Background: End-stage renal disease is a state of enhanced oxidative stress (OS) and hemodialysis (HD) and renal anemia further augment this disbalance. Anemia correction with erythropoietin (EPO) may improve oxidative status. However, there is no evidence of time dependent effects of EPO therapy on redox status of HD patients.Objective: The aim of this study was to evaluate whether the duration of EPO treatment may affect OS parameters in uremic patients.Patients and methods: 104 HD patients and 29 healthy volunteers were included. Patients were divided into 3 groups according to the duration of EPO treatment. Forth group consisted of HD patients without EPO treatment. Plasma and erythrocyte malondialdehyde (MDA, MDArbc), reactive carbonyl groups (RCG), plasma sulfhydryl (-SH) groups and total antioxidative capacity (TAC) levels were evaluated.Results: HD patients both with and without EPO treatment, showed a significant increase in all oxidative parameters without significance between EPO treated and -untreated group. The decrease in MDA and MDArbc levels coincided with the duration of EPO treatment. A negative correlation was observed between the duration of EPO treatment and serum MDA (r=˗0.309, p=0.003). Increasing periods of EPO treatment were associated with decrease in RCG, without significance between EPO groups. Increase in TAC accompanied increasing durations of EPO treatment, with EPO treatment for more than 24 months causing the most striking changes (p<0.05). There were no significant differences in ˗SH levels between EPO subgroups.Conclusion: Our results suggest that long term administration of EPO attenuated the lipid peroxidation process and restored the levels of antioxidants.

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Objectives: To assess the degree of immunosuppressive medication adherence in kidney transplant patients (KTPs) and to determine if there is a difference in the rate of adherence to tacrolimus (Tac), cyclosporine (CsA) and sirolimus (Sir). Subjects and Methods: From a total of 63 KTPs treated at the Clinic of Nephrology, Clinical Centre Niš, Serbia, 60 participated in the study by responding to questionnaires. They were divided into the adherence group (n = 43) and the nonadherence group (n = 17) according to their degree of adherence which was measured using a validated survey form, the simplified medication adherence questionnaire. The KTP adherence to the different immunosuppressive regimens (Tac, CsA and Sir) was compared. Statistical analysis was performed using the Student t test. Results: Adherence was observed in 43 (71.7%) patients, and only 17 (28.3%) did not follow the prescribed therapy. The estimated glomerular filtration rate was significantly lower in the nonadherence group (38.52 ± 18.22 ml/min) than in the adherence group (52.43 ± 16.91 ml/min, p < 0.05). With regard to the Tac level, a significant difference was also found between the adherers and the nonadherers (6.30 ± 2.06 vs. 5.0 ± 1.52 ng/ml, p < 0.05). Conclusion: The KTPs in this study demonstrated a high level of adherence.Nonadherence was associated with worse graft function and a lower Tac level. Knowledge about the degree of adherence could help the early identification of nonadherent patients and the development of strategies to improve this.

Objective: The purpose of this study was to derive population pharmacokinetics (PPK) model of tacrolimus clearance, identify and describe factors that influence it in Serbian kidney transplant patients. Methods: Population pharmacokinetics analysis was performed using nonlinear mixedeffects model (NONMEM) program from Serbian adult kidney transplant patients receiving triple immunosuppressive therapy, including oral tacrolimus. Details of drug dosage history, sampling time and tacrolimus concentration in 63 patients (44 males and 19 females), 27 -57 years old (age mean 40.88 ± 7.01 years) were collected retrospectively. Effects of several covariates on tacrolimus clearance were tested: total body weight, gender, age, posttransplantation days, hemoglobin count, CRP, alanine aminotransferase/aspartate aminotransferase, total daily dose of tacrolimus, co-medication with cotrimoxasole, omeprazole, mycophenolate mofetil and prednisone (> 25 mg). Results: Typical mean value of tacrolimus clearance, estimated by the base model (without covariates), in our population was 1.03 l h -1 . The final model showed that tacrolimus clearance increased with total daily dose and concomitant administration of high-dose prednisone (> 25 mg). The magnitude of prednisone effect was + 1.16 l h -1 . Final model was validated in a group of 17 patients, showing good predictive performance. Conclusions: The derived model describes well tacrolimus clearance in terms of characteristics of Serbian kidney transplant patients, offering basis for rational individualization of tacrolimus dosing regimens.

Tacrolimus (Tac) is an immunosuppressive drug with a narrow therapeutic width and highly variable pharmacokinetics. Therefore, monitoring of Tac blood concentrations is of utmost importance in the management of renal transplant recipients. The occurrence and intensity of adverse effects depend on blood concentration and total exposure of the organism to this drug. This implies finding a new gender-dependent predictable method for Tac exposure monitoring based on determination of the area under the time concentration curve (AUC). The primary aim of this study was to investigate gender differences in systemic body exposure to Tac in renal transplant patients after the first oral dose and in a steady state by determining 12-h AUC (AUC(0-12)). The secondary objective was to find the best sampling time in which measured Tac concentration best predicts AUC value with respect to gender. Tac pharmacokinetic study was conducted in 20 kidney transplant recipients (10 men/10 women) on quaternary immunosuppressive therapy. The first oral Tac dose (0.05 mg/kg) was given on the fifth day post-transplant. After reaching steady state, regimen stabilized and dosage was adjusted in accordance with the level of Tac. Blood concentrations were measured by microparticle enzyme immunoassay method. AUC(0-12) for each patient was calculated after the first oral Tac dose and in the steady state from a plot of Tac concentration versus time from 0 to 12 h using the trapezoid rule. Associations between each sampling time point of concentrations within 12 h after the administration and AUC(0-12) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple stepwise regression analyses. Statistically significant difference was found in AUC(0-12) between male and female patients after the first oral dose (p < 0.01), but this difference was lost in a steady state. In female recipients C(2) seemed to be good indicator of total body exposure to Tac after the first oral dose and this was also confirmed in a steady state. The three-point sampling method was required for calculating AUC after the first oral dose in male patients, whereas in the steady state, concentration of C(8) seemed to be a good indicator of abbreviated AUC for a Tac monitoring strategy in male patients. Non-compartment Tac pharmacokinetic and regression analysis showed gender difference in total Tac exposure and determined the best predictable Tac concentrations after the first oral dose. Our study confirmed gender-dependent pharmacokinetics in a steady state in terms of best sampling time in which measured Tac concentration best predicts AUC value.

Abstract. The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic-pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters [creatinine (Cre) clearance and serum Cre level] were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post-transplant. Individuals carrying the CYP 3A5

Occurrence of urosepsis is not uncommon following urinary tract infections (UTI). However, there is a lack of evidence explaining the risk factors predisposing to urosepsis in patients with chronic kidney disease (CKD). This retrospective study was undertaken to evaluate the incidence and possible risk factors for urosepsis among patients hospitalized with UTI in a cohort of CKD patients. Patients were divided into the urosepsis group and the non-urosepsis group. Of 489 hospitalized patients with UTI, 70 (14.3%) acquired urosepsis. Stepwise multivariate logistic regression demonstrated that diabetes, urinary catheter and length of hospital stay (p < 0.001 for all) were significant independent predictive risk factors for urosepsis in CKD patients with UTI in addition to age, glomerular filtration rate, hydronephrosis, acute kidney injury and E. coli infection (p < 0.05 for all). Finally, Klebsiella spp. cases were associated with significantly higher odds for urosepsis than E. coli cases (OR: 3.5, 95% CI: 2.86–7.23, p < 0.001 vs. OR: 1.38, 95% CI: 1.19–3.69, p = 0.038). Diabetes, presence of an indwelling urinary catheter, length of hospitalization, and infection with Klebsiella spp were independent risk factors for urosepsis in CKD patients with UTI.

Monitoring of tacrolimus blood concentration is of utmost importance in the management of renal transplant recipients because of Narrow Therapeutic Index and highly variable pharmacokinetics. The aim of this study was to detect inter-patient pharmacokinetic variability of tacrolimus and to assess the predictability of individual tacrolimus concentrations at various times of the area under the curve (AUC) seeking to find the best sampling time to predict the exposure of tacrolimus in renal transplant recipients with triple therapy. This oral dose tacrolimus pharmacokinetics study was conducted in 18 Serbian renal transplant recipients on triple immunosuppressive therapy, including basiliximab. The first oral dose of tacrolimus (0.05 mg ⁄ kg) was given on day 5 post-transplant; blood concentration was measured by microparticle enzyme immunoassay method. Associations between each sampling time-point of concentrations and AUC 12 were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses. The variance in the strength of association between predicted AUC (AUC p ) and AUC 12 was reflected by linear regression coefficients. AUC 12 showed remarkable inter-individual variations after the first oral dose of tacrolimus. The area of the maximum AUC was four times higher than that of the minimum AUC. C 4 seems to be an indicator of total body exposure to tacrolimus. Alternatively, the concentrations at 1.5, 4 and 8 hr as an abbreviated AUC were as good a predictor as a full pharmacokinetic study. Our results show a significant difference between men and women. A three-point sampling method seemed to be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy.Rejection prophylaxis using calcineurin inhibitors (cyclosporine or tacrolimus) remains the best practice pending publication of long-term results using newer agents [1][2][3]. The choice of cyclosporine or tacrolimus depends on immunological risk, recipient characteristics, concomitant immunosuppression and socio-economic factors. Tacrolimus (FK 506) is superior to cyclosporine in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastrointestinal side effects [3,4]. Monitoring of tacrolimus blood concentrations is of utmost importance in the management of renal transplant recipients because of the narrow therapeutic range and highly variable pharmacokinetics of the drug [1][2][3][4]. If the concentration is lower than the range, the transplanted kidney will be rejected because of insufficient immunosuppression by tacrolimus. If the concentration is higher than the range, adverse effects will be observed because of the excess concentration of tacrolimus. High systemic exposure to tacrolimus might induce many side effects including nephrotoxicity, neurotoxicity and post-transplant diabetes mellitus [3,4]. Therapeutic monitoring of tacrolimus plays a crucial role not only in ...