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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: CC-chemokines are now widely accepted in the recruitment of leukocytes from the blood compartment into tissues, and their role in the progression of atherosclerosis has been documented. Recombinant human erythropoietin (EPO) has become widely used to treat anemic HD patients. However, little is known about the effect of EPO on the plasma CC-chemokine levels and intima-media thickness (IMT) in HD patients., Methods: Assessment of 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 IMT were performed in 26 stable HD patients and 15 healthy controls. The patients were divided into 3 groups: group I (n = 8, without EPO), group II (n = 9, EPO at a mean dose of 76 +/- 48 U/kg/week for more than 4 months), and group III (n = 9, EPO at a mean dose of 110.5 +/- 21 U/kg/week for more than 12 months), none of them on iron therapy., Results: MCP-1, MIP-1alpha, MIP-1beta and IMT values were significantly higher, whereas RANTES were significantly lower in HD patients without EPO therapy than those in healthy controls. CC-chemokine levels were found to be significantly lower in patients administered EPO when compared to subjects without EPO. In the patients treated with EPO for more than 12 months IMT values were significantly decreased compared to patients not receiving this hormone., Conclusion: These results suggest that long-term EPO therapy decreased CC-chemokine and IMT values in patients undergoing regular HD in the absence of concomitant iron supplementation., (Copyright (c) 2006 S. Karger AG, Basel.)

Background: Hepcidin synthesis in hepatocytes is modulated in response to anemia, hypoxia or inflammation. A cross-sectional study was performed to assess hepcidin correlations with markers of iron status, erythropoietin therapy and markers of inflammation in hemodialyzed patients and in the healthy volunteers., Methods: Iron status, complete blood count, creatinine, albumin, lipids were assessed using standard laboratory methods. Hepcidin and high-sensitivity CRP were measured using commercially available kits., Results: Serum iron, TIBC, TSAT, erythrocyte count, Hb, Ht, platelet count, albumin, and cholesterol were lower, whereas ferritin and hepcidin were higher in hemodialyzed patients over controls. Hepcidin correlated positively with triglycerides, albumin, aspartate aminotransferase, lymphocyte count, ferritin and erythropoietin dose and negatively with erythrocyte count, Hb, and Ht in hemodialyzed patients. In multiple regression analysis, triglycerides (beta value was 0.28, p = 0.02) and albumin (beta value was -0.31, p = 0.006) were correlates of hepcidin in hemodialyzed patients., Conclusions: Elevated hepcidin levels in hemodialyzed patients may be due to functional iron deficiency and anemia. Liver plays an important role in the synthesis of hepcidin. Low-grade inflammation, frequently found in hemodialyzed patients, might also contribute to elevated hepcidin concentration. Hypothesis that hepcidin might link anemia, inflammation and liver function in kidney disease should be further evaluated.

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)