Cyclosporine Metabolites’ Metabolic Ratios May Be Markers of Cardiovascular Disease in Kidney Transplant Recipients Treated with Cyclosporine A-Based Immunosuppression Regimens
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.
KeywordsKidney transplantation Cyclosporine Cyclosporine metabolites Cardiovascular disease Arrhythmia Hypertriglyceridemia Obesity Overweight
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).
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
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.
Before the study procedures all patients have given their written informed consent.
- 1.System USRD. (2017). Annual Data Report. Epidemiology of kidney disease in United States 2017.Google Scholar
- 7.Lunde, I., Bremer, S., Midtvedt, K., Mohebi, B., Dahl, M., Bergan, S., et al. (2014). The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. European Journal of Clinical Pharmacology, 70, 685–693.CrossRefGoogle Scholar
- 10.Combalbert, J., Fabre, I., Fabre, G., Dalet, I., Derancourt, J., Cano, J. P., et al. (1989). Metabolism of cyclosporin A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450IIIA gene subfamily. Drug Metabolism and Disposition, 17(2), 197–207.PubMedGoogle Scholar
- 11.Aoyama, T., Yamano, S., Waxman, D. J., Lapenson, D. P., Meyer, U. A., Fischer, V., et al. (1989). Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. Journal of Biological Chemistry, 264(18), 10388–10395.PubMedGoogle Scholar
- 13.Elens, L., van Schaik, R. H., Panin, N., Meyer, M., Wallemacq, P., Lison, D., et al. (2011). Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors’ dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics, 12(10), 1383–1396.CrossRefGoogle Scholar
- 14.Hryniewiecka, E., Zegarska, J., Zochowska, D., Samborowska, E., Jazwiec, R., Kosieradzki, M., et al. (2018). Cardiovascular disease in kidney transplantation and its association with blood concentrations of cyclosporine and cyclosporine metabolites. Transplantation Proceedings, 145(4), 247–254.Google Scholar
- 15.Textor, S., Canzanello, V. J., & Taler, S. J. (1994). Cyclosporine-induced hypertension after transplantation. Mayo Clinic Proceedings, 23, 2614–2622.Google Scholar
- 19.Bianchi, R., Rodella, L., & Rezzani, R. (2003). Cyclosporine A up-regulates expression of matrix metalloproteinase 2 and vascular endothelial growth factor in rat heart. International Immunopharmacology, 3, 423–433.Google Scholar
- 21.Sadeg, N., Pham-Huy, C., Rucay, P., Righenzi, S., Halle-Pannenko, O., Claude, J. R., et al. (1993). In vitro and in vivo comparative studies on immunosuppressive properties of cyclosporines A, C, D and metabolites M1, M17 and M21. Immunopharmacology and Immunotoxicology, 15(2–3), 163–177.CrossRefGoogle Scholar
- 26.Hryniewiecka, E., Żegarska, J., Żochowska, D., Jaźwiec, R., Borowiec, A., Samborowska, E., et al. 2016). Hydroxylated, hydroxymethylated, dihydroxylated, and trihydroxylated cyclosporine metabolites can be nephrotoxic in kidney transplant recipients. Transplantation Proceedings, 48, 1551–1555.CrossRefGoogle Scholar