Pharmacodynamic monitoring of cyclosporine A by NFAT-regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients.
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.
Billing
Heiko
H
University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, Germany.
Giese
Thomas
T
Sommerer
Claudia
C
Zeier
Martin
M
Feneberg
Reinhard
R
Meuer
Stefan
S
Tönshoff
Burkhard
B
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
D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D016572:Cyclosporine