Dimitrios Grekas

Increase in Oxidative Stress but Not in Antioxidant Capacity with Advancing Stages of Chronic Kidney Disease

Background/Aims: Increased oxidative stress in chronic kidney disease (CKD) was suggested to be both a cause and an effect of renal injury. However, the evolution of oxidant stress from early stages of renal function decline is not fully clear. This study aimed to determine the oxidant-antioxidant balance across the whole range of renal function. Methods: A total of 116 patients with CKD (85 predialysis patients divided into groups according to CKD stage, and 31 patients with end-stage renal disease (ESRD) on hemodialysis treatment), as well as 29 healthy subjects were evaluated. Plasma levels of 15-F2t-isoprostane (15-F2t-IsoP), a valid marker of oxidant stress, as well as total antioxidant capacity (TAC) and serum levels of vitamin E were measured in all participants. Results: Plasma 15-F2t-IsoP levels were higher in predialysis and ESRD patients compared to healthy subjects and were progressively increasing with advancing CKD stages (p < 0.001). In contrast, plasma TAC was similar between healthy subjects and predialysis patients, and presented a small reduction in ESRD patients (p < 0.001). Vitamin E levels were higher in healthy subjects compared to any other group (p < 0.001) and slightly higher in ESRD patients compared to predialysis patients (p < 0.01), but did not differ significantly between the groups of predialysis patients. Plasma 15-F2t-IsoP levels were inversely correlated with estimated glomerular filtration rate in predialysis patients (r = –0.65, p < 0.001). Conclusions: This study shows that 15-F2t-IsoP levels increase progressively with advancing CKD stages, whereas TAC and vitamin E levels remain rather stable with the loss of renal function and change only in patients with ESRD.

Effects of Exercise Training on Noninvasive Cardiac Measures in Patients Undergoing Long-term Hemodialysis: A Randomized Controlled Trial

BACKGROUND Noninvasive screening studies may identify hemodialysis (HD) patients at increased risk of sudden cardiac death. Interventions that improve the findings of such screening studies may reduce sudden cardiac death. STUDY DESIGN Randomized and controlled clinical trial. SETTING & PARTICIPANTS 59 HD patients were randomly assigned to an exercise training group (group A; 30 patients) or control group (group B; 29 patients). INTERVENTION Group A participated in a 10-month supervised exercise training program during the HD sessions (3 times weekly). OUTCOMES Each risk factor separately and the composite risk score. Patients were considered high risk according to the criteria (aerobic capacity: peak oxygen consumption [Vo(2)peak] < or = 14 mL/kg/min, left ventricular ejection fraction < or = 30%, SD of normal RR intervals [SDNN] < or = 70 milliseconds, positive T-wave alternans, or positive late potentials). Statistical analysis included a 2-group comparison of change scores and analysis of covariance adjusting for baseline. MEASUREMENTS At entry and end of the study, Vo(2)peak and left ventricular ejection fraction were estimated, heart rate variability was calculated (measurement of SDNN, mean RR intervals), and the ratio between low- (LF) to high-frequency (HF) components (LF/HF) and late potentials and T-wave alternans were detected. RESULTS Baseline measurements were similar between the 2 groups. At follow-up, 9 patients from group A and 20 from group B (P = 0.003) were considered high risk. The change in number of risk markers over time was significantly different between groups (-0.5 +/- 0.7 in group A versus 0.07 +/- 0.3 in group B; P < 0.001). Additionally, the change in Vo(2)peak over time was 3.5 +/- 3.2 in group A and -0.2 +/- 3.5 mL/kg/min in group B (P < 0.001), left ventricular ejection fractions were 3.4% +/- 3.9% and 0.2% +/- 7.7% (P < 0.05), SDNNs were 12.6 +/- 16.3 and -1.1 +/- 10.2 milliseconds (P < 0.001), and LF/HF ratios were 0.3 +/- 0.4 and -0.1 +/- 0.3 (P < 0.001), respectively. Change in numerical score of the signal-averaged electrocardiogram also was found to be statistically different (P < 0.05) between groups. LIMITATIONS Clinical outcomes, including survival, were not assessed. CONCLUSIONS Exercise training improves aerobic capacity and ameliorates some indicators of risk of sudden cardiac death in HD patients.

Depression, heart rate variability, and exercise training in dialysis patients:

Background Functional limitations, altered cardiac autonomic activity, and psychological distress are known disorders in chronic hemodialysis (HD) patients, relating to increased morbidity and mortality. The aim of this study was to examine the influence of an exercise training program on emotional parameters and heart rate variability (HRV) indices, as well as to determine whether emotional stress contributes to autonomic dysfunction in these patients. Methods Forty-four HD patients were randomly assigned into group A (24 patients, aged 46.3 ± 11.2 years), who participated in a 1-year intradialytic exercise training program and group B (20 patients, aged 45.8 ± 10.8 years), who were used as controls. At baseline and a year after, measures of HRV were obtained for the estimation of standard deviation of RR intervals, the mean square successive differences, percentage of RR intervals differing by more than 50 ms from the preceding RR interval (pNN50), and low to high frequency components. Emotional parameters (Beck Depression Inventory – BDI and Hospital Anxiety and Depression Scale – HADS) were also assessed by validated questionnaires. Moreover, all patients performed a spiroergometric study for the estimation of VO2peak. Results At baseline, all measurements were similar in the two groups and remained almost unchanged after a year in group B. After a year of training, VO2peak increased from 16.79 ± 5.24 to 22.33 ± 4.90 ml/kg per min (P >0.001) in group A. Trained patients also showed an increase in standard deviation of RR intervals by 58.8% (P >0.001), the mean square successive differences by 68.1% (P >0.001), pNN50 by 23.5% (P >0.001), and a low to high frequency ratio by 17.3% (P >0.001). Finally, at the end of the study, group A showed a decrease in BDI score by 34.5% (P >0.001) and HADS by 23.9% (P >0.001). Canonical correlation revealed significant inverse correlation among depression (in BDI and HADS) and HRV indices before and after exercise training. Conclusion Cardiac autonomic modulation seemed to be sensitive to the experience of persistent depression in HD patients. Significantly, exercise training reduced emotional distress and concomitantly improved HRV.

Role of asymmetrical dimethylarginine in the progression of renal disease

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.

Lipid Peroxidation After Acute Renal Ischemia and Reperfusion in Rats: The Effect of Trimetazidine

Lipid peroxidation is a critical pathway of reactive oxygen species inducing tissue injury in postischemic acute renal failure. In order to evaluate the effect of renal ischemia reperfusion on kidneys, renal tissue malondialdehyde (MDA, nmol/g wet weight) concentration was measured in 29 male Wistar rats subjected to a midline abdominal incision and 60 min occlusion of the left renal artery. A right nephrectomy was performed at the beginning of the ischemic period. The animals were separated in four groups. Groups 1 (n = 7) and 3 (n = 7) underwent 60 min of ischemia and 15 min of reperfusion, respectively. Groups 2 (n = 8) and 4 (n = 7) were subjected to the same procedure but, in addition, they received 2.5 mg/kg TMZ into the tail vein 2 h prior to the left renal artery occlusion. A significant elevation of MDA after 60 min of ischemia (1.43 vs. 2.1, p < 0.001), which was augmented after 15 min of reperfusion (1.4 vs. 3.72, p < 0.001) was observed. Furthermore, there was a significant reduction of renal tissue MDA in ischemic rats treated with TMZ (group 3) (2.1 vs. 1.52, p < 0.001). The maximum reduction of renal tissue MDA was observed in ischemic-reperfused rats (group 4) that had received TMZ (3.72 vs. 1.36, p < 0.001). It is suggested that lipid peroxidation is a critical event in postischemic acute renal failure, and TMZ is a useful protective agent of renal damage from oxygen free radicals.

Effects of exercise training during hemodialysis on cardiac baroreflex sensitivity.

BACKGROUND Arterial baroreflex sensitivity (BRS) evaluation has been increasingly used as an index of cardiac autonomic control. Cardiac autonomic dysfunction leading to depressed BRS has been associated with an increased risk of ventricular arrhythmias and sudden death in patients with chronic kidney disease (CKD) on hemodialysis (HD). AIM The purpose of this study was to investigate the effects of an exercise training program during hemodialysis on BRS in CKD patients. PATIENTS AND METHODS 43 HD patients participated in the study. They were randomly assigned into either a 7-month exercise training program during HD (Group A: n=22 patients) or a sedentary control group (Group B: n=21 patients). Additionally, 20 sex- and age-matched sedentary individuals comprised a healthy control group (Group C). All patients at the beginning and the end of the study underwent a tilt test for evaluation of BRS and an exercise testing with spiroergometric study for cardiorespiratory capacity estimation. The level of Hb, medications and the HD procedure remained stable during the study. RESULTS At baseline BRS was found to be reduced by 51.5% (p<0.05) and baroreflex effectiveness index (BEI) by 36.4% (p<0.05) in Group A compared with Group C. Initially, all HD patients had also significantly lower exercise time and VO2 peak than the healthy subjects. After training, Group A showed a significant improvement in BRS by 23.0% (p<0.05), in BEI by 27.0% (p<0.05), in event and ramp count by 35.0% (p<0.05) and 29.0% (p<0.05), respectively as well as in VO2 peak by 22.4% (p<0.05) and in exercise time by 40.9% (p<0.05). Significant correlations were found between BRS and METs (r=0.476, p<0.05), BRS and VO2 peak (r=0.443, p<0.05), BEI and METs (r = 0.492, p<0.05), BEI and VO2 peak (r=0.467, p<0.05), event count and VO2 peak (r=0.715, p<0.01), event count and exercise time (r=0.799, p<0.01), in Group A at the end of the study. CONCLUSIONS Our results indicate that HD patients had considerably reduced cardiorespiratory capacity and impaired cardiac BRS compared to healthy sedentary individuals. Importantly, exercise training during HD yielded a marked increase of the indices representing baroreflex activity in association to the improvement of their functional capacity.

Elevated asymmetric dimethylarginine is associated with oxidant stress aggravation in patients with early stage autosomal dominant polycystic kidney disease.

Background/Aims: In experimental models of polycystic kidney disease impaired bioavailability of nitric oxide (NO) and elevated mRNA expression of oxidative stress markers at the kidney level was noted. However, clinical studies investigating the potential role of endothelial dysfunction and oxidative stress in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) are limited. We evaluated asymmetric dimethylarginine (ADMA) as marker of NO synthase inhibitor as well as 15-F2t-Isoprostane and oxidized-low density lipoprotein (oxidized-LDL) as measures of oxidative stress in patients with early stages ADPKD. Methods: We recruited 26 ADPKD patients (Group A) with modestly impaired renal function (eGFR 45-70 ml/min/1.73m2), 26 age- and sex-matched ADPKD patients (Group B) with relatively preserved renal function (eGFR)>70 ml/min/1.73m2), and 26 age- and sex-matched controls (Group C). Determination of circulating levels of ADMA, 15-F2t-Isoprostane, oxidized-LDL and routine biochemistry was performed. Results: Group A and B had significantly higher ADMA levels as compared to controls (1.68±0.7 vs 0.51±0.2 μmol/l, P<0.001 and 1.26±0.7 vs 0.51±0.2 μmol/l, P<0.001, respectively). 15-F2t-IsoP and oxidized-LDL levels were also significantly higher in Group B relative to controls (788.8±185.0 vs 383.1±86.0 pgr/ml, P<0.001 and 11.4±6.6 vs 6.4±2.6 EU/ml, P<0.05 respectively) and were further elevated in Group A. In correlation analysis, ADMA levels exhibited strong associations with levels of 15-F2t-Isoprostane (r=0.811, P<0.001) and oxidized-LDL (r=0.788, P<0.001), whereas an inverse correlation was evident between ADMA and eGFR (r=-0.460, P<0.001). Conclusion: This study shows elevation in circulating levels of ADMA along with aggravation of oxidative stress from the early stages of ADPKD.

Influenza Vaccination in Chronic Hemodialysis Patients. The Effect of Zinc Supplementation

Since influenza increases the mortality of chronically ill patients we decided to study the effectiveness of influenza vaccination in hemodialysis (HD) patients. Nineteen HD patients aged from 20 to 60 years, on unrestricted diet and with no febrile episode, were studied. Blood samples were collected before the intramuscular injection of 0.5 mL multivalent influenza vaccine (Inflexal Berna) and every 2 weeks thereafter. At the end of 4th week a second vaccination was done and a dosage of 200 mg of zinc acetate (60 mg elemental zinc) was given daily to each patient for at least 4 weeks. Before vaccination the antibody titers to influenza virus ranged from 1:10 to 1:80 and after vaccination from 1:20 to 1:640. Four weeks after vaccination 6/19 (31.5%), 8/19 (42%), and 10/19 (52.5%) patients showed a fourfold or greater increase at serum antibody titers to antigens A/Singapore, A/Sichuan, and B/Beijing, respectively. The zinc supplementation after the second vaccination induced a similar increase of serum antibody titers to the A/Singapore but some even greater increase of the antibody titers to the A/Sichuan and B/Beijing. Serum immunoglobulins and complement components C3/C4 were not changed during this study. It is suggested that about 50% of uremic patients respond to the influenza vaccination and that zinc treatment does not increase this responsiveness.

Association between Hyperhomocysteinemia and Ultrasonographic Atherosclerotic Indices of Carotid Arteries in Chronic Hemodialysis Patients

Background: Atherosclerotic cardiovascular events are a major cause of morbidity and the main cause of mortality in hemodialysis patients. Hyperhomocysteinemia – which is a consistent finding in uremic patients – is considered an independent risk factor for cardiovascular disease (CVD). However, the relationship between plasma homocysteine (Hcy) concentrations and atherosclerotic CVD has not been extensively investigated. Patients and Methods: 37 patients undergoing chronic hemodialysis and 30 healthy individuals (control group), sex- and age-matched, were included in this study. Both healthy controls and hemodialysis patients underwent echo-Doppler carotid artery examination. The right and left carotid arteries were assessed separately. Our observation included measurements of the ultrasound images of the intimal wall thickness, the lumen diameter and the atherosclerotic plaques. We determined plasma Hcy, vitamin B12 and folic acid levels and serum cholesterol, triglycerides, HDL, ApoA-I, ApoB-100, Lp(a), CRP, albumin and creatinine levels in blood samples from both studied groups. We also determined the urea reduction ratio in the patient groups. The epidemiological as well as the biochemical data were correlated with the findings of the carotid artery examination. Results: Plasma Hcy levels were significantly increased in hemodialysis patients compared to controls (33 ± 12.3 vs. 12.27 ± 7.47 µmol/l, p < 0.001). Intimal wall thickness, lumen diameter and number of atherosclerotic plaques of both carotid arteries were significantly higher (p < 0.01 or p < 0.001) in patients compared to controls. There was a significant positive correlation between plasma Hcy levels and the number of the atherosclerotic plaques (r = 0.41, p < 0.01 in the right and r = 0.49, p < 0.001 in the left carotid artery). Lumen diameter was significantly (p < 0.01) associated with age, MAP and CRP levels. Significant correlations (p = 0.05–0.01) were also found between the number of the plaques and age as well as the duration of hemodialysis, while folic acid levels were inversely correlated with the number of the plaques. Conclusions: Both hyperhomocysteinemia and atherosclerotic indices of the carotid arteries are more prevalent in hemodialysis patients compared to healthy controls. Elevated plasma Hcy levels were associated with the carotid artery atherosclerotic indices in chronic hemodialysis patients.

Adaptation and Validation of the Kidney Disease Quality of Life-Short Form Questionnaire in the Greek Language

Aim: The aim of this study was to examine the validity, reproducibility and internal consistency of a Greek translation of the Kidney Disease Quality of Life-Short Form (KDQOL-SF) questionnaire. Methods: The KDQOL-SF questionnaire was translated from English to Greek and was administered in 240 randomly selected patients undergoing hemodialysis in six Renal Units in Greece. The instrument’s validity was tested by examining the association between patient’s KDQOL-SF scores and comorbidity assessed with the Index of Coexistent Disease. Reproducibility was examined by readministering the questionnaire in 50 randomly selected patients within 1 month. Internal consistency was assessed by estimating Cronbach’s alpha coefficient. Results: Patients were divided into two groups according to the severity of comorbidity assessed with the Index of Coexistent Disease. Those with less comorbid conditions had significantly higher scores in most components of the KDQOL-SF questionnaire, confirming its validity. The correlation coefficients between the two administrations of the instrument ranged from 0.88 to 0.98 for each of the main components, which was above the desired level of 0.85. Cronbach’s alpha coefficient ranged from 0.91 to 0.92 for the various components, values well above the minimum desired 0.70 level. Conclusions: The present study shows that the Greek version of the KDQOL-SF questionnaire has high validity, reproducibility and internal consistency. Production of validated translations of the KDQOL-SF questionnaire in various languages will help promote health-related quality of life of end-stage renal disease patients all over the world.