Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients

Transplantation. 2008 Jan 27;85(2):179-84. doi: 10.1097/TP.0b013e31815feede.


Background: We investigated cyclosporine A (CsA) concentrations at the site of action, inside T-lymphocytes, to evaluate its applicability as a new supplementary therapeutic drug monitoring method after renal transplantation.

Method: In this prospective single-center study, 20 kidney transplant recipients, mean age 54 (range 21-74) years, on CsA-based immunosuppression were included within 2 weeks posttransplant and followed for 3 months. Nine patients also had one full 12-hour pharmacokinetic profile performed. T-lymphocytes were isolated from 7 ml whole blood using Prepacyte and intracellular CsA concentrations were determined using a validated liquid chromatography double mass spectrometry method.

Results: Seven patients (35%) experienced acute rejections (all biopsy verified) during the first three months posttransplantation. Intracellular CsA concentrations tended to decline 1 week prior to acute rejection and the decrease was significant (-27.1+/-14.6%, P=0.014) three days before the rejection episodes were recognized clinically. In addition, the intracellular CsA area under the curve 0-12 measured during stable phase was 182% higher in the rejection-free patients (P=0.004). There was no difference between patients experiencing rejection and the rejection-free patients with respect to CsA C2-levels, dose (mg/kg), human leukocyte antigen mismatch, donor age, recipient age, or ABCB1 genotyping.

Conclusion: Intracellular CsA T-lymphocyte concentrations declined significantly 3 days prior to a rejection episode and there was a general lower intracellular exposure of CsA in recipients experiencing rejection. Intracellular measurement of CsA therefore seems to have a potential to further improve individualization of therapeutic drug monitoring. Larger studies are needed to elucidate the role for intracellular T-lymphocyte measurements in ordinary clinical care, for both CsA and other immunosuppressive drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adult
  • Aged
  • Cyclosporine / blood*
  • Cyclosporine / pharmacokinetics
  • Female
  • Genotype
  • Graft Rejection / immunology*
  • Graft Survival / immunology
  • Humans
  • Immunosuppressive Agents / blood*
  • Immunosuppressive Agents / pharmacokinetics
  • Kidney Transplantation / immunology*
  • Lymphocyte Count*
  • Male
  • Middle Aged
  • Pilot Projects
  • T-Lymphocytes / immunology*


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • Cyclosporine