Frontiers in Cardiovascular Medicine (Mar 2024)
Increased levels of a mycophenolic acid metabolite in patients with kidney failure negatively affect cardiomyocyte health
- Eva Harlacher,
- Eva Harlacher,
- Corinna Schulte,
- Corinna Schulte,
- Sonja Vondenhoff,
- Sonja Vondenhoff,
- Philippe Schmitt-Kopplin,
- Philippe Schmitt-Kopplin,
- Philippe Diederich,
- Philippe Diederich,
- Christian Hemmers,
- Christian Hemmers,
- Julia Moellmann,
- Julia Wollenhaupt,
- Julia Wollenhaupt,
- Rogier Veltrop,
- Rogier Veltrop,
- Erik Biessen,
- Erik Biessen,
- Erik Biessen,
- Michael Lehrke,
- Björn Peters,
- Björn Peters,
- Georg Schlieper,
- Christoph Kuppe,
- Jürgen Floege,
- Jürgen Floege,
- Vera Jankowski,
- Vera Jankowski,
- Nikolaus Marx,
- Nikolaus Marx,
- Joachim Jankowski,
- Joachim Jankowski,
- Joachim Jankowski,
- Joachim Jankowski,
- Heidi Noels,
- Heidi Noels,
- Heidi Noels,
- Heidi Noels
Affiliations
- Eva Harlacher
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Eva Harlacher
- University Hospital RWTH Aachen, Aachen, Germany
- Corinna Schulte
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Corinna Schulte
- University Hospital RWTH Aachen, Aachen, Germany
- Sonja Vondenhoff
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Sonja Vondenhoff
- University Hospital RWTH Aachen, Aachen, Germany
- Philippe Schmitt-Kopplin
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Neuherberg, Germany
- Philippe Schmitt-Kopplin
- Analytical Food Chemistry, Technical University of Munich, Freising, Germany
- Philippe Diederich
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Philippe Diederich
- University Hospital RWTH Aachen, Aachen, Germany
- Christian Hemmers
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Christian Hemmers
- University Hospital RWTH Aachen, Aachen, Germany
- Julia Moellmann
- Department of Internal Medicine I, Cardiology, University Hospital RWTH Aachen, Aachen, Germany
- Julia Wollenhaupt
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Julia Wollenhaupt
- University Hospital RWTH Aachen, Aachen, Germany
- Rogier Veltrop
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Rogier Veltrop
- University Hospital RWTH Aachen, Aachen, Germany
- Erik Biessen
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Erik Biessen
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
- Erik Biessen
- Aachen-Maastricht Institute for Cardiorenal Disease (AMICARE), RWTH Aachen Campus, Aachen, Germany
- Michael Lehrke
- Department of Internal Medicine I, Cardiology, University Hospital RWTH Aachen, Aachen, Germany
- Björn Peters
- Department of Nephrology, Skaraborg Hospital, Skövde, Sweden
- Björn Peters
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Georg Schlieper
- 0Division of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany
- Christoph Kuppe
- 0Division of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany
- Jürgen Floege
- Department of Internal Medicine I, Cardiology, University Hospital RWTH Aachen, Aachen, Germany
- Jürgen Floege
- 0Division of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Aachen, Germany
- Vera Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Vera Jankowski
- University Hospital RWTH Aachen, Aachen, Germany
- Nikolaus Marx
- Department of Internal Medicine I, Cardiology, University Hospital RWTH Aachen, Aachen, Germany
- Nikolaus Marx
- Aachen-Maastricht Institute for Cardiorenal Disease (AMICARE), RWTH Aachen Campus, Aachen, Germany
- Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Joachim Jankowski
- University Hospital RWTH Aachen, Aachen, Germany
- Joachim Jankowski
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
- Joachim Jankowski
- Aachen-Maastricht Institute for Cardiorenal Disease (AMICARE), RWTH Aachen Campus, Aachen, Germany
- Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Heidi Noels
- University Hospital RWTH Aachen, Aachen, Germany
- Heidi Noels
- Aachen-Maastricht Institute for Cardiorenal Disease (AMICARE), RWTH Aachen Campus, Aachen, Germany
- Heidi Noels
- 1Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
- DOI
- https://doi.org/10.3389/fcvm.2024.1346475
- Journal volume & issue
-
Vol. 11
Abstract
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.
Keywords
- chronic kidney disease
- cardiovascular disease
- uremic toxin
- cardiomyocyte
- drug metabolite
- mycophenolate mofetil
