Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial.
Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.
Gotti
E
E
Negri Bergamo Labs, Mario Negri Institute for Pharmacological Research, Via Gavazzeni II, Bergamo 24125, Italy.
Perico
N
N
Gaspari
F
F
Cattaneo
D
D
Lesti
M D
MD
Ruggenenti
P
P
Segoloni
G
G
Salvadori
M
M
Rigotti
P
P
Valente
U
U
Donati
D
D
Sandrini
S
S
Federico
S
S
Sparacino
V
V
Mourad
G
G
Bosmans
J-L
JL
Dimitrov
B D
BD
Iordache
B E
BE
Remuzzi
G
G
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use; D000704:Analysis of Variance; D019540:Area Under Curve; D001706:Biopsy; D002986:Clinical Trials as Topic; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000097:blood* / Q000627:therapeutic use*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000627:therapeutic use; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D009173:Mycophenolic Acid