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Increased levels of a mycophenolic acid metabolite in patients with kidney failure negatively affect cardiomyocyte health.
Front. Cardiovasc. Med. 11:1346475 (2024)
Chronic kidney disease (CKD) significantly increases cardiovascular risk and mortality, and the accumulation of uremic toxins in the circulation upon kidney failure contributes to this increased risk. We thus performed a screening for potential novel mediators of reduced cardiovascular health starting from dialysate obtained after hemodialysis of patients with CKD. The dialysate was gradually fractionated to increased purity using orthogonal chromatography steps, with each fraction screened for a potential negative impact on the metabolic activity of cardiomyocytes using a high-throughput MTT-assay, until ultimately a highly purified fraction with strong effects on cardiomyocyte health was retained. Mass spectrometry and nuclear magnetic resonance identified the metabolite mycophenolic acid-β-glucuronide (MPA-G) as a responsible substance. MPA-G is the main metabolite from the immunosuppressive agent MPA that is supplied in the form of mycophenolate mofetil (MMF) to patients in preparation for and after transplantation or for treatment of autoimmune and non-transplant kidney diseases. The adverse effect of MPA-G on cardiomyocytes was confirmed in vitro, reducing the overall metabolic activity and cellular respiration while increasing mitochondrial reactive oxygen species production in cardiomyocytes at concentrations detected in MMF-treated patients with failing kidney function. This study draws attention to the potential adverse effects of long-term high MMF dosing, specifically in patients with severely reduced kidney function already displaying a highly increased cardiovascular risk.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Cardiomyocyte ; Cardiovascular Disease ; Chronic Kidney Disease ; Drug Metabolite ; Mycophenolate Mofetil ; Uremic Toxin; Bound Uremic Toxins; Drug-metabolism; Cardiovascular-disease; Transplant Recipients; Molecular-mechanisms; Pharmacokinetics; Mofetil; Statement; Events; Risk
ISSN (print) / ISBN
2297-055X
e-ISSN
2297-055X
Zeitschrift
Frontiers in Cardiovascular Medicine
Quellenangaben
Band: 11,
Artikelnummer: 1346475
Verlag
Frontiers
Verlagsort
Lausanne
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Research Unit Analytical BioGeoChemistry (BGC)
Förderungen
German Research Foundation (DFG)