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Cyclosporine Metabolites’ Metabolic Ratios May Be Markers of Cardiovascular Disease in Kidney Transplant Recipients Treated with Cyclosporine A-Based Immunosuppression Regimens

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Abstract

Cardiovascular disease (CVD) remains one of the primary causes of death after kidney transplantation (KTX). Cyclosporine (CsA) metabolites may play a role in CVD. Metabolic ratio (MR) may be considered a measure of intra-individual differences of CsA metabolism. The study was aimed at analysis of associations of CVD with indices of CsA metabolism: MRs and dose-adjusted CsA concentrations (C/D and C/D/kg). The study was performed in the Department of Immunology, Transplant Medicine, and Internal Diseases of the Medical University of Warsaw and involved 102 KTX recipients. Whole blood concentrations of cyclosporine A, AM1, AM9, AM4N, demethylcarboxylated (dMC-CsA), dihydroxylated (DiH-CsA), trihydroxylated (TriH-CsA) cyclosporine metabolites were determined by liquid chromatography coupled with tandem mass spectrometry. Lower AM9/CsA were observed in diabetics. Patients with coronary disease and/or myocardial infarction had lower dMC-CsA/CsA and higher AM4N/CsA. Supraventricular arrhythmia (SVA) was associated with higher AM1/CsA and AM4N/CsA. Hypertriglyceridemia (hTG) was associated with lower AM9/CsA, higher C/D and C/D/kg. Decrease of AM9/CsA and AM4N and higher D/C were associated with overweight/obesity. Systolic blood pressure (BP) positively correlated with dMC-CsA/CsA and negatively with C/D/kg. Diastolic BP correlated positively with AM1/CsA, dMC-CsA/CsA, DiH-CsA/CsA and TriH-CsA/CsA. We have demonstrated the association of coronary disease/myocardial infarction, SVA, hTG, overweight/obesity and elevated arterial BP with higher MRs of AM1, AM4N, dMC-CsA, DiH-CsA and TriH-CsA, and lower MRs of AM9, which may indicate deleterious and favourable effects of individual CsA metabolites on cardiovascular system and suggest engagement of specific enzymatic pathways.

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Acknowledgements

This work was supported by Polish National Science Centre (Grant No. 2013/09/B/NZ2/00275) and Polish National Centre of Research and Development (Grant No. NR13014410).

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Authors and Affiliations

  1. Department of Clinical Nursing, Medical University of Warsaw, 27 Ciolka St, Warsaw, Poland

    Ewa Hryniewiecka

  2. Department of Immunology, Transplant Medicine and Internal Diseases, Medical University of Warsaw, 59 Nowogrodzka St, Warsaw, Poland

    Ewa Hryniewiecka, Jolanta Żegarska, Dorota Żochowska & Leszek Pączek

  3. Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Science, 5a Pawinskiego St, Warsaw, Poland

    Emilia Samborowska, Radosław Jaźwiec & Michał Dadlez

  4. Department of General and Transplantology, Medical University of Warsaw, 59 Nowogrodzka St, Warsaw, Poland

    Maciej Kosieradzki

  5. Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, 1a Banacha St, Warsaw, Poland

    Sławomir Nazarewski

  6. Biology Department, Institute of Genetics and Biotechnology, 5a Pawinskiego St, Warsaw, Poland

    Michał Dadlez

  7. Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5a Pawinskiego St, Warsaw, Poland

    Leszek Pączek

Authors
  1. Ewa Hryniewiecka
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  2. Jolanta Żegarska
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  3. Dorota Żochowska
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  4. Emilia Samborowska
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  5. Radosław Jaźwiec
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  6. Maciej Kosieradzki
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  7. Sławomir Nazarewski
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  8. Michał Dadlez
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  9. Leszek Pączek
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Correspondence to Ewa Hryniewiecka.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The study protocol was approved by the MUW Ethical Committee. All procedures performed were in accordance with the ethical standards of the MUW Ethical Committee and with the 1964 Helsinki declaration and its later amendments.

Research Involving Human and Animal Participants

This article does not contain any studies with animal performed by any of the authors.

Informed Consent

Before the study procedures all patients have given their written informed consent.

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Handling Editor: Rajiv Janardhanan.

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Hryniewiecka, E., Żegarska, J., Żochowska, D. et al. Cyclosporine Metabolites’ Metabolic Ratios May Be Markers of Cardiovascular Disease in Kidney Transplant Recipients Treated with Cyclosporine A-Based Immunosuppression Regimens. Cardiovasc Toxicol 19, 255–263 (2019). https://doi.org/10.1007/s12012-018-9492-9

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  • DOI: https://doi.org/10.1007/s12012-018-9492-9

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