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      Management of Chronic Hyperkalemia in Patients With Chronic Kidney Disease: An Old Problem With News Options

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          Abstract

          Hyperkalemia is one of the main electrolyte disorders in patients with chronic kidney disease (CKD). The prevalence of hyperkalemia increases as the Glomerular Filtration Rate (GFR) declines. Although chronic hyperkalemia is not a medical emergency, it can have negative consequences for the adequate cardio-renal management in the medium and long term. Hyperkalemia is common in patients on renin-angiotensin-aldosterone system inhibitors (RAASi) or Mineralocorticoid Receptor Antagonists (MRAs) and can affect treatment optimization for hypertension, diabetes mellitus, heart failure (HF), and CKD. Mortality rates are higher with suboptimal dosing among patients with CKD, diabetes or HF compared with full RAASi dosing, and are the highest among patients who discontinue RAASis. The treatment of chronic hyperkalemia is still challenging. Therefore, in the real world, discontinuation or reduction of RAASi therapy may lead to adverse cardiorenal outcomes, and current guidelines differ with regard to recommendations on RAASi therapy to enhance cardio and reno-protective effects. Treatment options for hyperkalemia have not changed much since the introduction of the cation exchange resin over 50 years ago. Nowadays, two new potassium binders, Patiromer Sorbitex Calcium, and Sodium Zirconium Cyclosilicate (SZC) already approved by FDA and by the European Medicines Agency, have demonstrated their clinical efficacy in reducing serum potassium with a good safety profile. The use of the newer potassium binders may allow continuing and optimizing RAASi therapy in patients with hyperkalemia keeping the cardio-renal protective effect in patients with CKD and cardiovascular disease. However, further research is needed to address some questions related to potassium disorders (definition of chronic hyperkalemia, monitoring strategies, prediction score for hyperkalemia or length for treatment).

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          Most cited references86

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          2018 ESC/ESH Guidelines for the management of arterial hypertension

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            Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

            We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
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              Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy

              Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                04 June 2021
                2021
                : 8
                : 653634
                Affiliations
                [1] 1Department of Nephrology, Hospital Universitario 12 de Octubre , Madrid, Spain
                [2] 2Instituto de Investigación Hospital Universitario 12 de Octubre (imas12) , Madrid, Spain
                [3] 3Department of Medicine, Universidad Complutense de Madrid , Madrid, Spain
                [4] 4Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY, United States
                [5] 5Nephrology Department, Complejo Hospitalario de Navarra , Pamplona, Spain
                [6] 6Navarra Institute for Health Research, IdiSNA , Pamplona, Spain
                Author notes

                Edited by: Carlo Garofalo, Università della Campania Luigi Vanvitelli, Italy

                Reviewed by: Giuseppe Conte, University of Campania Luigi Vanvitelli, Italy; Silvio Borrelli, Università della Campania Luigi Vanvitelli, Italy

                *Correspondence: Enrique Morales emoralesr@ 123456senefro.org

                This article was submitted to Nephrology, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2021.653634
                8213200
                34150795
                7216ac21-aef2-487a-bea3-ca5404ec423a
                Copyright © 2021 Morales, Cravedi and Manrique.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 January 2021
                : 04 May 2021
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 89, Pages: 13, Words: 9850
                Categories
                Medicine
                Review

                hyperkalemia,chronic kidney disease,raasi,potassium binders,patiromer,zirconium

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