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 cyclosporine A (CsA) is important for graft outcome. Although CsA therapy is controlled 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 tested in a non-radioactive lymphocyte-transformation test and related to Pgp expression as determined by flow cytometry on mononuclear cells. Five groups, including healthy donors (CON; n = 25), patients on dialysis (DIAL; n = 25), patients before transplantation (PTX; n = 5) and after transplantation [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 significantly different from CON and DIAL. Overall a higher sensitivity to CsA was seen in patients after transplantation. In ATX, sensitivity to CsA was significantly higher than in PTX at a concentration of 1000 ng/ml CsA. However, comparing all groups no significant changes in Pgp expression were noted. Analysing the relationship between CsA sensitivity and Pgp expression, no significant heterogeneity could be observed between the different groups.


CONCLUSIONS
In conclusion, our data suggest that in vitro testing of CsA sensitivity prior transplantation and Pgp expression monitoring yield independent results and cannot substitute for each other as predictors of graft outcome. The differential role of each test for the evaluation of CsA sensitivity or resistance remains to be determined.
Zacher
T
T
Institut für Klinische Immunologie an der Medizinischen Klinik III mit Poliklinik der Universität Erlangen-Nürnberg, Erlangen, Germany. zacher@med3.imed.uni-erlangen.de
Thiele
B
B
Wassmuth
R
R
Albert
F W
FW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D016030:Kidney Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects*; D006435:Renal Dialysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine