Athanasios Sioulis

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.

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.

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.

Hemodiafiltration does not have additional benefits over hemodialysis on arterial stiffness, wave reflections and central aortic pressures.

Background/Aims: The hypothesis that dialytic modality affects arterial stiffness was never investigated. This study includes comparative evaluation of hemodiafiltration versus hemodialysis on arterial function during first and second weekly dialysis sessions. Methods: 24 patients receiving hemodiafiltration and another 24 age- and sex-matched controls receiving hemodialysis were included. Patients were evaluated before and after first and second weekly dialysis sessions. Applanation tonometry of peripheral arteries was applied to determine aortic and brachial pulse wave velocity and heart rate-adjusted augmentation index (AIx(75)). Results: Hemodiafiltration and hemodialysis reduced AIx(75), but not aortic and brachial pulse wave velocity. Intradialytic reductions in AIx(75) did not differ between hemodiafiltration and hemodialysis in first and mid-week dialysis. In multivariate linear regression, predictors of intradialytic reduction in AIx(75) were changes in body weight and central aortic systolic blood pressure, but not dialytic modality. Conclusion: This study showed that hemodiafiltration has similar effects with hemodialysis on wave reflections and stiffness.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function

Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m2), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Serum Fas Ligand, Serum Myostatin and Urine TGF-β1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function

Background/Aims: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-β1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function. Methods: Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-β1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques. Results: Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-β1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-β1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-β1 (OR 3.774, 95%CI 1.180-12.072, p=0.025). Conclusions: ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-β1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.