studied protein and carbohydrate restrictions that extend lifespan and healthspan, our work establishes a novel pro-longevity paradigm of inorganic nutrient limitation.
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Affiliation(s)
- Arjun N Sasikumar
- Buck Institute for Research on Aging, Novato, CA, United States of America
| | - David W Killilea
- Nutrition & Metabolism Center and Elemental Analysis Facility, Children's Hospital Oakland Research Institute, Oakland, CA, United States of America
| | - Brian K Kennedy
- Buck Institute for Research on Aging, Novato, CA, United States of America; Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Rachel B Brem
- Buck Institute for Research on Aging, Novato, CA, United States of America; Department of Plant and Microbial Biology, UC Berkeley, Berkeley, CA, United States of America.
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Rafique Z, Chouihed T, Mebazaa A, Frank Peacock W. Current treatment and unmet needs of hyperkalaemia in the emergency department. Eur Heart J Suppl 2019; 21:A12-A19. [PMID: 30837800 PMCID: PMC6392420 DOI: 10.1093/eurheartj/suy029] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hyperkalaemia is a common electrolyte abnormality and can cause life-threatening cardiac arrhythmia. Even though it is common in patients with diabetes, heart failure, and kidney disease, there is poor consensus over its definition and wide variability in its treatment. Medications used to treat hyperkalaemia in the emergent setting do not have robust efficacy and safety data to guide treatment leading to mismanagement due to poor choice of some agents or inappropriate dosing of others. Moreover, the medications used in the emergent setting are at best temporizing measures, with dialysis being the definitive treatment. New and old k binder therapies provide means to excrete potassium, but their roles are unclear in the emergent setting. Electrocardiograms are the corner stones of hyperkalaemia management; however, recent studies show that they might manifest abnormalities infrequently, even in severe hyperkalaemia, thus questioning their role. With an aging population and a rise in rates of heart and kidney failure, hyperkalaemia is on the rise, and there is a need, now more than ever, to understand the efficacy and safety of the current medications and to develop newer ones.
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Affiliation(s)
- Zubaid Rafique
- Baylor College of Medicine, Ben Taub General Hospital, Houston, TX, USA
| | - Tahar Chouihed
- Emergency Department, University Hospital of Nancy, France; Clinical Investigation Center-Unit 1433; INSERM U1116, University of Lorraine, Nancy, France
| | - Alexandre Mebazaa
- Department of Anesthesiology and Critical Care, APHP - Saint Louis Lariboisière University Hospitals, University Paris Diderot and INSERM UMR-S 942, Paris, France
| | - W Frank Peacock
- Baylor College of Medicine, Ben Taub General Hospital, Houston, TX, USA
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Long B, Warix JR, Koyfman A. Controversies in Management of Hyperkalemia. J Emerg Med 2018; 55:192-205. [DOI: 10.1016/j.jemermed.2018.04.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 02/07/2018] [Accepted: 04/10/2018] [Indexed: 12/24/2022]
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Davidson JP, King AJ, Kumaraswamy P, Caldwell JS, Korner P, Blanks RC, Jacobs JW. Evaluation of the Pharmacodynamic Effects of the Potassium Binder RDX7675 in Mice. J Cardiovasc Pharmacol Ther 2018; 23:244-253. [PMID: 29130735 PMCID: PMC5987854 DOI: 10.1177/1074248417741685] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/09/2017] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Hyperkalemia is a common complication in patients with heart failure or chronic kidney disease, particularly those who are taking inhibitors of the renin-angiotensin-aldosterone system. RDX7675, the calcium salt of a reengineered polystyrene sulfonate-based resin, is a potassium binder that is being investigated as a novel treatment for hyperkalemia. This study evaluated the pharmacodynamic effects of RDX7675 in mice, compared to 2 current treatments, sodium polystyrene sulfonate (SPS) and patiromer. METHODS Seven groups of 8 male CD-1 mice were given either standard chow (controls) or standard chow containing 4.0% or 6.6% active moiety of RDX7675, patiromer, or SPS for 72 hours. Stool and urine were collected over the final 24 hours of treatment for ion excretion analyses. RESULTS RDX7675 increased stool potassium (mean 24-hour excretion: 4.0%, 9.19 mg; 6.6%, 18.11 mg; both P < .0001) compared with controls (4.47 mg) and decreased urinary potassium (mean 24-hour excretion: 4.0%, 12.05 mg, P < .001; 6.6%, 6.68 mg, P < .0001; vs controls, 20.38 mg). The potassium-binding capacity of RDX7675 (stool potassium/gram of resin: 4.0%, 1.14 mEq/g; 6.6%, 1.32 mEq/g) was greater (all P < .0001) than for patiromer (4.0%, 0.63 mEq/g; 6.6%, 0.48 mEq/g) or SPS (4.0%, 0.73 mEq/g; 6.6% 0.55 mEq/g). RDX7675 and patiromer decreased urinary sodium (mean 24-hour excretion: 0.07-1.38 mg; all P < .001) compared to controls (5.01 mg). In contrast, SPS increased urinary sodium excretion (4.0%, 13.31 mg; 6.6%, 17.60 mg; both P < .0001) compared to controls. CONCLUSIONS RDX7675 reduced intestinal potassium absorption and had a greater potassium-binding capacity than patiromer or SPS in mice. The calcium-based resins RDX7675 and patiromer reduced intestinal sodium absorption, unlike sodium-based SPS. These results support further studies in humans to confirm the potential of RDX7675 for the treatment of patients with hyperkalemia.
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Palaka E, Leonard S, Buchanan-Hughes A, Bobrowska A, Langford B, Grandy S. Evidence in support of hyperkalaemia management strategies: A systematic literature review. Int J Clin Pract 2018; 72. [PMID: 29381246 DOI: 10.1111/ijcp.13052] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 12/06/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Hyperkalaemia is a potentially life-threatening condition that can be managed with pharmacological and non-pharmacological approaches. With the recent development of new hyperkalaemia treatments, new information on safe and effective management of hyperkalaemia has emerged. OBJECTIVES This systematic literature review (SLR) aimed to identify all relevant comparative and non-comparative clinical data on management of hyperkalaemia in adults. Our secondary aim was to assess the feasibility of quantitatively comparing randomised controlled trial (RCT) data on the novel treatment sodium zirconium cyclosilicate (ZS) and established pharmacological treatments for the non-emergency management of hyperkalaemia, such as the cation-exchangers sodium/calcium polystyrene sulphonate (SPS/CPS). METHODS MEDLINE, Embase and the Cochrane Library were searched on 3rd April 2017, with additional hand-searches of key congresses and previous SLRs. Articles were screened by two independent reviewers. Eligible records reported interventional or observational studies of pharmacological or non-pharmacological management of hyperkalaemia in adults. RESULTS Database searches identified 2,073 unique records. Two hundred and one publications were included, reporting 30 RCTs, 29 interventional non-RCTs and 43 observational studies. Interventions investigated in RCTs included ZS (3), SPS/CPS (3), patiromer (4) and combinations of temporising agents (6 RCTs). A robust and meaningful indirect treatment comparison between ZS and long-established cation-binding agents (SPS/CPS) was infeasible because of heterogeneity between studies (including time points and dosing) and small sample size in SPS/CPS studies. CONCLUSIONS Despite hyperkalaemia being associated with several chronic diseases, there is a paucity of high-quality randomised evidence on long-established treatment options (SPS and CPS) and a limited evidence base for hyperkalaemia management with these agents.
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New Therapeutic Approaches for the Treatment of Hyperkalemia in Patients Treated with Renin-Angiotensin-Aldosterone System Inhibitors. Cardiovasc Drugs Ther 2018; 32:99-119. [DOI: 10.1007/s10557-017-6767-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Abstract
PURPOSE OF REVIEW The aim of this paper is to discuss strategies for prevention and management of hyperkalemia in patients with heart failure, including the role of novel therapies. RECENT FINDINGS Renin-angiotensin-aldosterone system (RAAS) antagonists, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) decrease mortality and morbidity in heart failure but increase the risk of hyperkalemia, especially when used in combination. Prevention of hyperkalemia and its associated complications requires careful patient selection, counseling regarding dietary potassium intake, awareness of drug interactions, and regular laboratory surveillance. Recent data suggests that the risk of hyperkalemia may be further moderated through the use of combined angiotensin-neprilysin inhibitors, novel MRAs, and novel potassium binding agents. Clinicians should be mindful of the risk of hyperkalemia when prescribing RAAS inhibitors to patients with heart failure. In patients at highest risk, such as those with diabetes, the elderly, and advanced chronic kidney disease, more intensive laboratory surveillance of potassium and creatinine may be required. Novel therapies hold promise for reducing the risk of hyperkalemia and enhancing the tolerability of RAAS antagonists.
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Affiliation(s)
- Ersilia M DeFilippis
- Cardiovascular Division (ASD) and Department of Medicine (EMD, ASD), Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Akshay S Desai
- Cardiovascular Division (ASD) and Department of Medicine (EMD, ASD), Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. .,Advanced Heart Disease Section, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
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Georgianos PI, Agarwal R. Revisiting RAAS blockade in CKD with newer potassium-binding drugs. Kidney Int 2017; 93:325-334. [PMID: 29276100 DOI: 10.1016/j.kint.2017.08.038] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 08/21/2017] [Accepted: 08/24/2017] [Indexed: 01/13/2023]
Abstract
Among patients with proteinuric chronic kidney disease (CKD), current guideline recommendations mandate the use of agents blocking the renin angiotensin aldosterone system (RAAS) as first-line antihypertensive therapy based on randomized trials demonstrating that RAAS inhibitors are superior to other antihypertensive drug classes in slowing nephropathy progression to end-stage renal disease. However, the opportunities for adequate RAAS blockade in CKD are often limited, and an important impediment is the risk of hyperkalemia, especially when RAAS inhibitors are used in maximal doses or are combined. Accordingly, a large proportion of patients with proteinuric CKD may not have the anticipated renoprotective benefits since RAAS blockers are often discontinued due to incident hyperkalemia or are administered at suboptimal doses for fear of the development of hyperkalemia. Two newer potassium binders, patiromer and sodium zirconium cyclosilicate (ZS-9), have been shown to effectively and safely reduce serum potassium levels and maintain long-term normokalemia in CKD patients receiving background therapy with RAAS inhibitors. Whether these novel potassium-lowering therapies can overcome the barrier of hyperkalemia and enhance the tolerability of RAAS inhibitor use in proteinuric CKD awaits randomized trials.
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Affiliation(s)
- Panagiotis I Georgianos
- Division of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Rajiv Agarwal
- Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA.
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Abstract
Hyperkalemia is a frequently detected electrolyte abnormality that can cause life-threatening complications. Hyperkalemia is most often the result of intrinsic (decreased glomerular filtration rate; selective reduction in distal tubule secretory function; impaired mineralocorticoid activity; and metabolic disturbances, such as acidemia and hyperglycemia) and extrinsic factors (e.g., drugs, such as renin-angiotensin-aldosterone system inhibitors, and potassium intake). The frequent use of renin-angiotensin-aldosterone system inhibitors in patients who are already susceptible to hyperkalemia (e.g., patients with chronic kidney disease, diabetes mellitus, or congestive heart failure) contributes to the high incidence of hyperkalemia. There is a need to understand the causes of hyperkalemia and to be aware of strategies addressing the disorder in a way that provides the most optimal outcome for affected patients. The recent development of 2 new oral potassium-binding agents has led to the emergence of a new paradigm in the treatment of hyperkalemia.
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Affiliation(s)
- Linda Fried
- Medicine, Epidemiology, and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Csaba P Kovesdy
- Clinical Outcomes and Clinical Trials Program in Nephrology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Biff F Palmer
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Kovesdy CP, Appel LJ, Grams ME, Gutekunst L, McCullough PA, Palmer BF, Pitt B, Sica DA, Townsend RR. Potassium homeostasis in health and disease: A scientific workshop cosponsored by the National Kidney Foundation and the American Society of Hypertension. ACTA ACUST UNITED AC 2017; 11:783-800. [PMID: 29030153 DOI: 10.1016/j.jash.2017.09.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 09/08/2017] [Accepted: 09/08/2017] [Indexed: 12/16/2022]
Abstract
While much emphasis, and some controversy, centers on recommendations for sodium intake, there has been considerably less interest in recommendations for dietary potassium intake, in both the general population and patients with medical conditions, particularly acute and chronic kidney disease. Physiology literature and cohort studies have noted that the relative balance in sodium and potassium intakes is an important determinant of many of the sodium-related outcomes. A noteworthy characteristic of potassium in clinical medicine is the extreme concern shared by many practitioners when confronted by a patient with hyperkalemia. Fear of this often asymptomatic finding limits enthusiasm for recommending potassium intake and often limits the use of renin-angiotensin-aldosterone system blockers in patients with heart failure and chronic kidney diseases. New agents for managing hyperkalemia may alter the long-term management of heart failure and the hypertension, proteinuria, and further function loss in chronic kidney diseases. In this jointly sponsored effort between the American Society of Hypertension and the National Kidney Foundation, 3 panels of researchers and practitioners from various disciplines discussed and summarized current understanding of the role of potassium in health and disease, focusing on cardiovascular, nutritional, and kidney considerations associated with both hypo- and hyperkalemia.
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Affiliation(s)
| | | | - Morgan E Grams
- Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lisa Gutekunst
- Suburban Dialysis, Williamsville, NY; Davita, Inc, Denver, CO
| | - Peter A McCullough
- Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; The Heart Hospital, Plano, TX
| | - Biff F Palmer
- University of Texas Southwestern Medical Center, Dallas, TX
| | - Bertram Pitt
- University of Michigan School of Medicine, Ann Arbor, MI
| | | | - Raymond R Townsend
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Kovesdy CP, Appel LJ, Grams ME, Gutekunst L, McCullough PA, Palmer BF, Pitt B, Sica DA, Townsend RR. Potassium Homeostasis in Health and Disease: A Scientific Workshop Cosponsored by the National Kidney Foundation and the American Society of Hypertension. Am J Kidney Dis 2017; 70:844-858. [PMID: 29029808 DOI: 10.1053/j.ajkd.2017.09.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 09/08/2017] [Indexed: 12/31/2022]
Abstract
While much emphasis, and some controversy, centers on recommendations for sodium intake, there has been considerably less interest in recommendations for dietary potassium intake, in both the general population and patients with medical conditions, particularly acute and chronic kidney disease. Physiology literature and cohort studies have noted that the relative balance in sodium and potassium intakes is an important determinant of many of the sodium-related outcomes. A noteworthy characteristic of potassium in clinical medicine is the extreme concern shared by many practitioners when confronted by a patient with hyperkalemia. Fear of this often asymptomatic finding limits enthusiasm for recommending potassium intake and often limits the use of renin-angiotensin-aldosterone system blockers in patients with heart failure and chronic kidney diseases. New agents for managing hyperkalemia may alter the long-term management of heart failure and the hypertension, proteinuria, and further function loss in chronic kidney diseases. In this jointly sponsored effort between the American Society of Hypertension and the National Kidney Foundation, 3 panels of researchers and practitioners from various disciplines discussed and summarized current understanding of the role of potassium in health and disease, focusing on cardiovascular, nutritional, and kidney considerations associated with both hypo- and hyperkalemia.
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Affiliation(s)
| | | | - Morgan E Grams
- Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lisa Gutekunst
- Suburban Dialysis, Williamsville, NY; Davita, Inc, Denver, CO
| | - Peter A McCullough
- Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; The Heart Hospital, Plano, TX
| | - Biff F Palmer
- University of Texas Southwestern Medical Center, Dallas, TX
| | - Bertram Pitt
- University of Michigan School of Medicine, Ann Arbor, MI
| | | | - Raymond R Townsend
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Abuelo JG. Treatment of Severe Hyperkalemia: Confronting 4 Fallacies. Kidney Int Rep 2017; 3:47-55. [PMID: 29340313 PMCID: PMC5762976 DOI: 10.1016/j.ekir.2017.10.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/08/2017] [Accepted: 10/02/2017] [Indexed: 01/03/2023] Open
Abstract
Severe hyperkalemia is a medical emergency that can cause lethal arrhythmias. Successful management requires monitoring of the electrocardiogram and serum potassium concentrations, the prompt institution of therapies that work both synergistically and sequentially, and timely repeat dosing as necessary. It is of concern then that, based on questions about effectiveness and safety, many physicians no longer use 3 key modalities in the treatment of severe hyperkalemia: sodium bicarbonate, sodium polystyrene sulfonate (Kayexalate [Concordia Pharmaceuticals Inc., Oakville, ON, Canada], SPS [CMP Pharma, Farmville, NC]), and hemodialysis with low potassium dialysate. After reviewing older reports and newer information, I believe that these exclusions are ill advised. In this article, I briefly discuss the treatment of severe hyperkalemia and detail why these modalities are safe and effective and merit inclusion in the treatment of severe hyperkalemia.
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Affiliation(s)
- J Gary Abuelo
- Division of Hypertension and Kidney Diseases, Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island, USA
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Advances in the management of hyperkalemia in chronic kidney disease. Curr Opin Nephrol Hypertens 2017; 26:235-239. [DOI: 10.1097/mnh.0000000000000320] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Groene P, Hoffmann G. [Safe treatment of acute hyperkalemia : The 1:4 and other principles]. Anaesthesist 2017; 66:426-430. [PMID: 28409198 DOI: 10.1007/s00101-017-0306-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Acute hyperkalemia is a dangerous electrolyte disorder, which must be treated immediately. It can lead to cardiac arrhythmia and death due to alterations in cell membrane potentials. The resulting alterations in the electrocardiogram (ECG) are multifarious and need to be rapidly recognized. Treatment consists of various stages. In addition to membrane stabilization, which is always necessary, potassium must be displaced into the intracellular space and then eliminated from the body. A commonly applied method for displacement of potassium into the intracellular space involves the administration of insulin-glucose mixtures, which is associated with many complications. In the clinical routine many prescription variations are applied, which do not always appear to be ideal with respect to the individual risk-benefit ratio. A practically useful and easily memorized insulin-glucose mixture has a relationship of 1IU insulin to 4g glucose. The therapeutic elimination from the body is carried out using an enhanced diuresis or the utilization of renal replacement procedures. Special attention must be paid to the continous monitoring of potassium and blood sugar levels. After overcoming the acute situation, attention must be paid to treatment of the underlying disorder and if necessary to readjustment of the long-term medication of the patient.
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Affiliation(s)
- P Groene
- Klinik für Anästhesiologie, Klinikum der Universität München, Marchioninistr. 15, 81337, München, Deutschland.
| | - G Hoffmann
- Klinik für Anästhesiologie, Klinikum der Universität München, Marchioninistr. 15, 81337, München, Deutschland
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Meaney CJ, Beccari MV, Yang Y, Zhao J. Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia. Pharmacotherapy 2017; 37:401-411. [PMID: 28122118 PMCID: PMC5388568 DOI: 10.1002/phar.1906] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia. DESIGN A systematic review and meta-analysis of phase II and III clinical trial data was completed. PATIENTS OR PARTICIPANTS Eight studies (two phase II and four phase III trials with two subgroup analyses) were included in the qualitative analysis, and six studies (two phase II and four phase III trials) were included in the meta-analysis. MEASUREMENTS AND RESULTS Significant heterogeneity was found in the meta-analysis with an I2 value ranging from 80.6-99.6%. A random-effects meta-analysis was applied for all end points. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, a significant -0.70 mEq/L (95% confidence interval [CI] -0.48 to -0.91 mEq/L) change was noted in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was -0.36 mEq/L (range of standard deviation 0.07-0.30). The primary end point for ZS-9-change in potassium at 48 hours-was -0.67 mEq/L (95% CI -0.45 to -0.89 mEq/L). By 1 hour after ZS-9 administration, change in potassium was -0.17 mEq/L (95% CI -0.05 to -0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with the adverse effects of urinary tract infections (1.1%) and edema (0.9%). CONCLUSION Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary end point of this meta-analysis. Given the adverse effect profile and the observed time-dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia.
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Affiliation(s)
- Calvin J Meaney
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York
| | - Mario V Beccari
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York
| | - Yang Yang
- Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York
| | - Jiwei Zhao
- Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York
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Beccari MV, Meaney CJ. Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review. CORE EVIDENCE 2017; 12:11-24. [PMID: 28356904 PMCID: PMC5367739 DOI: 10.2147/ce.s129555] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Hyperkalemia is a serious medical condition that often manifests in patients with chronic kidney disease and heart failure. Renin-angiotensin-aldosterone system inhibitors are known to improve outcomes in these disease states but can also cause drug-induced hyperkalemia. New therapeutic options exist for managing hyperkalemia in these patients which warrant evidence-based evaluation. AIM The objective of this article was to review the efficacy and safety evidence for patiromer, sodium zirconium cyclosilicate (ZS9), and sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia. EVIDENCE REVIEW Current treatment options to enhance potassium excretion are SPS and loop diuretics, which are complicated by ambiguous efficacy and known toxicities. Patiromer and ZS9 are new agents designed to address this treatment gap. Both unabsorbable compounds bind potassium in the gastrointestinal (GI) tract to facilitate fecal excretion. The capacity to bind other medications in the GI tract infers high drug-drug interaction potential, which has been demonstrated with patiromer but not yet investigated with ZS9 or SPS. Phase II and III clinical trials of patiromer and ZS9 demonstrated clear evidence of a dose-dependent potassium-lowering effect and the ability to initiate, maintain, or titrate renin-angiotensin-aldosterone system inhibitors. There is limited evidence base for SPS: two small clinical trials indicated potassium reduction in chronic hyperkalemia. All agents may cause adverse GI effects, although they are less frequent with ZS9. Concerns remain for SPS to cause rare GI damage. Electrolyte abnormalities occurred with patiromer and SPS, whereas urinary tract infections, edema, and corrected QT-interval prolongations were reported with ZS9. CONCLUSION Patiromer and ZS9 have improved upon the age-old standard SPS for the treatment of hyperkalemia. Additional research should focus on drug-drug interactions in patients on multiple medications, incidence of rare adverse events, and use in high-risk populations.
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Affiliation(s)
- Mario V Beccari
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Calvin J Meaney
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
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Abstract
Hyperkalemia is a frequent clinical abnormality in patients with chronic kidney disease, and it is associated with higher risk of mortality and malignant arrhythmias. Severe hyperkalemia is a medical emergency, which requires immediate therapies, followed by interventions aimed at preventing its recurrence. Current treatment paradigms for chronic hyperkalemia management are focused on eliminating predisposing factors, such as high potassium intake in diets or supplements, and the use of medications known to raise potassium level. Among the latter, inhibitors of the renin-angiotensin aldosterone system are some of the most commonly involved medications, and their discontinuation is often the first step taken by clinicians to prevent the recurrence of hyperkalemia. While this strategy is usually successful, it also deprives patients of the recognized benefits of this class, such as their renoprotective effects. The development of novel potassium binders has ushered in a new era of hyperkalemia management, with a focus on chronic therapy while maintaining the use of beneficial, but hyperkalemia-inducing medications such as renin-angiotensin aldosterone system inhibitors. This review article examines the incidence and clinical consequences of hyperkalemia, and its various treatment options, with special emphasis on novel therapeutic agents and the potential benefits of their application.
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Affiliation(s)
- Csaba P Kovesdy
- University of Tennessee Health Science Center, 956 Court Ave, Memphis, TN, 38163, USA.
- Memphis VA Medical Center, Memphis, TN, USA.
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Lee J, Moffett BS. Treatment of pediatric hyperkalemia with sodium polystyrene sulfonate. Pediatr Nephrol 2016; 31:2113-7. [PMID: 27215929 DOI: 10.1007/s00467-016-3414-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 05/03/2016] [Accepted: 05/05/2016] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To describe the safety and efficacy of sodium polystyrene sulfonate (SPS) in pediatric patients with acute hyperkalemia. METHODS A retrospective chart review of all patients less than 18 years of age administered SPS for acute hyperkalemia at Texas Children's Hospital between 2011 and 2014. RESULTS Our cohort consisted of 156 patients (mean age 6.8 ± 6.1 years). The peak mean potassium concentration observed was 6.5 ± 0.77 mmol/l prior to administration of SPS. The mean SPS dose was 0.64 ± 0.32 g/kg. The majority (91 %) of the SPS doses were given orally. The nadir mean potassium concentration in the 48 h post-SPS was 4.7 ± 1.2 mEq/l, which occurred at 16.7 ± 14.7 h post-dose. In the 48 h following SPS administration, 68 (43 %) patients required at least one additional intervention after SPS dose. Patients who required an additional intervention after initial SPS dose differed significantly in weight, baseline serum potassium, and were more likely to have received SPS treatment via the rectal route. A gastrointestinal adverse event was documented in 24 (15 %) patients. CONCLUSIONS SPS was used effectively and safely in the majority of patients in this report. However, it may not be appropriate as a first single-line agent in patients with severe acute hyperkalemia who require a greater than 25 % reduction in serum potassium levels or those at a high risk for cardiac arrhythmias.
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Affiliation(s)
- Ji Lee
- Department of Pharmacy, Texas Children's Hospital, 6621 Fannin Street, Suite WB1120, Houston, TX, 77030, USA.,Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Brady S Moffett
- Department of Pharmacy, Texas Children's Hospital, 6621 Fannin Street, Suite WB1120, Houston, TX, 77030, USA. .,Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
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