Kidney transplantation is the best option for kidney replacement therapy, even considering that most of the times the grafts do not survive as long as their recipients. In the Khalil et al's experience, published in this issue of the Journal, they analyze their second kidney graft survival and describe those significant predictors of early loss. This editorial comments on the results and put in perspec tive that most of the times, long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason, and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.

Background Mycophenolic acid is widely used immunosuppressive drug, associated with adverse effects which increase patient morbidity and decrease medication adherence. Objective To evaluate the adverse effects in renal transplant recipients under mycophenolate treatment with respect to gender. Setting University Clinical Centre of Nis, Clinic of Nephrology, Serbia. Method This research included 96 renal transplant recipients, who received immunosuppressive regimen, based on tacrolimus or cyclosporin A, prednisone and mycophenolic acid. The high-performance liquid chromatography method combined with protein precipitation was used for the analysis of mycophelate concentration in human plasma. Drug concentration and dose-adjusted concentration were determined with respect to the patients' gender. An adverse effect scoring system developed by nephrologists within the University of Buffalo Nephrology/Transplant Program was used to monitor adverse effects of therapy. Main outcome measure Individual and scores of adverse effects in relation to the dosing regimen and gender. Results Results showed statistically lower dose and concentrations in men compared to the women in our investigation group. Also, female patients demonstrated higher mean scores (cumulative and subscores) within the same dosing regimens of mycophenolic acid. The gastrointestinal score was significantly higher in women who received a dose greater than 720 mg compared to men (0.20 ± 0.12 vs 0.12 ± 0.12). Women demonstrated higher individual adverse effects such as diarrhea and skin changes (41.7 vs 17.0; p = 0.038 and 62.5 vs 30.2; p = 0.037, respectively). Conclusions The results of our research showed that recipients' gender may play an important role in pharmacokinetic profile of mycophenolic acid, suggesting that women had higher concentration of mycophenolic acid and more serious side effects.

The increased tolerability of enteric-coated mycophenolate sodium (EC-MPS), compared to mycophenolate mofetil, among kidney transplant recipients has the potential to facilitate cyclosporine (CsA) minimization. Therefore, a prospective trial to determine the optimum EC-MPS dose in CsA-based immunosuppression regimens is necessary.

A comparative, parallel, randomized, open-label study was performed for 140 patients from four centers to compare the efficacy and tolerability of low dose CsA with standard dose EC-MPS (the investigational group) versus standard dose CsA with low dose EC-MPS (the control group) for six months in de novo kidney transplant recipients. Graft function, the incidence of efficacy failure [biopsy-confirmed acute rejection (BCAR), death, graft loss, loss to follow-up], and adverse events were compared.

The mean estimated glomerular filtration rate (eGFR) of the investigational group at six months post-transplantation was non-inferior to that of the control group (confidence interval between 57.3 mL/min/1.73m² and 67.4 mL/min/1.73 m², p<0.001). One graft loss was reported in the control group, and no patient deaths were reported in either group. The incidence of BCAR of the investigational group was 8.7%, compared to 18.8% in the control group (p=0.137), during the study period. There were no significant differences (p>0.05) in the incidence of discontinuations and serious adverse events (SAE) between the groups.

CsA minimization using a standard dose of EC-MPS kept the incidence of acute rejection and additional risks as low as conventional immunosuppression and provided therapeutic equivalence in terms of renal graft function and safety issues.

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.