Early Immunosuppressive Exposure of Enteric-Coated-Mycophenolate Sodium Plus Tacrolimus Associated with Acute Rejection in Expanded Criteria Donor Kidney Transplantation

Abstract

Background:Immunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR.Methods:We performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC)0-12h and Tac C0 were measured at the 1st week and the 1st month posttransplant, respectively. The correlation was assessed by multivariate logistic regression.Results:The occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC0-12h at the 1st week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUC0-12h level was <30 mg·h-1·L-1 at the 1st week (15.0% vs. 44.4%) or the Tac C0 was <4 ng/ml at the 1st month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC0-12h at the 1st week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac C0 at the 1st month (OR: 0.904, 95% CI: 0.822–0.986) had significant inverse correlation with BPAR (P < 0.05).Conclusions:Low-level exposure of MPA and Tac C0 in the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC0-12h <30 mg·h-1·L-1 and Tac C0 <4 ng/ml should be avoided in the first few weeks after transplantation.

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention

“…A substantial increase in rejection rates has been reported with an initial MPA AUCt 0-12 <30 mg/L.h and 1 of the following: >3 human leukocyte antigen mismatches, panel reactive antibody >15%, repeat transplant, delayed graft function, or African American descent; 89 if concurrent underexposure to other immunosuppressants 93 or for expanded criteria donation. 97,98 Elsewhere, similar rejection “thresholds” have been reported in contemporary regimen. 41,91 Rapid and effective target concentration attainment could ameliorate this risk in such individuals.…”

“…For tacrolimus cotreated transplant recipients, 7 of 11 cohorts (comprising 1373 of 1696 individuals, 81.0%) revealed a statistically significant association. 41,85,89,91,93,97,98 Two further cohorts reported a trend (11.9% of individuals). 80,94 This left 2 cohorts (7.2% of individuals).…”

“…However, the validity of MPA AUCt 0-12 as a biomarker for drug exposure, causally linked to drug effect, will still apply with different drug combinations or populations, although exposure target may differ. Second, precision dosing aims to maximize benefits and minimize toxicities: in contemporary cohorts, there remains MPA underexposure associated with rejection, 41,89,91,93,97,98 dose-dependent toxicities, 129,130,134 and overexposure associated with toxicities, 80,94,99,104,105 highlighting a potential value of TCI.…”

Predictive Score Model for Delayed Graft Function Based on Hypothermic Machine Perfusion Variables in Kidney Transplantation

“…[ 1 2 ] The high incidence of delayed graft function (DGF) and the higher risk of early graft dysfunction and failure were the main concerns of DCD kidney transplantation. [ 3 4 5 ]…”

“…Therefore, several predictive models for DGF have been developed within the last few years. [ 4 13 14 15 16 17 ]…”