title: Pharmacodynamic monitoring of cyclosporine A by NFAT-regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients.
abstract: Pharmacokinetic monitoring of CsA is unsatisfactory, because at comparable CsA blood concentrations, the frequency and severity of adverse effects vary considerably among patients. We have therefore recently developed a precise, reliable, and robust whole-blood pharmacodynamic assay that measures the suppression of CsA-target genes in T lymphocytes. Because of the different characteristics of CsA pharmacokinetics in children and the higher propensity for infectious complications, this assay requires validation in the pediatric patient population. We therefore quantified in a prospective study of 45 pediatric renal transplant recipients the residual expression of NFAT-regulated genes in lymphocytes by RT-PCR and correlated these findings with the frequency of recurrent infections in the maintenance period post-transplant. Patients with recurrent infections showed a significantly stronger inhibition of NFAT-regulated gene expression (18.2%) than patients without recurrent infections (31.7%; p = 0.012). This difference was specific, because various PK parameters of CsA and the concomitant immunosuppressive therapy were comparable between patients. Multivariate regression analysis showed that patient age and residual NFAT-regulated gene expression were the only independent determinants of recurrent infections. By ROC curve analysis, a cutoff value of 23% residual NFAT-regulated gene expression had the highest sensitivity (71.1%) and specificity (65.4%) for the discrimination of patients with and without recurrent infections. Pharmacodynamic monitoring of CsA by measurement of residual NFAT-regulated gene expression in T lymphocytes has the potential to identify over-immunosuppressed pediatric renal transplant recipients and is therefore a useful tool for the optimization of CsA therapy.
authors.affiliation: University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Billing
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommerer
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Reinhard
authors.initials: R
authors.lastname: Feneberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Meuer
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007239:Infections / Q000209:etiology; D016030:Kidney Transplantation / Q000379:methods*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D016572:Cyclosporine