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Introduction: CCL23 is a new CC chemokine involved in leukocyte trafficking and inflammatory diseases. Inflammation, oxidative stress, and diabetes are common in patients with chronic kidney disease (CKD), particularly in those with cardiovascular disease (CVD)., Objectives: The aim of this study was to evaluate CCL23 concentrations in patients with CKD and to identify the factors affecting its plasma level., Patients and Methods: CCL23 levels, inflammatory markers (high-sensitivity C-reactive protein, interleukin 6, and tumor necrosis factor α) and oxidative stress markers (neopterin and Cu/Zn superoxide dismutase [Cu/Zn SOD]) were measured in the plasma of patients with mild-to-moderate CKD (group A) and severe CKD (group B) both with and without diabetes and in controls., Results: CCL23 concentrations were higher in group B, particularly in patients with diabetes compared with controls (P <0.001) and group A (P <0.01). The inflammatory markers were increased in CKD patients but they were not correlated with CCL23 levels. In contrast, there were associations between CCL23 and oxidative stress markers and kidney function. The presence of diabetes, Cu/Zn SOD, and percentage of lymphocytes were found to be independent factors affecting CCL23 concentrations in the whole CKD group. In patients without diabetes, only Cu/Zn SOD was independently associated with CCL23., Conclusions: CCL23 levels were increased in patients with severe CKD and were strongly correlated with kidney function. The coexistence of diabetes and oxidative stress independently affected CCL23 levels, while the presence of CVD and inflammation had no impact on its concentrations.

Aims: Dyslipidemia and oxidative stress are commonly present in patients during maintenance dialysis treatment. However, the significance of oxidized LDL (oxLDL) as a marker of oxidative stress in uremia is still unresolved. The aim of this study was to establish the role of oxLDL and oxLDL/LDL ratio as markers of lipoprotein abnormalities and oxidative stress in the dialyzed patients., Main Methods: Plasma oxLDL level was measured by ELISA, and oxLDL/LDL ratio was calculated in 106 dialyzed patients and 20 controls. The linkages between oxLDL, oxLDL/LDL ratio and lipid profile and oxidative stress markers malondialdehyde (MDA) and Cu/Zn superoxide dismutase (Cu/Zn SOD) levels were also analyzed., Key Findings: OxLDL levels and oxLDL/LDL ratio were similar in hemodialyzed patients and controls, whereas these parameters were lower in peritoneally dialyzed patients when compared to healthy individuals. In contrast, both MDA and Cu/Zn SOD levels were significantly higher in uremics than in controls. oxLDL and oxLDL/LDL ratio positively correlated with lipid profile (except of HDL), whereas there were no positive associations between these parameters and both MDA and Cu/Zn SOD. Multiple regression analysis confirmed that increased oxLDL/HDL and TC/HDL ratios and total cholesterol levels are the parameters which independently predicted oxLDL in dialyzed patients. In the case of oxLDL/LDL ratio, the independent variables were oxLDL/HDL ratio, total cholesterol and HDL levels., Significance: oxLDL levels and oxLDL/LDL ratio seem to be the markers of lipoprotein abnormalities rather than the markers of oxidative stress in the population of dialyzed patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: We evaluated the impact of residual renal function (RRF) on oxidative stress (SOX) and CD40/CD40L system in haemodialysis (HD) patients., Design and Methods: We determined sCD40, sCD40L and SOX marker-Cu/Zn superoxide dismutase (Cu/Zn SOD) levels in HD patients with RRF, with anuria (A) and in healthy controls., Results: sCD40 and Cu/Zn SOD plasma levels were higher in both groups of dialyzed patients compared to controls (all p<0.001), and they were higher in A than in RRF patients (all p<0.01). In RRF group, sCD40/sCD40L and Cu/Zn SOD were significantly higher in anti-HCV-seropositive (anti-HCV[+]) patients than in their anti-HCV[-] counterparts. This phenomenon was not observed in A group. Multiple regression analysis showed that Cu/Zn SOD, kt/V and low fibrinogen were the independent factors affecting sCD40 levels in the whole HD group., Conclusions: The loss of RRF and HCV seropositivity increased plasma levels of sCD40/sCD40L and oxidative status in HD patients., (Copyright © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Cellular adhesion molecules and oxidative stress play a role in the pathogenesis of atherosclerosis in patients with chronic kidney disease (CKD). Recently, it has been postulated that the kynurenine (KYN) pathway could be involved in the pathogenesis of atherosclerosis., Methods: We evaluated the KYN, kynurenic acid (KYNA), anthranilic acid (AA), and their relations with cellular adhesion molecules: soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), sE-selectin, sP-selectin, and Cu/Zn superoxide dismutase (Cu/Zn SOD) levels as the markers of oxidative stress in the population of 132 patients with CKD and 28 healthy controls., Results: Compared with the controls, 2 groups of dialyzed patients had significantly increased KYN (both P < 0.01), KYNA, AA, sICAM-1, sVCAM-1, and Cu/Zn SOD levels (all P < 0.001, respectively). KYN, AA, sICAM-1, and sVCAM-1 concentrations were significantly higher in undialyzed patients with CKD compared with healthy subjects (P < 0.001, P < 0.01, and both P < 0.05, respectively). sICAM-1 and sVCAM-1 were positively associated with KYN (P < 0.0001 and P < 0.01), KYNA (P < 0.05 and P < 0.0001), AA (P < 0.01 and P < 0.0001), and with Cu/Zn SOD (both P < 0.0001, respectively) in the whole CKD group. The positive relationship existed between sICAM-1, sVCAM-1 and age, high-sensitivity C-reactive protein, creatinine, and the duration of dialysis therapy. Multivariable analysis showed that KYN was a strong independent correlate of sICAM-1, whereas Cu/Zn SOD and platelets independently and significantly predicted sVCAM-1 in patients with CKD., Conclusions: This study demonstrated that KYN is independently and significantly associated with elevated sICAM-1, whereas oxidative status and platelets independently and significantly predicted increased sVCAM-1 levels in patients with CKD.

Introduction: Increased oxidative stress (SOX) is one of the most potent inductors of endothelial dysfunction in end-stage renal disease (ESRD) patients. Kynurenines are the metabolites of tryptophan (TRP) degradation in mammals. However, the role of kynurenines in the function of the endothelium is still not recognized., Materials and Methods: We determined the plasma concentrations of TRP, kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), quinolinic acid (QA); markers of SOX: Cu/Zn superoxide dismutase (Cu/Zn SOD), malondialdehyde (MDA); and endothelial dysfunction markers: thrombomodulin (TM) and von Willebrand factor (vWF) levels in 148 ESRD patients and healthy controls., Results: TM, vWF, KYN, 3-HKYN and QA levels were significantly elevated in ESRD patients compared to controls. TRP concentrations in uremics were significantly lower than in healthy people. Both dialyzed groups showed a significant increase Cu/Zn SOD and MDA levels compared to controls. TM and vWF were positively associated with kynurenine pathway metabolites: KYN, 3-HKYN, QA (all p<0.001), and with SOX markers: Cu/Zn SOD (both p<0.0001) and MDA levels (p<0.05, and p<0.0001; respectively) in the whole ESRD group. The positive relationship were between Cu/Zn SOD and KYN (p<0.010), 3-HKYN and QA levels (both p<0.0001), whereas MDA was correlated with 3-HKYN and QA concentrations (both p<0.05). Multiple stepwise regression analysis showed that KYN metabolites and oxidative status were the independent variables significantly associated with increased both TM and vWF levels in uremic patients., Conclusions: Our study demonstrated that kynurenine metabolites and increased oxidative status are independently and significantly associated with endothelial dysfunction in ESRD patients.

Increased oxidative stress (SOX), inflammation and accelerated atherosclerosis have been reported in end-stage renal disease (ESRD), but their associations with kynurenine pathway activation remain unknown. We determined the plasma concentrations of kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA); three distinct SOX markers: Cu/Zn superoxide dismutase (Cu/Zn SOD), total peroxide and malondialdehyde (MDA), high sensitivity C-reactive protein (hs CRP) as a indicator of inflammation, and intima-media thickness (IMT)--an early reflection of the systemic atherosclerosis in the population of 124 patients with ESRD. In uraemia, the concentrations of KYN, KYNA and QA were increased by 37-105%, by 84-428%, and by 394-1018% of the control values; respectively. These changes were accompanied by significant increase in kyna/kyn and qa/kyn ratios, reflecting increased activity of kynurenine pathway enzymes. KYN, QA and qa/kyn ratio were positively associated with inflammation, SOX markers, and IMT values in uraemics. Moreover, multiple stepwise regression analysis identified age, presence of diabetes mellitus, QA and qa/kyn ratio as the independent variables significantly associated with increased IMT in this population. In conclusion, the results of the present study suggest a relationship between kynurenine pathway activation and increased oxidative stress, inflammation and the progression of atherosclerosis in end-stage renal disease patients.

Increased oxidative stress (SOX), inflammation and prevalence of cardiovascular disease (CVD) have been reported in end-stage renal disease (ESRD), but their associations with kynurenine (KYN) pathway activation remain unknown. We determined the plasma concentrations of tryptophan (TRP), KYN, 3-hydroxykynurenine (3-HKYN); two distinct SOX markers: Cu/Zn superoxide dismutase (Cu/Zn SOD) and total peroxide; and high sensitivity C-reactive protein (hs CRP) as a indicator of inflammation in 146 ESRD patients and healthy controls. Analysis of TRP degradation through the KYN pathway demonstrated that in uremia the concentrations of this aminoacid were decreased by 40-60% in comparison with controls. In contrast, the plasma levels of KYN and 3-HKYN in ESRD patients were increased by 32-96% and 184-306%, respectively. These changes were accompanied by significant increase in the kyn/trp ratios by 140-240%, and 3-hkyn/kyn ratios by 40-154% in uremics compared to controls. ESRD patients showed a significant increase in Cu/Zn SOD, total peroxide and hs CRP levels between controls and all patients group. KYN and 3-HKYN were positively associated with inflammation and SOX markers in uremics. Logistic regression analysis showed that age, gender, presence of DM (all p<0.001), elevated hs CRP (p<0.01) and 3-HKYN levels (p<0.05) were independently associated with the presence of CVD in this population. These results suggest a relationship between KYN pathway activation and increased SOX, inflammation and CVD prevalence in ESRD patients.

Elevated VEGF levels has been reported in patients with chronic renal failure (CRF), but the reasons for its higher level in renal insufficiency remain unknown. We assessed VEGF, SOX markers: total peroxide, Cu/Zn superoxide dismutase (Cu/Zn SOD), the levels of autoantibodies against oxidized LDL (OxLDL-Ab), and inflammation markers: high sensitivity C-reactive protein (hs CRP), interleukine-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in 55 CRF patients and 18 controls. The patients with CRF showed a significant increase in plasma levels of VEGF, markers of inflammation, total peroxide and Cu/Zn SOD levels compared with controls. The strong positive associations were between VEGF and creatinine, urea, phosphate and CaxP product (all p<0.0001), Cu/Zn SOD (p<0.001) and hs CRP levels (p<0.01). VEGF showed a strong inverse relationship with eGFR (p<0.0001). In multiple regression analysis increased Cu/Zn SOD, phosphate and creatinine levels were found to be independent factors affecting VEGF. This study documented significant elevation in plasma values of VEGF in patients with CRF, which appears early during the progression of renal insufficiency. Increased oxidative stress, phosphate levels and impaired elimination by kidney were the main factors affecting the plasma levels of this growth factor in CRF patients.

Introduction: The aim of the present study was to establish whether the presence of chronic viral hepatitis (PVH) could be implicated in the elevation of oxidative stress (SOX) and haemostasis system in haemodialysis (HD) patients., Materials and Methods: In HD patients with and without PVH and in controls we compared the markers of: coagulation pathway- tissue factor (TF) and its inhibitor (TFPI), prothrombin fragment F (1+2) (F (1+2)); fibrinolysis: tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR), plasminogen activator inhibitor 1 (PAI-1), plasmin/antiplasmin complexes (PAP); and a marker of SOX-Cu/Zn superoxide dismutase (Cu/Zn SOD) levels., Results: Patients, particularly those with PVH, showed a significant increase in the markers of the coagulation, fibrinolysis and oxidative status as compared to controls. All parameters of coagulation/fibrinolysis system were directly associated with the PVH and Cu/Zn SOD levels, and there was a relationship between the PVH and Cu/Zn SOD levels. Multivariable analysis showed that PVH and increased SOX were identified as independent variables significantly associated with the disturbances of coagulation/fibrinolysis system in these patients., Conclusions: We concluded that PVH is a novel determinant of the increased oxidative stress as well as the disturbances of coagulation/fibrinolysis system in haemodialysis patients.

The abnormalities of tissue factor and its inhibitor system, increased oxidative stress and the presence of diabetes may be involved in the mechanism of thrombotic complication in peritoneal dialysis patients. We compared the plasma levels of tissue factor, its inhibitor and markers of oxidative stress (malondialdehyde and Cu/Zn superoxide dismutase) in 16 diabetic peritoneal dialysis patients, 40 nondiabetic peritoneal dialysis patients, and 20 healthy control individuals. We tried to establish whether there is an association between tissue factor, its inhibitor and oxidative stress in these patients. Compared with the control individuals, the patients both with and without diabetes showed a significant increase in plasma concentrations of Cu/Zn superoxide dismutase (P < 0.01 and P < 0.001, respectively), malondialdehyde (both P < 0.05), tissue factor (both P < 0.001) and tissue factor pathway inhibitor (P < 0.01 and P < 0.001, respectively). The differences in oxidative status and coagulation parameters between patients with and without diabetes were not statistically significant. In all peritoneal dialysis patients, both tissue factor and its inhibitor were positively related to Cu/Zn superoxide dismutase (r = 0.310, P < 0.05 and r = 0.460, P < 0.001, respectively) and malondialdehyde levels (r = 0.337, P < 0.05 and r = 0.361, P < 0.01, respectively). Our data suggest a relationship between increased oxidative stress and elevated tissue factor and its inhibitor levels in peritoneal dialysis patients, particularly those with diabetes.

Matrix metalloproteinases (MMPs)/their inhibitors (TIMPs) system and elevated oxidative stress (SOX) have been implicated as important factors in atherosclerosis and vascular remodeling. The aim of the present study was to investigate whether MMPs/TIMPs system is associated with SOX in hemodialyzed (HD) patients. We compared the serum levels of metalloproteinases and their inhibitors, markers of SOX, inflammation and atherosclerosis between HD patients (n=40) with and without cardiovascular disease (CVD) and controls (n=20). Cu/Zn superoxide dismutase (Cu/Zn SOD) were elevated (all p<0.001), whereas total lipid peroxide levels were similar in HD patients and controls. The autoantibodies against oxidized LDL (OxLDL-Ab) levels were increased only in patients with CVD (p<0.05). Intima media thickness (IMT) in both CVD and in patients without CVD significantly exceeded those in the control (p<0.001 and p<0.01, respectively). Serum pre-HD values of MMP-2, TIMP-1 and TIMP-2 were significantly increased in HD patients, especially in the CVD group (all p<0.001), and they were associated with those of Cu/Zn SOD, IMT and CVD prevalence. Multiple regression analysis showed that MMP-2, Cu/Zn SOD levels and age independently and significantly predicted elevated IMT in HD patients. Our results suggest the association between SOX and the MMPs/TIMPs system in HD patients, which could represent one of the mechanisms involved in the progression of atherosclerosis in this population.

Aims: We designed a study to evaluate whether erythropoietin (EPO), given to patients on continuousambulatory peritoneal dialysis (CAPD) both with and without diabetes mellitus (DM), influences tissue factor (TF), tissue factor pathway inhibitor (TFPI) and oxidative stress (SOX)., Methods: We assessed TF, TFPI and a marker of SOX, Cu/Zn superoxide dismutase (Cu/Zn SOD) in 16 diabetic CAPD patients (8 with EPO therapy), 39 non-diabetic CAPD patients (23 with EPO therapy) and 18 healthy controls., Results: Patients on CAPD showed a significant increase in plasma concentrations of TF, TFPI and Cu/Zn SOD as compared to controls. EPO therapy was related to a decrease in these parameters in diabetic patients, whereas in non-diabetic patients EPO did not affect their levels. In diabetics, TF was positively correlated with TFPI and Cu/Zn SOD levels. There was a positive relationship between TFPI and Cu/Zn SOD, whereas inverse relationships existed between TFPI and haemoglobin, haematocrit (Ht), EPO dose and triglycerides. Multivariate analysis showed that independent variables linked to TFPI levels in diabetic patients were Cu/Zn SOD, Ht and EPO dose., Conclusion: Our data suggest that correction of anaemia with EPO therapy is associated with a significant decrease in TF, TFPI and SOX in diabetic CAPD patients., (Copyright 2007 S. Karger AG, Basel.)

Introduction: Although the general improvement caused by recombinant human erythropoietin (rHuEPO) in the correction of uraemic anaemia cannot be questioned, some data suggest that the changes in the haemostasis, endothelial function and oxidative stress (SOX) are induced. The aim of the present study was to investigate the effect of one-year rHuEPO therapy on the coagulation activation, endothelial injury markers and SOX in haemodialysis (HD) patients., Materials and Methods: Assessment of coagulation activation pathway: tissue factor (TF), its inhibitor (TFPI) and prothrombin fragment 1+2 (F1+2); endothelial injury markers: von Willebrand factor antigen (vWF:Ag) and thrombomodulin (TM); and several parameters related to SOX: total peroxide, Cu/Zn superoxide dismutase (Cu/Zn SOD) and autoantibodies to oxidized LDL (OxLDL-Ab) levels were performed in stable HD patients, treated for 12 months with rHuEPO (n=18; mean dose 113.5+/-41 U/kg/week) or not (with Hg<10 g/dl, n=8 and with Hg>10 g/dl, n=12), none of them on iron therapy., Results: Patients with Hg<10 g/dl had a significantly lower erythrocytes count, Ht and Hg levels than those with Hg>10 g/dl and those on rHuEPO therapy. Long-term rHuEPO therapy does not affect coagulation pathway and SOX markers. Treatment with this hormone resulted in a tendency to decrease TM and vWF:Ag concentrations, however these changes did not reach a statistical significance., Conclusions: These results suggest that one-year rHuEPO therapy seems to exert no additional influence on coagulation activation, endothelial cell damage/activation markers and oxidative stress in patients undergoing regular HD in the absence of concomitant iron supplementation and irrespective from haemoglobin levels.

Objectives: The present study was undertaken to clarify the role of the impaired renal function and the dialysis therapy on plasma levels of proatherogenic cytokines and Cu/Zn superoxide dismutase (Cu/Zn SOD)--as a marker of oxidative stress (SOX) in uraemia., Design and Methods: We have measured the levels of Cu/Zn SOD, monocyte chemoattractant protein-1 (MCP-1) macrophage inflammatory proteins (MIP-1alpha, MIP-1beta) and vascular endothelial growth factor (VEGF) in the plasma of predialysis (CRF) (n=42), on maintenance hemodialysis (HD) (n=25) or peritoneal dialysis (PD) (n=45) patients and in the healthy volunteers (n=20)., Results: The increase in Cu/Zn SOD levels was in PD and HD patients compared to controls (215.56+/-125.18 and 356.28+/-122.57 versus 53.53+/-23.65 ng/ml, respectively). In plasma of the CRF, PD and HD subjects we have also observed the significant increase in the levels of MIP-1beta: [31.5 (2-149), 33.0 (1-203) and 76.0 (9-345), respectively]; MCP-1 (616.50+/-240.15, 943.64+/-348.99 and 968.50+/-355.85, respectively) and VEGF (387.93+/-184.63, 371.56+/-125.18 and 645.56+/-136.30, respectively) compared to healthy people. In the predialysis group, creatinine clearance correlated with Cu/Zn SOD and cytokine levels. Moreover, the cytokine levels were also associated with age. In dialysis patients, the correlations were between duration of dialysis treatment and both Cu/Zn SOD and cytokine levels. There was also a direct relationship between Cu/Zn SOD and both MIP-1beta and VEGF levels., Conclusions: This study has shown that impaired renal function, age and duration of dialysis treatment are associated with increased oxidative stress and proatherogenic cytokine levels in uremic patients.

Background: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in the atherosclerosis. Recombinant human erythropoietin (EPO) has become widely used to treat anemic hemodialyzed (HD) patients; however, an increased mortality has been reported for HD patients with cardiovascular disease when randomly assigned to normal hematocrit by EPO. Therefore, we conducted a study examining the effect of EPO on MMPs/TIMPs system, oxidative stress and inflammation in these patients., Methods: Assessment of MMP-2, MMP-9, TIMP-1 and TIMP-2 were performed in 20 stable HD patients and 15 healthy controls. Additionally, the effects of EPO on malondialdehyde (MDA)--a marker of SOX and C-reactive protein (CRP) levels--as a marker of inflammation were also investigated. Of the 20 patients, 10 were receiving EPO therapy [HD-EPO(+)] for 12 months or more and 10 were not receiving EPO therapy [HD-EPO(-)]. Both groups were not receiving iron supplementation., Results: All parameters, with the exception of MMP-9, were lower in the healthy subjects compared with the HD subjects, irrespective of EPO administration. There was no difference in MMPs/TIMPs system, MDA and C-reactive levels between HD-EPO(+) and HD-EPO(-) patients., Conclusion: Erythropoietin therapy did not influence MMPs/TIMPs system, inflammation, or SOX in a low-risk HD patient population, in the absence of concomitant iron supplementation and mean Hg levels within target., (2007 S. Karger AG, Basel)

Background: Vascular endothelial growth factor is involved in the process of atherogenesis. Increased oxidative stress has been reported in hemodialyzed patients, but its influence on vascular endothelial growth factor levels remains unknown., Material/methods: The levels of two oxidative stress markers, Cu/Zn superoxide dismutase and autoantibodies against oxidized LDL, and the level of vascular endothelial growth factor were measured in pre-dialysis samples of hemodialyzed patients with and without cardiovascular disease and in healthy controls., Results: Vascular endothelial growth factor levels were significantly increased in both hemodialysis groups compared with controls (all p < 0.001), more so in patients with than those without cardiovascular disease (p < 0.05). Cu/Zn superoxide dismutase levels were elevated in both patient groups (all p < 0.001), whereas the levels of autoantibodies against oxidized LDL were increased only in the patients with cardiovascular disease (p < 0.05) compared with the controls. Vascular endothelial growth factor level positively correlated with Cu/Zn superoxide dismutase level (p < 0.01) and with the levels of autoantibodies against oxidized LDL (p < 0.05) in the whole hemodialysis group., Conclusions: Our data indicate for the first time a relationship between oxidative stress and VEGF levels in hemodialyzed patients, particularly in those with cardiovascular disease. This association may represent one of the mechanisms involved in the progression of atherosclerosis in this population.

Introduction: Enhanced oxidative stress (SOX) and changes in the fibrinolytic system are common in end-stage renal failure patients undergoing maintenance dialysis. This study attempted to verify the existence of a relationship between SOX documented by Cu/Zn superoxide dismutase (Cu/Zn SOD) and fibrinolysis analyzed by tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and plasmin/antiplasmin (PAP) complexes in dialysis patients., Materials and Methods: Twenty-seven patients on maintenance haemodialysis (HD) and 16 on maintenance peritoneal dialysis (CAPD) were examined together with 18 healthy controls. Pre-dialysis blood levels of all the parameters were determined using commercially ELISA kits., Results: Cu/Zn SOD, uPA and PAP levels were increased in both groups of dialyzed patients compared to the controls. PAI-1 was significantly lower in CAPD subjects compared to HD subjects and control group. PAI-1/uPA ratio and PAI-1/tPA ratio were significantly decreased in CAPD and HD compared to controls, being significantly lower in CAPD patients relative to HD patients. In the patients, increased Cu/Zn SOD levels directly correlated with those of uPA (r=0.565, p<0.0001) and PAP (r=0.335, p<0.05); the fibrinolytic markers were also positively associated with each other (r=0.377, p<0.05)., Conclusions: The positive association between Cu/Zn SOD and both uPA as well as PAP levels suggests a link between SOX and the fibrinolytic activity in dialysis patients. We hypothesize that increased SOX-mediated fibrinolytic activity may be a part of the counter-system against activation of blood coagulation in these patients.

Objectives: We wanted to study the imbalance between antioxidant and oxidant generating systems resulting in oxidative stress (SOX) in end-stage renal disease (ESRD). We suggest that the plasma levels of Cu/Zn superoxide dismutase (Cu/Zn SOD) may be a new, sensitive marker of SOX in this population., Design and Methods: We measured the levels of Cu/Zn SOD and the traditional SOX markers-malondialdehyde (MDA), total peroxide, and autoantibodies against oxidized LDL (OxLDL-Ab) in the plasma of 132 uremic patients. In addition, circulating enzyme levels were analyzed in relation to the inflammation and presence of diabetes mellitus (DM)., Results: Cu/Zn SOD levels were significantly higher in chronic renal failure (CRF) patients (P < 0.05), and in both dialyzed groups (both P < 0.001) than in controls, and were positively correlated with MDA, creatinine (both P < 0.001) and OxLDL-Ab (P < 0.01) in the whole uremic group., Conclusions: The plasma levels of Cu/Zn SOD may be a simple, sensitive marker of SOX in ESRD, independent from DM and inflammation.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), beta-chemokines, increased oxidative stress (SOX) and inflammation have been implicated as important factors in atherosclerosis and vascular remodeling. We hypothesized the possible roles of beta-chemokines [monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta) and regulated upon activation, normal T-cell expressed and secreted (RANTES)] as regulators of the metabolism of the vascular extracellular matrix in conditions of increased SOX in hemodialysis (HD) patients. We compared pre-dialysis levels of MMP-9/TIMP-1 system, beta-chemokines, Cu/Zn superoxide dismutase (Cu/Zn SOD) as a marker of SOX and C-reactive protein (CRP) as a marker of inflammation in HD patients with and without cardiovascular disease (CVD) to those of controls. HD patients, particularly those with CVD, showed a significant increase in values of Cu/Zn SOD, CRP, TIMP-1, TIMP-1/MMP-9 ratio, MCP-1 and MIP-1beta, whereas RANTES levels were lower than in the controls. The levels of MIP-1alpha as well as MMP-9 in all HD groups were similar to the controls. The positive correlations were observed between the MMP-9/TIMP-1 system and beta-chemokines, SOX and inflammation in whole HD group and in the subgroup with CVD. Multivariate analysis showed that the duration of dialysis followed by Cu/Zn SOD, MIP-1alpha and beta levels were the significant positive predictors of TIMP-1. In conclusion, our data show that MMP-9/TIMP-1 system and beta-chemokines could cooperate in conditions of elevated SOX, which ultimately predisposes hemodialysis patients to accelerated atherosclerosis.

Cardiovascular diseases (CVD), being mostly a clinical manifestation of atherosclerosis, are the main cause of mortality in patients with chronic renal failure (CRF). It is now generally accepted that the first step in atherosclerosis is endothelial dysfunction. Recently, oxidative stress (SOX) has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction both in general and uremic populations. The aim of the present study was to establish the effect of two different method of dialysis therapy: hemodialysis (HD) and continuous peritoneal dialysis (CAPD) on the markers of SOX: lipid peroxides, Cu/Zn superoxide dismutase (Cu/Zn SOD) and autoantibodies against oxidized LDL (OxLDL-Ab), and endothelial injury: antigen of the von Willebrand factor (vWF : Ag), soluble thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) in 43 patients with CRF. Compared with the control subjects, patients with CRF showed a significant increase in plasma concentrations of Cu/Zn SOD, which was more elevated in HD than in CAPD group. The lipid peroxide levels were increased only in the post-HD samples, whereas OxLDL-Ab were more elevated in HD than in CAPD group. Markers of endothelial injury were significantly higher in dialyzed patients relative to controls, and were positively correlated themselves as well as with Cu/Zn SOD levels. The patients on HD and CAPD are exposed to increased SOX as well as to endothelial injury. The association between Cu/Zn SOD and the endothelial injury markers suggests the possible effect of oxidative stress on endothelial dysfunction in CRF patients.

HBV and HCV infections are associated with the increased production of reactive oxygen species (ROS) within the liver that are responsible for the oxidation of intracellular molecules and activation transcription factors. The aim of the present study was to establish whether the presence of hepatitis could be implicated in the elevation of oxidative stress (SOX) and plasma proinflammatory and chemoattractant cytokine levels in uraemic patients. The markers of SOX-autoantibodies to oxidized LDL (OxLDL-Ab); total peroxides; and the major antioxidant enzyme Cu/Zn superoxide dismutase (Cu/Zn SOD); as well as tumor necrosis factor-alpha (TNF-alpha); regulated upon activation, normal T cell expressed and secreted (RANTES); and macrophage inflammatory protein-1alpha (MIP-1alpha) and beta (MIP-1beta) levels were measured in the plasma of uraemic patients with hepatitis in comparison to subjects without hepatitis and to healthy volunteers. The values of total peroxide, Cu/Zn SOD, TNF-alpha, and MIP-1beta, were significantly elevated in uraemic patients when compared to the controls, whereas RANTES were decreased. MIP-1alpha and OxLDL-Ab were similar in the two groups. Cu/Zn SOD, MIP-1beta and RANTES concentrations were significantly higher in the hepatitis-positive relative to the hepatitis-negative group. Both MIP-1beta and RANTES were directly associated with Cu/Zn SOD levels and the presence of hepatitis. Multiple stepwise regression analysis has shown that the duration of dialysis, followed by the presence of hepatitis, independently and significantly predicted increased Cu/Zn SOD levels, whereas elevated Cu/Zn SOD as an independent variable was significantly associated with both increased both MIP-1beta and RANTES in uraemic patients. These results suggest that the presence of viral hepatitis status and liver injury are novel determinants of increased oxidative stress, as well as of increased MIP-1beta and RANTES levels in uraemic patients.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), together with extrinsic coagulation pathway activation and increased oxidative stress (SOX) have all been implicated as important factors in atherosclerosis and vascular remodelling. The aim of the present study was to investigate whether the MMPs/TIMPs system is associated with activation of the extrinsic coagulation pathway in conditions of increased SOX in hemodialysis (HD) patients. In HD patients, with and without cardiovascular disease (CVD), and in controls, we compared pre-dialysis levels of MMP-2, MMP-9,TIMP-1,TIMP-2; the markers of extrinsic coagulation pathway-tissue factor (TF) and its inhibitor (TFPI), prothrombin fragment F1+2 (F1+2); a marker of SOX-Cu/Zn superoxide dismutase (Cu/Zn SOD) and a surrogate of atherosclerotic disease-intima media thickness (IMT). Hemodialysis patients, particularly those with CVD, showed a significant increase in values of MMP-2/TIMPs, markers of the extrinsic coagulation pathway, Cu/Zn SOD and IMT as compared to controls. The markers of coagulation activation positively correlated with the MMP-2/TIMPs system, whereas they did not correlate with MMP-9. In addition, both MMP-2/TIMPs as well as extrinsic coagulation parameters were related to the prevalence of increased SOX, IMT and CVD. Multiple stepwise regression analysis showed that low TIMP-2 followed by increased Cu/Zn SOD and MMP-2 levels independently and significantly predicted elevated IMT on maintenance HD patients. In conclusion, our data suggest that the MMP-2/TIMPs system and an activated extrinsic coagulation pathway could cooperate in conditions of elevated SOX and could influence arterial remodeling resulting in the presence of CVD in haemodialysis patients.

Background/aim: Recently emerging evidence suggests that oxidative stress (SOX) may participate in atherogenesis. The aim of the present study was to establish whether enhanced SOX, involving endothelial injury, activation of coagulation, and inflammatory reaction, could be implicated in atherosclerotic diseases in haemodialysis (HD) patients., Methods: Markers of SOX, endothelial injury, coagulation, and cytokines, were measured in the plasma of HD patients with and without cardiovascular disease (CVD), and of healthy controls by ELISA methods. Remodeling of the carotid arteries was assessed by measuring the intima-media thickness (IMT) as a surrogate of atherosclerotic disease in all groups., Results: Markers of SOX, endothelial injury, and extrinsic coagulation pathway activation and IMT values were significantly elevated in HD patients, especially in those with CVD when compared with the control group. The von Willebrand factor antigen (vWF:Ag) levels were more increased in the patients with CVD than in those without. Furthermore, the plasma levels of tumour necrosis factor alpha, monocyte chemo-attractant protein 1, and macrophage inflammatory protein 1 beta were significantly higher only in the HD group with CVD when compared with the controls. The IMT was strongly and directly correlated with Cu/Zn superoxide dismutase. Both IMT and Cu/Zn superoxide dismutase were positively correlated with age, thrombomodulin, vWF:Ag, tissue factor, tissue factor pathway inhibitor, prothrombin fragment F1 + 2, monocte chemo-attractant protein 1, macrophage inflammatory protein 1 beta, and tumour necrosis factor alpha levels. Multivariate analysis identified vWF:Ag as the only independent variable significantly associated with an increased IMT., Conclusions: The present study suggests that enhanced SOX, involved pro-atherogenic cytokine and chemokines levels, endothelial injury, and coagulation activation may constitute a pathway for accelerated atherosclerosis in HD patients. The significant, independent association between IMT and vWF:Ag should be assessed in future studies to determine whether vWF:Ag elevation is causative or a by-product of the increased IMT., (Copyright 2004 S. Karger AG, Basel)

Background: Increased oxidative stress (SOX) has been reported in hemodialyzed (HD) patients, but its influence on CC-chemokine levels remains unknown., Methods: The levels of 3 distinct SOX markers (Cu/Zn superoxide dismutase (Cu/Zn SOD), total lipid peroxide, and autoantibodies against oxidized LDL (OxLDL-Ab)), as well as those of 4 CC-chemokines (monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta), regulated upon activation, normal T cell expressed and secreted (RANTES), and tumor necrosis factor-alpha (TNF-alpha)) were measured pre- and post-HD session in 15 HD patients with cardiovascular disease (CVD) and 12 HD patients without CVD (pre- and post-HD session) and 17 controls., Results: Cu/Zn SOD levels were elevated in HD patients (both before and after HD) compared to controls (p < 0.001). Total lipid peroxide levels were similar in the controls in pre-dialysis samples, but were increased after a HD session (p < 0.001). Pre-dialysis OxLDL-Ab levels were increased only in the HD group with CVD compared to controls (p < 0.05). The pre-dialysis plasma levels of TNF-alpha (p < 0.001), MCP-1 (p < 0.001) and MIP-1beta (p < 0.01) were increased both in all HD patients and subgroups with CVD when compared to the controls, and remained significantly elevated when measured after HD. Dialysis increased MCP-1 (p < 0.05) and MIP-1beta (p < 0.001) levels as compared to the controls as well as in patients without CVD. Plasma RANTES was significantly lower before HD (p < 0.05) and after HD (p < 0.001) in patients with CVD. Patients without CVD and all HD patients also had lower RANTES before and after HD when compared to controls (all p < 0.001). A positive correlation was observed between plasma pre-dialysis Cu/Zn SOD levels and the other SOX markers (all p < 0.05), age (p < 0.05) and duration of hemodialysis (p < 0.001). A positive relationship existed between plasma Cu/Zn SOD levels and those of MCP-1, MIP-1beta and TNF-alpha (all p < 0.001). RANTES levels negatively correlated with Cu/Zn SOD (p < 0.0001).TNF-alpha positively correlated with age (p < 0.05), total lipid peroxide (p = 0.010), MCP-1 (p < 0.01) and MIP-1beta levels (p < 0.01). An identifiable association exists between MCP-1 and MIP-1beta levels (p < 0.01), whereas both MCP-1 and MIP-1beta were inversely correlated with RANTES (both p < 0.05)., Conclusion: Our data indicate for the first time a probable functional relationship between oxidative stress and CC-chemokine levels in hemodialyzed patients, particularly in those with cardiovascular disease. This relationship may represent one of the mechanisms involved in the progression of atherosclerosis in these patients., (Copyright 2004 S. Karger AG, Basel)

Enhanced oxidative stress (SOX), endothelial dysfunction and haemostatic abnormalities are common in end-stage renal failure patients undergoing maintenance haemodialysis (HD). We studied associations among circulating immunoreactive total lipid peroxides as a marker of short-time SOX, autoantibodies against oxidized LDL as a surrogate of prolonged SOX, copper/zinc superoxide dismutase (Cu/Zn SOD) as a major antioxidant enzyme, tissue factor (TF) as a principal initiator of extrinsic coagulation pathway counteracted by its inhibitor (TFPI), and prothrombin fragment 1+2 (F 1+2) as a surrogate of activated haemostasis.Pre-dialysis blood levels of all the markers studied were higher in 24 clinically stable HD patients compared to 11 healthy controls. Spearman's correlations among the three SOX markers were positive but nonsignificant in both HD patients and controls. In HD subjects, increased Cu/Zn SOD levels directly correlated with those of TF (rho=0.551, p=0.005) and TFPI (rho=0.501, p=0.001); the coagulation markers were also positively associated with each other (rho=0.663, p=0.0004). In healthy subjects, the relations between Cu/Zn SOD, TF and TFPI levels were inverse but not significant, and the direct association between TF and TFPI was nonsignificant either. In conclusion, increased plasma levels of Cu/Zn SOD, the antioxidant enzyme with emerging endothelial cell-protective and antithrombotic properties, may be a novel part of the system counteracting activated extrinsic coagulation system in maintenance HD patients.

Background: Hepatocyte growth factor (HGF) and copper/zinc superoxide dismutase (Cu/Zn SOD) protect against tissue injury, including that due to oxidative stress (SOX). We studied whether they could be associated with each other, SOX markers, prevalence of viral hepatitis, and cardiovascular disease (CVD) and their laboratory surrogates in maintenance hemodialysis (HD) patients., Methods: In 24 patients, pre-dialysis serum HGF, plasma Cu/Zn SOD, total lipid peroxides, and serum autoantibodies against oxidized LDL were measured by ELISAs. Viral hepatitis B and C markers were determined by third generation microparticle ELISAs, and CVD was identified on a clinical basis., Results: In HD patients, circulating HGF, Cu/Zn SOD, and the other SOX markers were higher than in healthy controls, and HGF directly correlated with Cu/Zn SOD levels (P = 0.0006). Both HGF (P = 0.021) and Cu/Zn SOD (P=0.017) were positively associated with prevalence of viral hepatitis and serum alanine aminotransferase activity (P = 0.021 and P=0.040, respectively). Presence of CVD directly correlated with HGF (P = 0.001) but not with Cu/Zn SOD levels (P = 0.087). Circulating HGF positively related to serum C-reactive protein (P = 0.043). In patients without viral hepatitis and CVD, both HGF and Cu/Zn SOD were lower than in those with, and higher than in healthy controls. CVD (P = 0.003) and viral hepatitis (P = 0.024) were independent predictors of increased HGF, while positive viral hepatitis marker predicted increased Cu/Zn SOD levels (P = 0.019) in HD patients. There were no associations between HGF and the SOX markers in controls., Conclusions: In maintenance HD patients, circulating Cu/Zn SOD and HGF levels are increased, likely as a part of the reparatory reaction against liver damage. Viral hepatitis status and liver function should be considered in further studies of Cu/Zn SOD in these subjects.