Interplay between mineral bone disorder and cardiac damage in acute kidney injury: from Ca 2+ mishandling and preventive role of Klotho in mice to its potential mortality prediction in human

Biomarkers of mineral bone disorders (MBD) including phosphorus, fibroblast growth factor (FGF)-23 and Klotho are strongly altered in patients with acute kidney injury (AKI) who have high cardiac outcomes and mortality rates. However, the crosslink between MBD and cardiac damage after an AKI episode...

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Bibliographic Details
Published in:Translational research : the journal of laboratory and clinical medicine 2022-05, Vol.243, p.60
Main Authors: González-Lafuente, Laura, Navarro-García, José Alberto, Rodríguez-Sánchez, Elena, Aceves-Ripoll, Jennifer, Poveda, Jonay, Vázquez-Sánchez, Sara, Mercado-García, Elisa, Fernández-Velasco, María, Kuro-O, Makoto, Liaño, Fernando, Ruilope, Luis M, Ruiz-Hurtado, Gema
Format: Article
Language:English
Subjects:
Acute Kidney Injury - etiology
Animals
Arrhythmias, Cardiac
Biomarkers - metabolism
Calcium - metabolism
Cardiomegaly - metabolism
Female
Humans
Male
Mice
Mice, Transgenic
Minerals - metabolism
Myocytes, Cardiac - physiology
Phosphorus - metabolism
Retrospective Studies
Troponin T - metabolism
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Summary:Biomarkers of mineral bone disorders (MBD) including phosphorus, fibroblast growth factor (FGF)-23 and Klotho are strongly altered in patients with acute kidney injury (AKI) who have high cardiac outcomes and mortality rates. However, the crosslink between MBD and cardiac damage after an AKI episode still remains unclear. We tested MBD and cardiac biomarkers in an experimental AKI model after 24 or 72 hours of folic acid injection and we analyzed structural cardiac remodeling, intracellular calcium (Ca ) dynamics in cardiomyocytes and cardiac rhythm. AKI mice presented high levels of FGF-23, phosphorus and cardiac troponin T and exhibited a cardiac hypertrophy phenotype accompanied by an increase in systolic Ca release 24 hours after AKI. Ca transients and contractile dysfunction were reduced 72 hours after AKI while diastolic sarcoplasmic reticulum Ca leak, pro-arrhythmogenic Ca events and ventricular arrhythmias were increased. These cardiac events were linked to the activation of the calcium/calmodulin-dependent kinase II pathway through the increased phosphorylation of ryanodine receptors and phospholamban specific sites after AKI. Cardiac hypertrophy and the altered intracellular Ca dynamics were prevented in transgenic mice overexpressing Klotho after AKI induction. In a translational retrospective longitudinal clinical study, we determined that combining FGF-23 and phosphorus with cardiac troponin T levels achieved a better prediction of mortality in AKI patients at hospital admission. Thus, monitoring MBD and cardiac damage biomarkers could be crucial to prevent mortality in AKI patients. In this setting, Klotho might be considered as a new cardioprotective therapeutic tool to prevent deleterious cardiac events in AKI conditions.
ISSN:1878-1810