Nikola Stefanović

How the duration period of erythropoietin treatment influences the oxidative status of hemodialysis patients.

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.

Monitoring of antibiotic consumption and development of resistance by enterobacteria in a tertiary care hospital

Antibiotics are the most frequently used drugs in hospitalized patients, but studies have shown that the prescribed antibiotics may be inappropriate and may contribute to antibiotic resistance. We carried out a survey of antibiotic consumption and antibiotic resistance in our tertiary care university hospital, from 2005 to 2013. We focus on cephalosporins, one of the most prescribed groups of antibiotics in the tertiary health care. The objective was to identify any relationship between ceftriaxone consumption and resistance by enterobacteria.

Population Pharmacokinetics of Carvedilol in Patients with Congestive Heart Failure

The aim of this study was to derive population pharmacokinetic (PK) model for clearance (CL) of carvedilol in adult patients with chronic heart failure (CHF). Medication and demographic data were obtained from 52 Caucasian patients with CHF taking carvedilol. Population PK analysis was performed by nonlinear mixed-effects modeling (NONMEM) to estimate and identify different factors that could affect carvedilol CL. A total of 55 plasma concentrations were collected from 52 patients with mean age of 63.02 ± 11.95 years and total body weight (TBW) of 77.96 ± 13.46 kg. Total daily doses of carvedilol in the target population had wide range of variability (6.25-50 mg), followed by high variability of drug plasma concentrations (1-59.07 ng/mL). The typical mean value for carvedilol CL, estimated by the base model, in the target population was 43.8 L/h. The TBW, concomitant therapy with digoxin, and tobacco using were determinants of a derived population model. The final regression model for the CL of carvedilol is: [Formula: see text] Our results suggest that the TBW, concomitant therapy with digoxin, and tobacco using are the main subjects of carvedilol PK variability.

The assessment of renalase: searching for the best predictor of early renal dysfunction by multivariate modeling in stable renal transplant recipients.

BACKGROUND Renal transplant dysfunction has been shown to be an independent risk factor for cardiac, non-cardiovascular, and all-cause mortality in post-transplantation follow-up. MATERIAL AND METHODS We enrolled 73 renal transplant recipients who were more than 12 months post-renal transplant surgery, had stable graft function, and were on standard immunosuppression. The purpose of the study was to observe the relation between renal dysfunction and endothelial dysfunction parameters (nitrates, asymmetric and symmetric dimethylarginine, and endothelial nitric oxide synthase), and renalase, and to hypothesize the best predictor of early renal dysfunction by multivariate modeling. The other aim was to observe differences with regard to immunosuppression. RESULTS Non-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate in transplant recipients with increased renalase concentration (p=0.026); age-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate with increased renalase concentration (p=0.042), also after multivariable adjustment (p=0.032). Increased plasma endothelial nitric oxide synthase concentration was a protective factor for glomerular filtration rate (p=0.011). After adjustment for age (p=0.045), and after multivariate modeling, endothelial nitric oxide synthase was shown to be a protective factor for glomerular filtration rate (p=0.014). Significant differences in immunosuppression were found in plasma renalase in patients maintained on cyclosporine (p=0.027). CONCLUSIONS Renalase was shown to be strong predictor of decreased glomerular filtration rate and was significantly higher in the group of patients on cyclosporine. Endothelial nitric oxide synthase was identified as a strong protective factor for kidney function.

Tacrolimus as a Part of Immunosuppressive Treatment in Kidney Transplantation Patients: Sex Differences

BACKGROUND Metabolism interaction between corticosteroids and tacrolimus (Tac) exists and can be an important factor in providing rational pharmacotherapy in kidney transplantation patients. Both Tac and corticosteroids can induce adverse metabolic effects, such as hyperglycemia, post-transplantation diabetes mellitus, and dyslipidemia. OBJECTIVE The main goal of this study was to detect corticosteroid dose influence on Tac level within the first 6 months of immunosuppressive therapy. The secondary goal of this research was to investigate sex differences on Tac-corticosteroid interaction. We also monitored biochemical-parameter changes, which are related to immunosuppressive treatment. METHODS This retrospective pharmacokinetic study included 30 Serbian patients after kidney transplantation. Patients received a quaternary immunosuppressive regimen including Tac, mycophenolate, mofetil, basiliximab, and corticosteroids. To compare dose-normalized level and dose of Tac in different days after transplantation, we performed the Friedman test and Wilcoxon matched-pairs signed rank sum test. Mann-Whitney test was performed to compare differences in dose of Tac, level of Tac, and dose-normalized level of Tac between male and female patient groups. We used the Friedman test to compare biological and clinical data. RESULTS Obtained results show statistical significance between dose of Tac on day 180 post transplantation and dose on days 7, 14, 21, and 60 post transplantation. There was a statistical difference in dose-normalized level of Tac between days 7 and 21 post transplantation (P < 0.01), days 7 and 60 (P < 0.01), and between days 7 and 180 (P < 0.05). There is a statistical significance between male and female levels of Tac on day 21 after transplantation (P < 0.01). Significance also exists on day 60 after transplantation between male and female dose-normalized levels (P < 0.05). There is also a statistical difference in glucose, cholesterol, triglyceride, serum creatinine, and urea level and activity of alanine aminotransferase and alkaline phosphatase before and after operation. CONCLUSION Our study shows that dose of corticosteroid affects Tac level in kidney transplantation patients. Tac dose and level changes showed that corticosteroid-Tac interaction has more influence on male than female patients. According to biochemical monitoring, the immunosuppressive therapy used at present is quite well tolerated.

Dimethylarginine – biomarkers in progression of kidney disease / Dimetilarginini – biomarkeri u progresiji bubrežnih oboljenja

Summary Decreased nitric oxide (NO) production and/or impaired NO bioavailability may occur in patients with the chronic kidney disease (CKD), and could contribute to elevation of blood pressure, cardiovascular disease (CVD) and progression of renal injury in these patients. Free guanidinomethylated arginine residues occur endogenously as a result of proteolysis of post-translational methylated tissue proteins. The asymmetric dimethyl arginine (ADMA) is a competitive inhibitor of the nitric oxide synthase (NOS) enzymes. The kidney has a predominant role in ADMA elimination by combining two mechanisms; urinary excretion and metabolization of ADMA The degradation of ADMA is accomplished intracellularly by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). ADMA is not only a uremic toxin, but also a strong marker of the endothelial dysfunction and atherosclerosis and a stronger independent predictor of all-cause mortality and cardiovascular outcome in patients with the chronic renal failure. There are at least four mechanisms that may explain the accumulation of ADMA in CKD: increased methylation of proteins, increased protein turnover, decreased metabolism by DDAH and impaired renal excretion. A strong positive correlation between symmetric dimethyl arginine (SDMA) and creatinine suggests that SDMA might be of value as a marker of the renal function. Reduced NO elaboration secondary to accumulation of ADMA and elevated inflammation may be important pathogenic factors for endothelial dysfunction in patients with the renal disease. Elevation of ADMA may be a missing link between CVD and CKD. Kratak sadržaj Smanjenje koncentracije NO i/ili nedovoljna raspolo`ivost ovog molekula kod pacijenata sa bubre`nim bolestima mo`e biti razlog pove}anja krvnog pritiska, kardiovaskularnih bolesti (KVS) i progresije bubre`nog o{te}enja. Metilarginini nastaju u procesu proteolize posttranslaciono metilisanih argininskih rezidua u proteinima. Asimetri~ni dimetilarginin (ADMA) je kompetitivni inhibitor azot oksid sintaze (NOS). Najva`nija uloga bubrega u eliminaciji ADMA podrazumeva procese urinarne ekskrecije i razgradnju pod uticajem dimetilarginin dimetilaminohidrolaze (DDAH). Na aktivnost DDAH uti~u oksidativni stres i inflamacija. ADMA nije samo uremijski toksin ve} i zna~ajan marker endotelne disfunkcije i ateroskleroze, kao i nezavisni prediktor mortaliteta i kardiovaskularnih bolesti kod pacijenata sa HBI. Osnovni uzroci koji dovode do akumulacije ADMA su pove}ana metilacija proteina, njihov pove}an metabolizam, smanjena aktivnost DDAH i smanjena urinarna ekskrecija. Klirens simetri~nog dimetilarginina (SDMA) u plazmi zavisi samo od renalne funkcije (pozitivna korelacija sa kreatininom) i njena akumulacija predstavlja nespecifi~ni indikator uremijskih toksina. Redukovana koli~ina NO pra}ena akumulacijom ADMA, udru`ena sa inflamacijom mo`e biti va`an patogeni faktor endotelne disfunkcije kod bubre`nih pacijenata. Porast koncentracije ADMA mo`e biti veza izme|u KVS i HBI.

Variability of mycophenolic acid elimination in the renal transplant recipients – population pharmacokinetic approach

Abstract 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.

Oxidative and Nitrosative Stress in Stable Renal Transplant Recipients with Respect to the Immunosuppression Protocol – Differences or Similarities? / Oksidativni I Nitrozativni Stres U Odnosu Na Imunosupresivni Protokol Kod Pacijenata Sa Stabilnom Funkcijom Presađenog Bubrega – Razlike I Sličnosti

Summary Background: The aim of the study was to evaluate parameters of oxidative and nitrosative stress as well as antioxidative parameters in a group of renal transplant recipients with stable graft function and no clinical signs of cardiovascular disease. We also aimed to determine the correlations among these parameters and to evaluate potential differences in all the biomarkers with regard to the immunosuppression protocol. Methods: We enrolled 57 renal transplant recipients and 31 controls who were age and sex matched with the renal transplant recipients. All of the patients included in this study had post-renal transplant surgery at least 12 months earlier and were on standard immunosuppressive therapy. In this study, we determined thiobarbituric acid-reactive substances in plasma and red blood cells and advanced oxidation protein products, nitrosative stress parameters (asymmetric and symmetric dimethylarginine - ADMA and SDMA), and antioxidative parameters (total SH groups and catalase activity). Results: The results of our study demonstrated that the levels of oxidative and nitrosative stress were significantly increased compared to the healthy population (p<0.01 except for plasma catalase activity p<0.05). Correlation analysis showed significant positive correlations between: ADMA and SDMA (p<0.01); ADMA and nitrates (p<0.05); SDMA and nitrates (p<0.05); between OS parameters in the experimental group; AOPP and SH groups (p<0.05) and TBARS in plasma and SH groups (p<0.01), SDMA and AOPP (p< 0.05); SDMA and TBARS in plasma (p<0.05); SDMA and SH groups (p<0.01); nitrates and SH groups (p<0.05). Conclusion: There was no significant difference in oxidative and nitrosative stress parameters with respect to the immunosuppressive protocol. Kratok sadrzaj Uvod: Transplantacija bubrega sama po sebi popravlja bubrežnu funkciju, ali ne dovodi do potpunog oporavka. Cilj ovog rada bio je da se odrede parametri oksidativnog i nitrozativnog stresa kao i parametri antioksidativne zastite u populaciji pacijenata sa presacfenim bubregom sa stabilnom funkcijom grafta i bez kliničkih znakova kardiovasku- larne bolesti. Takođe, naš cilj je bio da se utvrdi povezanost među ispitivanim parametrima i procene potencijalne razlike između svih ispitivanih biomarkera u odnosu na imunosupresivni protokol. Metode: U istraživanje jeuključeno 57 pacijenata sa presadenim bubregom i 31 kontrolni subjekt, koji su po go- dinama i polu odgovarali pacijentima sa presađenim bubregom. Svi pacijenti uključeni u istrazivanje imali su transplantaciju bubrega najmanje 12 meseci pre početka istraživanja i bili su na standardnoj imunosupresivnoj terapiji. U ovom radu određivali smo reaktivne supstance tiobar- bituratne kiseline (TBARS) u plazmi i eritrocitima, uznapre- dovale produkte oksidacije proteina (AOPP), parametre nitrozativnog stresa (asimetrični i simetrični dimetilarginin- ADAAA i SDMA) i antioksidativne zastite (ukupne SH grupe i aktivnost katalaze). Rezultati: Rezultati naše studije su pokazali znatno više vrednosti parametara oksidativnog i nitrozativnog stresa kod pacijenata sa presađenim bubregom u odnosu na zdrave dobrovoljce (p<0,01 osim za aktivnost katalaze u plazmi, kada je p<0,05). Korelaciona analiza pokazala je znacajnu pozitivnu korelaciju između ADMA i SDMA (p<0,01); ADMA i nitrata (p<0,05); SDMA i nitrata (p<0,05); između parametara oksidativnog stresa u eksperimentalnoj grupi; AOPP i SH grupe (p<0,05), kao i TBARS u plazmi i SH grupe (p<0,01), SDMA i AOPP (p<0,05); SDMA i TBARS u plazmi (p<0,05); SDMA i SH grupe (p<0,01); nitrata i SH grupe (p<0,05). Zakljudak: Naši rezultati nisu ukazali na statistički značajnu razliku u ispitivanim parametrima među pacijentima na ciklosporinu A i takrolimusu

Quality of Life in Type 2 Diabetic Patients

Summary The presence of diabetes mellitus leads to a decrease in life quality in all domains. The aim of our study was to evaluate the quality of life (QOL) in diabetic patients and the factors affecting it in type 2 diabetic mellitus patients. We conducted a cross-sectional study that included 86 patients with type 2 diabetes mellitus, in the territory of the City of Niš. Health-related QOL of patients was measured using the short form survey (SF-36) that produces an 8-scale health profile. The average duration of diabetes was 12.76±8.08 years. The best QOL in all areas was observed in patients diagnosed with diabetes less than 10 years ago p<0.05) and younger than 65 years. Male respondents perceived a better QOL compared to women, especially in the vitality and pain domains. The patients with comorbidity (93.64%) had lower QOL score in all domains. There was no significant difference in the QOL of patients with diabetes compared to the level of education. High QOL represents an ultimate goal and an important outcome of all medical interventions in diabetic patients. Factors related to lower QOL included: older age, female gender, and existence of comorbidities. Uncontrolled diabetic patients had a lower QOL than controlled diabetics. Sažetak Prisustvo dijabetesa dovodi do pada kvaliteta života u svim domenima. Cilj našeg istraživanja bio je da procenimo kvalitet života bolesnika sa dijabetesom tip 2 i da utvrdimo faktore koji na to utiču. Sprovedena je studija preseka na teritoriji grada Niša kojom je obuhvaćeno 86 bolesnika sa dijabetes melitusom tip 2. Kvalitet života bolesnika procenjen je pomoću upitnika SF-36. Prosečna dužina trajanja dijabetesa iznosila je 12.76±8.08 godina. Najbolji kvalitet života u svim domenima uočen je kod bolesnika mlađih od 65 godina i kod onih kod kojih je dijabetes melitus dijagnostikovan pre manje od 10 godina (p<0.05). Muškarci su prijavili bolji kvalitet života od žena, posebno u oblasti vitalnosti i bolova. Bolesnici sa komorbiditetima (93.64%) su imali niži kvalitet života u svim domenima. Nije zabeležena značajna razlika u kvalitetu života ispitanika obolelih od dijabetesa u odnosu na stepen obrazovanja. Kvalitet života je važan zdravstveni ishod i predstavlja konačni cilj svih zdravstvenih intervencija. Faktori koji utiču na niži kvalitet života bili su ženski pol, starost i postojanje komorbiditeta.

Crosstalk of inflammatory mediators and lipid parameters as early markers of renal dysfunction in stable renal transplant recipients with regard to immunosuppression

BACKGROUND Kidney transplantation is still the treatment of choice for end-stage renal disease, therefore it is important to establish all modifiable risk factors for initiation of renal dysfunction. MATERIAL/METHODS We enrolled 73 renal transplant recipients, who were more than 12 months post-renal transplant surgery, had a stable graft function, had no clinically present cardiovascular disease, and were on standard immunosuppressive therapy. The concentrations of intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), CRP, lipids, and lipoproteins were measured. We used logistic regression to calculate non-adjusted, age, and multivariable-adjusted ORs and 95% confidence intervals for glomerular filtration rate, GFR <60 ml/min/1.73 m(2). RESULTS Non-adjusted OR showed that there was a significant risk of reduced GFR in patients with total cholesterol higher than 5.19 mmol/L, LDL cholesterol ≥ 4.1 mmol/L, non- HDL ≥ 4.2 mmol/L, and higher VCAM-1 concentration. After adjustment for age and in multivariable model, OR showed a significant risk for reduced GFR in patients with total cholesterol ≥ 5.2 mmol/L, LDL ≥ 4.1 mmol/L, non-HDL ≥ 4.2 mmol/L, and higher VCAM-1 concentration. HDL, triglycerides, CRP, and lipoprotein ratios did not have any significance as predictors of renal dysfunction. There were no differences in all evaluated parameters between groups in regard to immunosuppressive therapy. CONCLUSIONS Total cholesterol, LDL, non-HDL, and VCAM-1 are strong and independent predictors of renal dysfunction in stable renal transplant recipients. In contrast, HDL, CRP, triglycerides, and ICAM-1 did not seem to have any impact on renal dysfunction.