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Hyperkalemia in Chronic Kidney Disease in the New Era of Kidney Protection Therapies

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A Correction to this article was published on 11 October 2021

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Abstract

Despite recent therapeutic advances, chronic kidney disease (CKD) is one of the fastest growing global causes of death. This illustrates limitations of current therapeutic approaches and, potentially, unidentified knowledge gaps. For decades, renin-angiotensin-aldosterone system (RAAS) blockers have been the mainstay of therapy for CKD. However, they favor the development of hyperkalemia, which is already common in CKD patients due to the CKD-associated decrease in urinary potassium (K+) excretion and metabolic acidosis. Hyperkalemia may itself be life-threatening as it may trigger potentially lethal arrhythmia, and additionally may limit the prescription of RAAS blockers and lead to low-K+ diets associated to low dietary fiber intake. Indeed, hyperkalemia is associated with adverse kidney, cardiovascular, and survival outcomes. Recently, novel kidney protective therapies, ranging from sodium/glucose cotransporter 2 (SGLT2) inhibitors to new mineralocorticoid receptor antagonists have shown efficacy in clinical trials. Herein, we review K+ pathophysiology and the clinical impact and management of hyperkalemia considering these developments and the availability of the novel K+ binders patiromer and sodium zirconium cyclosilicate, recent results from clinical trials targeting metabolic acidosis (sodium bicarbonate, veverimer), and an increasing understanding of the role of the gut microbiota in health and disease.

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Acknowledgements

This Review was planned as part of the activity of the European Renal and Cardiovascular Medicine working (EURECAm) group and all authors are EURECAm members.

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Authors and Affiliations

  1. Vascular and Renal Translational Research Group, UDETMA, REDinREN del ISCIII, IRBLleida, Lleida, Spain

    José M. Valdivielso

  2. Department of Nephrology, University Hospital of Ioannina, Ioannina, Greece

    Olga Balafa

  3. Clinic for Internal Medicine, Department of Dialysis, University Medical Center Maribor, Maribor, Slovenia

    Robert Ekart

  4. Department of Renal Medicine, University Hospitals Birmingham, Edgbaston, Birmingham, UK

    Charles J. Ferro

  5. CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases, Ospedali Riuniti, 89124, Reggio Calabria, Italy

    Francesca Mallamaci

  6. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    Patrick B. Mark

  7. Inserm 1433 CIC-P CHRU de Nancy, Inserm U1116 and FCRIN INI-CRCT, Université de Lorraine, Nancy, France

    Patrick Rossignol

  8. Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloníki, Greece

    Pantelis Sarafidis

  9. Department of Nephrology and Dialysis, Sant’Anna Hospital, ASST Lariana, Como, Italy

    Lucia Del Vecchio

  10. School of Medicine, IIS-Fundacion Jimenez Diaz, University Autonoma of Madrid, FRIAT and REDINREN, Madrid, Spain

    Alberto Ortiz

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  1. José M. Valdivielso
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Correspondence to José M. Valdivielso.

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Funding

Sources of support: FIS/Fondos FEDER (PI18/01366, PI18/00610, PI19/00588, PI19/00815, DTS18/00032), ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC (REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, and Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. PR is supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program (reference: ANR-15-RHUS-0004), by the French PIA project “Lorraine Université d’Excellence” (reference: ANR-15-IDEX-04-LUE), the ANR FOCUS-MR (reference: ANR-15-CE14-0032-01), ERA-CVD EXPERT (reference: ANR-16-ECVD-0002-02), Contrat de Plan Etat Lorraine IT2MP and FEDER Lorraine.

Conflict of interest

JMV has received research grants from Vifor Fresenius Medical Care Renal Pharma. AO has received consultancy or speaker fees or travel support from AstraZeneca, Amicus, Amgen, Fresenius Medical Care, Bayer, Sanofi-Genzyme, Menarini, Kyowa Kirin, Alexion, Otsuka, and Vifor Fresenius Medical Care Renal Pharma and is Director of the Catedra Mundipharma-UAM of diabetic kidney disease and the Catedra AstraZeneca-UAM of chronic kidney disease and electrolytes. LdV has received consultancy or speaker fees from Astellas, GSK, Roche, Vifor Fresenius, and Mundipharma. PR reports personal fees from Ablative Solutions, AstraZeneca, Bayer, Boehringer-Ingelheim, Corvidia, CVRx, Fresenius, G3P (stocks), Grunenthal, Idorsia, KBP, Novartis, NovoNordisk, edito Relypsa, Sanofi, Sequana Medical, Servier, Stealth Peptides, Vifor, and Vifor Fresenius Medical Care Renal Pharma and is a cofounder of CardioRenal, a company developing sensors for the home monitoring of K+ and creatinine. OB, RE, CJF, FM, PBM, and PS state no conflict of interest.

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Author contributions

JMV drafted the outline, wrote sections of the manuscript, composed figures, and coordinated the final assembly. The rest of the authors wrote different sections of the manuscript and built the tables.

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The original article has been updated: Due to Acknowledgment update.

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Valdivielso, J.M., Balafa, O., Ekart, R. et al. Hyperkalemia in Chronic Kidney Disease in the New Era of Kidney Protection Therapies. Drugs 81, 1467–1489 (2021). https://doi.org/10.1007/s40265-021-01555-5

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