title: Hydroxylated, Hydroxymethylated, Dihydroxylated, and Trihydroxylated Cyclosporine Metabolites Can Be Nephrotoxic in Kidney Transplant Recipients.
abstract: BACKGROUND
  Cyclosporine (CsA) is an immunosuppressive agent whose use is associated with adverse effects, including nephrotoxicity. There are reports indicating that some CsA metabolites may contribute to these effects. This study was aimed at evaluation of CsA metabolites and correlating them with kidney function.
  
  
  METHODS
  In 62 kidney transplant recipients (41.9% women; overall mean age, 48.44 ± 11.75 years), concentrations of CsA and 4 groups of metabolites were assessed: hydroxylated (HCsA), hydroxymethylated (HMCsA), dihydroxylated (DHCsA), and trihydroxylated (THCsA). The results were normalized with the use of the metabolite-to-parent drug ratio, and results were linked with estimated glomerular filtration rate (eGFR) at 3 months before (-3M), point zero (0M), and after 3 (+3M) and 12 (+12M) months.
  
  
  RESULTS
  Multivariate analysis demonstrated the negative influence of eGFR -3M on HMCsA/CsA (β = -0.266; P < .05) and the negative influence of HCsA/CsA, HMCsA/CsA, DHCsA/CsA, and THCsA/CsA on eGFR +3M (β = -0.339, β = 0.396, β = -0.314, and β = -0.321, respectively; P < .005) and eGFR +12M (β = -0.363, β = -0.316, β = -0.267, and β = -0.312, respectively; P < .05). We did not detect such influence of CsA concentrations on eGFR +3M and +12M. The THCsA/CsA receiver operating characteristic cutoff value for prediction of improvement of kidney function at +12M was 0.143.
  
  
  CONCLUSIONS
  Our results suggest that impaired function of the transplanted kidney affects the accumulation of HMCsA. It is possible that the increased metabolite (HCsA, HMCsA, DHCsA, and THCsA) to cyclosporine ratio could influence or could be a marker of cyclosporine nephrotoxicity. In this context, the most promising marker seems to be THCsA/CsA ratio, but its real significance requires further studies to determine.
authors: Department of Clinical Nursing, Medical University of Warsaw, Warsaw, Poland.
authors: E
authors: E
authors: Hryniewiecka
authors: Transplantation Institute, Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
authors: J
authors: J
authors: Żegarska
authors: Transplantation Institute, Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
authors: D
authors: D
authors: Żochowska
authors: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors: R
authors: R
authors: Jaźwiec
authors: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors: A
authors: A
authors: Borowiec
authors: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors: E
authors: E
authors: Samborowska
authors: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors: W
authors: W
authors: Tszyrsznic
authors: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Department of Biology, University of Warsaw, Warsaw, Poland.
authors: M
authors: M
authors: Dadlez
authors: Transplantation Institute, Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland. Electronic address: leszek.paczek@wum.edu.pl.
authors: L
authors: L
authors: Pączek
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D066027:Transplant Recipients
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine