Gender differences in oxidative and nitrosative stress parameters in kidney transplant patients on tacrolimus-based immunosuppression.

BACKGROUND: 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. METHODS: 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. RESULTS: TBARS, CAT and SH in plasma were significantly higher in male patients than in female patients (p < 0.05, p < 0.01 and p < 0.05, respectively). There were no gender-dependent differences in AOPP, ADMA, SDMA and NOx in kidney transplant patients. Correlation analysis, Pearson and Spearman, showed significant correlations between tested oxidative and nitrosative stress parameters in male kidney transplant patients. Alternatively, in female patients, there were no significant correlations between tested parameters. CONCLUSION: Our findings show that men might be more prone to oxidative damage than women. ADMA, the proven marker of CV morbidity and mortality, may be more significant in male kidney transplant patients concerning oxidative stress control of its level and function.

Effect of periodontal treatment in renal transplant recipients.

OBJECTIVE: To evaluate the effect of periodontal treatment on gingival overgrowth in a group of renal transplant patients. SUBJECTS AND METHODS: Twenty-five renal transplant recipients receiving immunosuppressive therapy with cyclosporine A (CsA) were randomly assigned to 2 groups. Group 1 (n = 15) included patients who had been specifically referred to a dental clinic to prevent gingival overgrowth and were given full periodontal therapy. Group 2 (n = 10) was comprised of patients who did not receive any professional periodontal cleaning. Patients from both groups were examined to determine their periodontal status before and after 3, 6 and 12 months in terms of their plaque index, gingival index and gingival overgrowth. During the examination, their overall health was stable. RESULTS: For group 1, the scores were 1.89 (baseline), 0.98 (6 months) and 0.56 (12 months), and hence there were significant reductions (p = 0.0001). The gingival indices were 1.71 (baseline), 0.76 (6 months) and 0.35 (12 months), and the reductions were also significant (p = 0.0001). A significant association was observed between poor oral hygiene and the degree of gingival overgrowth. The 1-year post-treatment follow-up showed that patients in group 1 did not develop gingival overgrowth due to the use of CsA as group 2 did without prior periodontal therapy. CONCLUSION: Oral hygiene status was the most important variable related to the development and degree of gingival overgrowth due to the use of CsA.

Influence of dialysis modality and membrane flux on insomnia severity in haemodialysis patients.

AIM: Insomnia is an important problem in dialysis patients. A greater prevalence of insomnia in chronic kidney disease compared with non-renal patients suggests a role for uraemic toxins in contributing to insomnia. The aim of this study was to examine if dialysis modality and membrane permeability is associated with the frequency and severity of insomnia in haemodialysis patients. METHODS: In our cross-sectional study, we evaluated 122 patients who were divided into three groups: on-line haemodiafiltration, high flux haemodialysis and low flux haemodialysis. The frequency and severity of insomnia was evaluated with the Insomnia Severity Index. RESULTS: Insomnia was present in 47.5% of all patients. The majority of patients who reported insomnia were receiving low flux haemodialysis (80%), followed by patients on high flux haemodialysis (43.6%) and haemodiafiltration (20.9%). Patients using low flux membranes, had a significantly higher Insomnia Severity Index (11.9 ± 6.6) compared with patients receiving high flux haemodialysis (6.8 ± 6.3) and haemodiafiltration (5.2 ± 7.0). The insomnia severity index did not differ between patients receiving high flux haemodialysis compared with on-line haemodiafiltration. CONCLUSION: This study indicates that different haemodialysis modalities are associated with insomnia and suggests a potential benefit of using high flux membranes.

Hepcidin and iron metabolism disorders in patients with chronic kidney disease.

BACKGROUND/AIM: [corrected] Hepcidin may play a pathogenetic role in iron metobolism disorders. The aim of this study was to determine the correlation between hepcidin concentration and parameters of iron metabolism in patients with different stage of chronic kidney disease (CKD). METHODS: The study involved 104 patients with CKD: 64 on hemodialysis (HD) and 40 patients in pre-dialysis stadium (pre-HD) with adequate erythropoetin therapy and iron supplementation. The HD group was divided in four subgroups according to the level of serum ferritin (up to 100; 100-199; 200-499 and over 500 ng/mL). Parameters of anemia, iron status, in flamation and hepcidin level were evaluated. RESULTS: The HD patients had a significantly lower eritrocyte count, erythrocytes indexes, hemoglobin and transferrin saturation and significantly higher iron, ferritin, hepcidin and total iron binding capacity (TIBC). The HD subgroups up to 199 ng/mL of serum feritin had lower high-sensitivity C-reactive protein (hsCRP), iron and higher unbuffered iron binding capacity (UIBC), transferrin saturation and TIBC compared to the HD subgroups over 200 ng/mL. The lowest and the highest ferritin subgroups had the highest hepcidin level and it showed significant correlation with ferritin. CONCLUSION: Hepcidin may serve as a marker for better diagnosing and monitoring anemia and iron metabolism disorders in CKD.

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, MDA(rbc)), 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 MDA(rbc) 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.

Indirect serum fibrosis markers in hepatitis C virus (HCV) infection.

UNLABELLED: 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. PATIENTS AND METHODS: 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. RESULTS: 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 (APRI < 0.5 and FIB-4 < 1.45) 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. CONCLUSION: 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.

Influence of dialysis modality and membrane flux on quality of life in hemodialysis patients.

BACKGROUND: The quality of life in patients undergoing hemodialysis is significantly disturbed. There are data that hemodiafiltration (HDF) may be more effective than conventional hemodialysis in the removal of uremic toxins and may reduce frequency and severity of intradialytic and postdialysis adverse symptoms in patients. Also, some researchers suggest advantages of using high-flux membranes compared with low-flux. OBJECTIVE: The aim of this study was to examine whether hemodialysis modality and membrane flux, independent of membrane biocompatibility, make differences in quality of life in patients. METHODS: In our cross-sectional study, we evaluated 124 patients who were divided, based on therapy, into three groups: online HDF, high-flux hemodialysis, and low-flux hemodialysis. Data were collected using the Short Form-36 questionnaire combined with special questionnaire, which included demographic and clinically related questions. RESULTS: Health-related quality of life was better in patients on HDF compared with patients on hemodialysis, especially compared with low-flux hemodialysis patients in most of the scales and in both dimensions: physical component scale and mental component scale. There were no statistically significant differences in Short Form-36 domains between high-flux hemodialysis and low-flux hemodialysis. CONCLUSION: Our data suggest the potential advantages of HDF with regard to influence on quality of life, which is sufficient to justify further research in prospective and longitudinal study design.

Gender differences in pharmacokinetics of tacrolimus and their clinical significance in kidney transplant recipients.

BACKGROUND: The possible influence of gender on tacrolimus disposition and response in kidney transplant recipients is an issue of medical importance. OBJECTIVE: The aim of this study was to detect interpatient pharmacokinetic variability of tacrolimus due to patients' gender and to assess the predictability of individual tacrolimus concentrations using abbreviated AUC measurements. The secondary objective was to find the best sampling time to predict the exposure of tacrolimus in kidney transplant recipients. METHODS: Gender-related first oral dose tacrolimus pharmacokinetics studies were conducted in 20 Serbian kidney transplant recipients (10 men/10 women) on quaternary immunosuppressive therapy. The first tacrolimus oral dose (0.05 mg/kg) was given on day 5 post-transplant. Blood concentrations were measured by microparticle enzyme immunoassay method. Associations between each sampling time point of concentrations and 12 hours after the administration AUC (AUC(0-12)) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple stepwise regression analyses. RESULTS: AUC(0-12) showed remarkable interindividual variations after the first tacrolimus oral dose. There were significantly lower values of AUC in women than men (P < 0.05). The most important time point influencing AUC(0-12) was the concentration of tacrolimus measured 2 hours after administration(C(2)) in women, whereas in men the most important time points were the concentrations at 1 (C(1)), 4 (C(4)), and 12 (C(12)) hours as an abbreviated AUC. CONCLUSION: Our results show significant differences between men and women. C(2) seems to be indicator of total body exposure to tacrolimus in the early period after kidney transplant in women. The three-point sampling method seems to be a good indicator of abbreviated AUC for a tacrolimus monitoring strategy in men.

Clinical pharmacokinetics of tacrolimus after the first oral administration in renal transplant recipients on triple immunosuppressive therapy.

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.

Prevalence and risk factors of myocardial remodeling in hemodialysis patients.

BACKGROUND: Left ventricular hypertrophy (LVH) is an independent risk factor for morbidity/mortality in patients with end stage renal disease (ESRD). Our study aimed to identify prevalence as well as independent risk factors that contribute to the development of LV geometric remodeling in our HD patients. METHODS: The left ventricles of 116 HD patients were classified echocardiographically into four different geometric patterns on the basis of LV mass and relative wall thickness. Furthermore, we measured inferior vena cava (IVC) diameter and its collapsibility index (CI) by echocardiography. Finally, we modeled a stepwise multiple regression analysis to determine the predictors of LV geometry. RESULTS: Our study provides evidence that HD patients had a prevalence of abnormal LV geometry in 92% and LVH in 81%. We found all four geometric models of LV. Most dominant were eccentric LVH. Concentric LVH was observed in 37, normal geometry (NG) in 9, and concentric remodeling (CR) in 13 of HD patients. Mean arterial blood pressure was significantly higher in the cLVH group (95 +/- 10 mmHg) than in the NG and CR groups (81.6 +/- 12.3 and 80 +/- 11.8, respectively, p < 0.001). The cLVH and eCLVH groups had significantly lower mean hemoglobin (10.3 +/- 1.4 g/dL and 10.6 +/- 1g/dL, respectively) compared with the NG group (11.9 +/- 1.4 g/dL), p < 0.001. Furthermore, interdialytic weight gain (kg) was significantly higher in eCLVH group (3.13 +/- 0.8) than in NG group (2.3 +/- 1.1), p < 0.001. Mean IVC index of the eLVH group (10.83 +/- 2.07 mm/m(2)) was significantly higher than corresponding indexes of NG (10.83 +/- 2.07 mm/m(2)), CR (8.31 +/- 1.32 mm/m(2)) and cLVH (8.12 +/- 2.06 mm/m(2)) groups (p < 0.001 for each comparisons). CONCLUSION: Mean arterial pressure, hemoglobin, IVC index, and interdialytic weight gain were found to be independent predictors of LV geometry (R(2) = 0.147; p < 0.001) in HD patients.