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Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6–12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6–12 months post-transplantation. The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.

Background and Aims The mortality of septic patients with acute kidney injury (s-AKI) prevails high. Atrial fibrillation is commonly observed in the setting of systemic inflammation or infection. The study aimed to assess the incidence and predictors of new-onset atrial fibrillation (NOAF) in this population and its impact on intrahospital mortality. Method We conducted a retrospective cohort study of 462 patients admitted to our unit for s-AKI between January 2016 and December 2020. NOAF was defined as AF discovered during hospitalization in patients with sinus rhythm on admission. Subjects were classified into NOAF (n=68) and non-NOAF groups (n=364). There were no major differences in sepsis severity between groups, and all patients underwent intermittent hemodialysis as a renal replacement treatment modality. Results The NOAF incidence in the whole s-AKI population was 14.7%. In a univariate analysis, age (72.4 in patients with NOAF vs. 62.1 years in patients without NOAF, respectively; p=0.018), male gender (33.5 vs. 14.6%; p= 0.004), history of coronary disease (23.5 vs. 6.1%; p=0.07) and vasopressor medication use (19.0 vs. 8.2%; p = 0.002) were associated with NOAF. 116 (25.1%) patients died during the hospitalization, while 346 patients (74.9%) were discharged from the hospital. NOAF occurring in s-AKI was independently associated with an increased hazard of intrahospital death (HR: 1.36; 95% CI: 1.09–1.51), compared to the non-NOAF group. Conclusion A clinically significant number of patients hospitalized for s-AKI have NOAF, and it is associated with poor hospital outcomes.

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 E. coli infection (p 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 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.

Bradykinin (BK), a vasoactive peptide, is considered to exert the renoprotective and cardioprotective effects. Furthermore, most of its effects are mediated by the activation of BK type 2 receptor (B2R), whose level of expression is influenced by insertion/deletion (+9/-9) gene polymorphism. The aim of this study was to investigate the potential influence of B2R +9/-9 gene polymorphism on kidney function and blood pressure in kidney transplant recipients (KTRs) within the first post-transplantation year. Secondary, the study analyzed the correlation between hypertensive status and graft function, with respect to the B2R +9/-9 gene polymorphism. The pharmacogenetic study included 95 KTRs with clinical and biochemical parameters evaluated in three time-points (3rd, 6th, 12th month). The graft function was assessed using the estimated glomerular filtration rate (eGFR), while systolic (SBP), diastolic (DBP), and mean blood pressure (MAP) were used as parameters for the evaluation of blood pressure control. The carriers of -9/-9 genotype had more stable graft function compared to both, heterozygotes and homozygous for +9 allele, not only in the early (up to 6 months) but as well in the late post-transplantation period (beyond 6 months). Also, the -9/-9 genotype carriers showed a tendency to significantly decrease MAP, SBP, and DBP in the observed period, whereby only in this patient group the significant association between hypertensive status and graft function was demonstrated. In conclusion, genotyping of B2R +9/-9 gene polymorphism alongside with biochemical and clinical parameters may identify patients with respect to the risk of more prompt decline of graft function.

Background and Aims Post-transplant weight gain and particularly visceral fat gain has been linked to the development of metabolic disorders and cardiovascular disease. Moreover, the effect of obesity on graft function after kidney transplantation has recently become a subject of interest. The aim of our study was to investigate the association of body mass index (BMI), body fat percentage (BF%) and waist-to-hip ratio (WHR) with the kidney function in kidney transplant patients. Method We conducted a cross-sectional study that enrolled 80 kidney transplant patients aged 23–75 years (mean age 46.7 ± 11.5 years, 60% males). Anthropometric measurements of weight, height, waist, and hip circumferences in addition to skinfold thickness were obtained. BH% was calculated using a 4-site skinfold thickness method calculated through the Jackson-Pollock equation with a Harpenden caliper, utilizing a BF% cutoff of 35% for women and 25% for men to define obesity. Results The calculated BMI in our study group was 32.7±8.7 kg/m2, a mean BF% of 29.9±8.5% and a mean WHR of 0.9±0.1 Statistically significant difference in GFR, BMI, WHR and BF% were observed between males and females (r=0.455, p=0.02; r=0.412, p=0.016; r=0.437, p=0.022; r=0.348, p=0.011), respectively. After adjustment for age, gender, donor group, donor age and years of dialysis before transplantation, higher levels of all obesity measures were related to lower eGFR: BMI per 1 SD (β coefficient −3.883, 95% confidence interval [CI] −5,422 to −3,132), WHR (β coefficient −4.443, 95% CI −6.201 to −3.772), and BF% (β coefficient −3.722, 95% CI −4.332 to −3.461). The combination of higher BF% (BF% >33 kg/m2) and central obesity (WHR >0.85 for women, >0.90 for men) was associated with the lowest eGFR compared with that in lean subjects. Conclusion The combination of high BF% and WHR may be an important risk factor for lower GFR in a kidney transplant recipient.

Background and Aims Low platelet count is a marker of adverse events in acute kidney injury (AKI) patients. Thrombocytopenia has often been reported as an indicator of underlying disease severity and worse patient outcomes; however, it’s role in the prediction of the risk of bleeding is not well defined. Our study aimed to assess the prognostic impact of admission thrombocytopenia in the risk of major bleeding in non-septic, non-post surgery AKI patients. Method This retrospective study enrolled patients with AKI hospitalized at tertiary care hospital during the three years. Admission thrombocytopenia was defined as a platelet count < 150x103/mL. The primary endpoint was major bleeding, as defined by the International Society on Thrombosis and Haemostasis. Results Of 178 included patients (age 61.7±11.1 years; 68.3% males), 26 (14.6%) had thrombocytopenia. These patients had more comorbidities: cancer (19.4 vs 9.6%; p=0.05); previous ulcer disease (17.6 vs. 8.8; p=0.04) and bleeding history (7.4% vs. 2.0%;p=0.04). While in a hospital, there was a trend for the use of more blood transfusions (7.4% vs. 2.7%; p=0.03) and more concomitant medications (12.7 vs. 5.1; p Conclusion Thrombocytopenia is a predictor of major intrahospital bleeding in the non-septic, non-post surgery AKI patients. It should be regarded in bleeding risk estimation and therapeutic strategy decisions.

Objective While kidney transplantation is the best treatment of renal insufficiency and is recommended for patients with a glomerular filtration rate below 30 mL/min, new onset diabetes after transplantation (NODAT) reduces the benefits of this treatment, and present a significant, independent predictor of patient mortality and loss of graft function. The aim of the study was to determine the incidence of NODAT, as well as the risk factors for new onset diabetes mellitus (DM). The study included 84 patients older than 18 years, who underwent kidney transplantation in the Clinical Center Nis in the period from 2007 to 2016. Impaired glucose tolerance was found in all of these patients in the first three post-transplantation months. In addition to physical examination and basic laboratory analyses, in all of kidney transplant patinents the levels of tacrolimus and glycosylated hemoglobin HbA1c were determined. NODAT was registered in 7 (8.3%) patients after average 17.2+10.8 days of kidney transplantation. The patients with NODAT had significantly higher levels of serum creatinine 210.72±120.29 μmol/L and decreased creatinine clearance 43.31±17.57 ml/min/1.73m2 compared with a group of patients with diabetes prior to kidney trans-plantation 180.16±82.78 μmol/L and 52.12±18.45 ml/min/1.73m2, respectively (p

The utilization of all potentials of small and medium-sized enterprises, in terms of their contribution to the growth and development of national economy and poverty reduction, is largely conditioned by the degree of institutional support provided by the state through relevant mechanisms. The role of small and medium-sized enterprises is particularly important in transition countries, which are faced with problems of high unemployment, low level of economic activity, lack of competition, lack of investment and are dominated by large and inefficient state enterprises. For these reasons, the development of small and medium-sized enterprises is seen one of the greatest development opportunities. The methodological approach used in this study is primarily based on presenting quantitative indicators of the level of development of small and medium-sized enterprises in Serbia and EU member states, which show that there is a direct correlation between the degree of industrialization of a country and the share of small and medium-sized enterprises in its economy.

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*1/*3 genotype had higher Tac dose requirements than CYP 3A5*3/*3 carriers at 6, 12 and 24 months after renal transplantation. The results revealed that ABCB1 polymorphism did not influence Tac dose requirements independently. Regression analysis showed that CYP 3A5 influenced the Tac dose-adjusted concentration as well as renal function up to 24 months post-transplant. These findings confirmed that CYP 3A5 polymorphism represents the most important determinant of Tac dose and exposure in the late period following renal transplantation. Furthermore, the obtained results indicate that the decline in renal function may be more pronounced in patients with CYP 3A5*1 in the long-term period after renal transplantation.

Introduction and Aims: Serum p-cresyl sulfate associates with cardiovascular disease in patients at different stages of chronic kidney disease. p-Cresyl sulfate concentrations are determined by intestinal uptake of p-cresol, human metabolism to p-cresyl sulfate and renal clearance. Whether intestinal uptake of p-cresol itself is associated with cardiovascular disease in patients with renal disease has not been studied to date. Methods: We performed a prospective study in patients with chronic kidney disease stage 1-5 (clinicaltrials.gov NCT00441623). Intestinal uptake of p-cresol, under steady state conditions, was estimated from 24h urinary excretion of p-cresyl sulfate. Primary endpoint was time to first cardiovascular event, i.e. cardiac death, myocardial infarction/ischemia, ventricular arythmia, cardiovascular surgery, cerebrovascular accident or symptomatic peripheral arterial disease. Statistical analysis was done using Kaplan Meier estimates and Cox proportional hazard analyses. Results: In a cohort of 200 patients, median 24h urinary excretion of p-cresyl sulfate was 457.47 µmol (IQR 252.68-697.17). After a median follow-up of 52 months, 25 patients reached the primary endpoint (tertile 1/2/3: 5/6/14 events, log rank P 0.0368, see figure). Higher urinary excretion of p-cresyl sulfate was related with cardiovascular events (univariate hazard ratio per 100 µmol increase: 1.112, P 0.0015). In multivariate analysis, urinary excretion of p-cresyl sulfate remained a predictor of cardiovascular events, independent of markers of renal function (Hazard ratio 1.120, P 0.0022) and in different models with other cardiovascular risk factors (Framingham risk factors, cardiovascular history, diabetes mellitus and biochemical parameters). The independent association between urinary excretion of p-cresyl sulfate and outcome persisted after correction for serum p-cresyl sulfate. Conclusions: Intestinal uptake of p-cresol associates with cardiovascular disease independent of renal function. Insights into mechanisms governing intestinal generation and absorption of p-cresol may lead to identification of novel therapeutic targets to reduce cardiovascular disease risk in patients with chronic kidney disease.

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

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 AUC12 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 (AUCp) and AUC12 was reflected by linear regression coefficients. AUC12 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. C4 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.

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 (p0.01), 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.

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.

Cardiovascular (CV) morbidity and mortality rates are still higher after kidney transplantation than in general population. It is known that oxidative and nitrosative stress may contribute to the progress of CV disease in a post-transplant period, but still gender aspect has not been elucidated completely. The aim of this study was to analyze the gender differences in the oxidative and nitrosative stress parameters, as well as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels among kidney transplant patients on tacrolimus-based immunosuppression. Our research included 35 patients (20 men and 15 women) with renal transplant and 25 healthy volunteers. Patients were on chronic immunosuppressive regimen, which included tacrolimus, mycophenolate mofetil and prednisone. In order to estimate oxidative and nitrosative stress, we determined plasma levels of thiobarbituric acid-reactive substances (TBARS), activity of catalase (CAT), levels of total (protein and non-protein) sulfhydryl (SH) groups, advanced oxidation protein products (AOPP), ADMA and SDMA, as well as nitrite/nitrate (NOx) ratio. TBARS, CAT and SH in plasma were significantly higher in male patients than in female patients (p

Assessment of liver fibrosis is important for making treatment decisions, as well as for predicting prognosis and therapeutic outcome in patients on chronic hemodialysis (HD) treatment and infected with hepatitis C virus (HCV). The aim of the present investigation was to evaluate changes in standard laboratory tests (AST, ALT, yGT, cholesterol and platelet count) and indirect serum fibrosis markers: AST-to-platelet ratio index (APRI), FIB-4 and Forns index, in chronically HCV-infected patients on maintenance HD with and without antiviral treatment.A total of 38 patients on chronic HD program more than 3 months and with chronic hepatitis C, were included in the study. According to local legislature 14 patients receive antiviral therapy (24 or 48 weeks, according to HCV genotype) adjusted for patients on HD: eight of them achieved sustained virological response (SVR) and six did not.All treated patients were HCV genotype 1. Baseline blood samples for standard laboratory tests and indirect serum fibrosis markers were collected on the day of antiviral treatment initiation, as well as at the end of follow-up treatment, 36 month later. At the beginning of antiviral treatment there were no significant differences in APRI, FIB-4, Forns and its components between patients who will achieve SVR and those who did not. A significant decrease of AST, ALT, yGT and APRI, and moderate decrease FIB-4 and Forns index was found at the end of follow-up in patients with SVR. In non-sustained responders group those three indexes and its components remained unchanged. Using cut-of values for APRI and FIB-4 (APRI0.5 and FIB-41.45) it was registered that raised percentage of patients with "no fibrosis" at the end of follow-up in those who achieved SVR. Absence of fibrosis measured by Forns index remained unchanged in all groups of patients.Simple indexes as APRI and FIB-4, successfully decrease after antiviral treatment of chronic hepatitis C in hemodialysis patients. These parameters seems to be useful in monitoring for liver fibrosis rate after antiviral treatment in patients on maintenance HD infected by HCV and can be used for estimation liver fibrosis progression in candidates for cadaveric renal transplantation.