Cyclosporine A sensitivity in vitro and P-glycoprotein expression in patients on dialysis and after kidney transplantation

Background: In allogeneic kidney transplantation the response to cyclospori ne A (CsA) is important for graft outcome. Although CsA therapy is controll ed by drug monitoring to ensure therapeutic CsA levels, the sensitivity to the effects of CsA varies among individuals. Since CsA is an antagonist of cytostatic drugs in P-glycoprotein (Pgp)-mediated transport, increased Pgp expression might contribute to an increased resistance to CsA. Methods: The sensitivity of lymphocytes at three different concentrations of CsA was te sted in a non-radioactive lymphocyte-transformation test and related to Pgp expression as determined by flow cytometry on mononuelear cells. Five grou ps, including healthy donors (CON; n = 25): patients on dialysis (DIAL; n = 25), patients before transplantation (PTX; n = 5) and after transplantatio n [short-term (ATX; n = 5) and long-term (LTX: n = 25)] were investigated. Results: In LTX, the sensitivity to CsA at 400 and 1000 ng/ml was significa ntly different from CON and DIAL. Overall a higher sensitivity to CsA was s een in patients after transplantation. In ATX, sensitivity to CsA was signi ficantly higher than in PTX at a concentration of 1000 ng/ml CsA. However, comparing all groups no significant changes in Pgp expression were noted. A nalysing the relationship between CsA sensitivity and Pgp expression, no si gnificant heterogeneity could be observed between the different groups. Con clusion: In conclusion, our data suggest that in vitro testing of CsA sensi tivity prior transplantation and Pgp expression monitoring yield independen t results and cannot substitute for each other as predictors of graft outco me. The differential role of each test for the evaluation of CsA sensitivit y or resistance remains to be determined. (C) 2000 Elsevier Science B.V. Al l rights reserved.