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      Effect of Iron Loading on Peripheral Blood Lymphocyte Subsets and on Circulating Cytokine Levels in Iron-Depleted Hemodialysis Patients Receiving Erythropoietin


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          Background/Aims: High doses of iron are recommended intravenously in iron-depleted hemodialysis (HD) patients receiving recombinant erythropoietin (EPO). Iron deficiency and mainly iron overload impair cellular and humoral immune response mechanisms. Imbalances in T cell subsets are common findings in disorders of iron metabolism. The aim of this study was to evaluate the effect of iron load on peripheral blood lymphocytes subsets and on circulating cytokine levels in HD iron depleted patients, treated with EPO. Methods: We studied 19 stable adult HD patients, 12 males, with a mean age 59 ± 11 years and mean HD duration 24 ± 14 months. All patients were iron deficient and were treated with unchanged EPO dose for the last 4 months before entering the study. The administered dose of iron was infused intravenously (1,000 mg iron sucrose) in 10 doses, during 10 consecutive HD sessions. Patients were screened before the commencement of the HD session on two occasions, once prior to the first dose of iron and 2 days after the 10th dose. Hematocrit (Ht), hemoglobin (Hb), iron, serum ferritin, transferrin saturation, interleukin (IL)-2, IL-4, IL-10, interferon-γ and tumor necrosis factor-α were measured. Major lymphocyte subsets (CD3+, CD19+, CD4+, CD8+, CD16+/56+, CD3+CD16+CD56+) and the ratio CD4+/CD8+ were also determined by two-color immunofluorescent analysis using flow cytometry. Results: Hb, transferrin saturation and ferritin increased significantly at the end of the study 11.2 ± 0.9 to 11.6 ± 0.8 g/dl, p < 0.005, 17.5 ± 6.9 to 23.0 ± 10.8 %, p < 0.05, and 70 ± 43 to 349 ± 194 µg/l, p < 0.005, respectively. IL-2 also increased significantly 27.8 ± 15.2 to 38.9 ± 12.8 pg/ml, p < 0.05. After iron load there was no significant change to the major lymphocyte subsets examined but a significant increase of the percentage and number of T lymphocytes with positive natural killer receptors (NKR+ T) cells was observed, 5.1 ± 3.7% to 6.3 ± 3.46%, p < 0.05, and 76.4 ± 40 to 101.5 ± 48 cells/µl, p < 0.005, respectively. Conclusion: Iron load in iron-deficient EPO-treated HD patients did not produce any changes in major lymphocyte subsets in peripheral blood, but it resulted in a significant increase of NKR+ T cells, a subpopulation important for local immune responses. Iron load for a relatively short period improved anemia of HD patients and influenced the levels of the circulating IL-2, which may regulate factors affecting the survival of patients.

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          Immunologic function and survival in hemodialysis patients.

          Although the medical determinants of mortality in patients with end-stage renal disease (ESRD) treated with hemodialysis (HD) are well appreciated, the contribution of immunologic parameters to survival in such patients is unclear, especially when variations in age, medical comorbidity and nutrition are controlled. In addition, although dysregulation of cytokine metabolism has been appreciated in patients with ESRD, the association of these parameters with outcomes has not been established. Recently, the type of dialyzer used in patients' treatment has been associated with survival, but the mechanisms underlying these findings, including their immune effects, have not been established. We conducted a prospective, cross-sectional, observational multicenter study of urban HD patients to determine the contribution of immunological factors to patient survival. We hypothesized increased proinflammatory cytokines would be associated with increased mortality, and that improved immune function would be associated with survival. Patients were assessed using demographic and anthropometric indices, Kt/V, protein catabolic rate (PCR) and immunologic variables including circulating cytokine [interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-12, IL-13 and tumor necrosis factor (TNF)-alpha] levels, total hemolytic complement activity (CH50), and T cell number and function. A severity index, previously demonstrated to be a mortality marker, was used to grade medical comorbidity. A Cox proportional hazards model, controlling for patients' age, severity index, level of serum albumin concentration, dialyzer type and dialysis site was used to asses relative survival risk. Two hundred and thirty patients entered the study. The mean (+/- SD) age of the population was 54.4 +/- 14.2 years, mean serum albumin concentration was 3.86 +/- 0.47 g/dl, mean PCR was 1.1 +/- 0.28 g/kg/day, and mean Kt/V 1.2 +/- 0.3. Patients' serum albumin concentration was correlated with levels of Kt/V and PCR, and their circulating IL-13 and TNF-alpha levels, but negatively with their circulating IL-2 levels, T-cell number and T-cell antigen recall function. T-cell antigen recall function correlated negatively with PCR, but not Kt/V. There was no correlation of any other immune parameter and medical or demographic factor. Immune parameters, were all highly intercorrelated. Mean level of circulating cytokines in HD patients were in all cases greater than those of a normal control group. There were few differences in medical risk factors or immune parameters between patients treated with different types of dialyzers. After an almost three-year mean follow-up period, increased IL-1, TNF-alpha, IL-6, and IL-13 levels were significantly associated with increased relative mortality risk, while higher levels of IL-2, IL-4, IL-5, IL-12, T-cell number and function, and CH50 were associated with improved survival. The difference in survival between patients treated with unmodified cellulose dialyzers and modified or synthetic dialyzers approached the level of statistical significance, but there were no differences in levels of circulating cytokines between these two groups. Higher levels of circulating proinflammatory cytokines are associated with mortality, while immune parameters reflecting improved T-cell function are associated with survival in ESRD patients treated with HD, independent of other medical risk factors. These factors may serve as markers for outcome. The mechanism underlying the relationship of immune function and survival, and the effect of interventions to normalize immune function in HD patients should be studied.
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            Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation.

            We have compared the efficacy of oral to intravenous iron for the chronic maintenance of iron stores in hemodialysis patients. Fifty-two hemodialysis patients with initial serum ferritin greater than 100 ng/mL and transferrin saturation greater than 15% were randomly assigned to one of two groups: those receiving oral iron therapy (n = 32) and those receiving intravenous iron dextran (100 mg twice weekly) (n = 20). At study completion (4 months), the mean hematocrit was significantly higher in the intravenous group than in the oral iron group (34.4% +/- 0.7% v 31.8% +/- 0.4%, respectively; P < 0.05), the final mean recombinant human erythropoietin dose was 46% lower in the intravenous iron group than in the oral group (4,050 +/- 634 U/treatment v 7,563 +/- 378 U/treatment; P < 0.05), and the mean serum ferritin was significantly higher in the intravenous group than in the oral iron group (753.9 +/- 30.2 ng/mL v 157.3 +/- 15.4 ng/mL, respectively; P < 0.05). We have found that administering iron intravenously instead of orally for chronic maintenance iron supplementation in hemodialysis patients resulted in improved erythropoiesis. We hypothesize that most hemodialysis patients have inadequate iron stores for optimal erythropoiesis when currently recommended levels of ferritin and transferrin saturation are used to guide therapy, and that the chronic use of intravenous iron could reduce recombinant human erythropoietin requirements by maximizing iron stores. The improvement in erythropoiesis was accompanied, however, by an increase in iron indices to levels that could be indicative of tissue iron overload. Future studies must be performed to determine whether lower doses of intravenous iron dextran would improve erythropoiesis without causing potential organ iron overload.
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              Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin.

              Anemia in patients with end-stage renal disease (ESRD) is treated with recombinant human erythropoietin (rhEPO) often in combination with iron. However, iron catalyzes the formation of toxic radicals, which might promote vascular damage, is a nutrient for microorganisms, and negatively affects immune pathways, thus increasing the risk for severe infections. We investigated 28 patients on chronic hemodialysis who were randomized to receive either rhEPO alone (N = 15) or rhEPO in combination with intravenous iron (N = 13) for a period of 12 weeks. We analyzed iron therapy associated changes in cytokine patterns and endogenous radical formation. Tumor necrosis factor-alpha (TNF-alpha) levels were increased in ESRD patients at study entry and then decreased significantly over time in subjects receiving additional iron, while they increased with rhEPO alone. In contrast, we found serum concentrations of the anti-inflammatory cytokine interleukin (IL)-4 to increase with iron therapy. A significant negative correlation between iron availability, as determined by transferrin saturation, and TNF-alpha levels (P = 0.008) and a positive one between transferring saturation and IL-4 (P = 0.02) pointed to the potential role of iron to induce immunologic changes. Interestingly, iron therapy resulted in a slight decrease in the amounts of endogenous peroxides, which may be referred to reduced TNF-alpha concentrations since peroxide concentrations were positively correlated to TNF-alpha levels (P = 0.046) and negatively to transferrin saturation (P = 0.02). Iron supplementation in ESRD patients down-regulates proinflammatory immune effector pathways and stimulates the expression of the anti-inflammatory cytokine IL-4. Such a condition is detrimental for host response toward invading pathogens. However, tissue damage by radicals such as endogenous peroxides may be reduced in this condition due to impaired TNF-alpha formation.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                November 2007
                21 September 2007
                : 107
                : 3
                : c97-c102
                aDepartment of Nephrology, General Hospital of Veria, Veria, bFirst Department of Internal Medicine, cDepartment of Biopathology, University of Thessaloniki, and dDepartment of Immunology and National Peripheral Histocompatibility Center, Hippokration Hospital of Thessaloniki, Thessaloniki, and eDepartment of Nephrology, University of Thrace, Thrace, Greece
                108650 Nephron Clin Pract 2007;107:c97–c102
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 05 November 2006
                : 16 May 2007
                Page count
                Figures: 2, Tables: 3, References: 26, Pages: 1
                Original Paper

                Cardiovascular Medicine,Nephrology
                Anemia,Cytokines,Erythropoietin,Hemodialysis,Intravenous iron administration,Iron load,Lymphocyte subsets,T cells


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