Hydroxylated, Hydroxymethylated, Dihydroxylated, and Trihydroxylated Cyclosporine Metabolites Can Be Nephrotoxic in Kidney Transplant Recipients

• Impaired function of kidney graft affects accumulation of hydroxymethylated CsA.
• Increased metabolite to CsA ratio influences graft function after 3 and 12 months.
• The most promising marker of future graft function appears to be trihydroxy CsA/CsA ratio.

BackgroundCyclosporine (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.MethodsIn 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.ResultsMultivariate 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.ConclusionsOur 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.