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      Abnormal Cytokine Synthesis as a Consequence of Increased Intracellular Oxidative Stress in Children Treated with Dialysis

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          Abstract

          Background/Aim: End-stage renal disease (ESRD) induces a clinical state of immunodeficiency with a higher incidence of infections and higher mortality due to infectious complications compared with the normal population. The definite mechanism responsible for the host defense alterations is not well understood. The aim of the study was to investigate intracellularly the relationship between cytokine synthesis and oxidative stress in peripheral blood lymphocytes in children with ESRD. Methods: Twenty-one children (age 11.7 ± 5.8 years) with ESRD treated with hemodialysis (HD; n = 10) and peritoneal dialysis (PD; n = 11) were studied. Nine healthy children of comparable age formed the control group. To determine intracellular oxidative stress we used dihydrorhodamine-123 (DHR), which after oxidation to rhodamine-123 (RHO) emitted a bright fluorescent signal. Intracellular oxidation of DHR in T lymphocytes reflected intracellular oxidative stress. The intracellular synthesis of cytokines (IL-2, IFN-γ, IL-4, IL-6) was also measured. Both parameters were detected at a single-cell level by flow cytometry. Lymphocyte subsets were evaluated using the monoclonal antibodies conjugated with fluorochromes. Results: We found that in T lymphocytes the mean fluorescence intensity (MFI), which reflected intracellular oxidative stress, was increased in ESRD patients compared to the controls (CD3+: 34.77 ± 11.55 vs. 22.55 ± 4.97, p < 0.01; CD3+CD8+: 34.31 ± 12.17 vs. 20.77 ± 4.89, p < 0.01; CD3+CD4+: 36.06 ± 6.98 vs. 24.44 ± 7.68, p < 0.001). HD patients showed slightly higher MFI compared to PD patients in CD3+ cells (39.32 ± 11.70 vs. 30.63 ± 10.20, NS), in CD3+CD8+ cells (37.90 ± 14.32 vs. 31.06 ± 9.34, NS) and in CD3+CD4+ cells (40.10 ± 2.28 vs. 29.33 ± 7.06, p < 0.001). The intracellular synthesis of IL-2 was higher in ESRD patients compared to the controls, both in CD3+ cells (31.34 ± 9.80 vs. 20.49 ± 15.26%, p < 0.05) and in CD3+CD4+ cells (36.10 ± 8.69 vs. 24.03 ± 16.95%, p < 0.05). The intracellular synthesis of IFN-γ, IL-4 and IL-6 was significantly lower in the ESRD group compared to the controls. Interestingly, in patients treated with HD, negative correlations between the degree of intracellular oxidative stress and intracellular cytokine synthesis in CD3+ lymphocytes were found. Conclusion: Our results show that patients with ESRD, especially those treated with HD, present increased oxidative stress in T lymphocytes, which may lead to decreased cytokine synthesis and abnormal immune response.

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          Most cited references 25

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          Renal replacement therapy in children: data from 12 registries in Europe.

          In June 2000 the ERA-EDTA Registry office moved to Amsterdam and started collecting core data on renal replacement therapy (RRT) entirely through national and regional registries. This paper reports the pediatric data from 12 registries. The analysis comprised 3,184 patients aged less than 20 years and starting RRT between 1980 and the end of 2000. The incidence of RRT rose from 7.1 per million of age-related population (pmarp) in the 1980-1984 cohort to 9.9 pmarp in the 1985-1989 cohort, and remained stable thereafter. The prevalence increased from 22.9 pmarp in 1980 to 62.1 in 2000. Hemodialysis was the commonest form of treatment at the start of dialysis, but peritoneal dialysis gained popularity during the late 1980s. Pre-emptive transplantation accounted for 18% of the first treatment modality in the 1995-2000 cohort. The relative risk of death of patients starting dialysis in the period 1995-2000 was reduced by 36% [adjusted hazard ratio (AHR) 0.64 [95% confidence interval (CI) 0.41-1.00] and that of those receiving a first allograft by 42% [AHR 0.58 (95% CI 0.34-1.00)], compared with patients in the period 1980-1984. The prevalence of RRT in children has continued to rise, while its incidence has been stable for about 15 years. Patient survival has improved in both dialysis patients and transplant recipients. The development of this pediatric registry will form the basis for more-detailed and focused studies in the future.
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            Production of interleukin-6, tumor necrosis factor alpha and interleukin-10 in vitro correlates with the clinical immune defect in chronic hemodialysis patients.

            In patients with chronic renal failure alterations in monokine production are a common feature. Their clinical relevance has not yet been proven. We show here a correlation between an overproduction of interleukin-(IL)-6 and tumor necrosis factor alpha (TNF alpha) upon stimulation with LPS by mononuclear cells in vitro and the clinical grade of immunodeficiency found in these patients. Higher levels of IL-6 and TNF alpha were correlated with an immunocompromized state, that is, non-responsiveness to hepatitis B vaccination, whereas patients with a better immune competence showed the same levels of these cytokines as healthy controls. Only the patients with a good immune function showed a high secretion of IL-10. The feedback mechanism of IL-10 for reducing monokine synthesis seems to be intact in these patients. Thus the secretion of IL-10 might be regarded as a compensatory mechanism which controls monokine induction by chronic renal failure and hemodialysis treatment. Immunocompromized patients who are unresponsive to hepatitis B vaccination seem to be unable to enhance IL-10 synthesis for control of monokine overproduction. This results in higher levels of IL-6 and TNF alpha that might be involved in the pathogenesis of reduced immune defense.
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              Flow cytometric measurement of intracellular cytokines.

              The identification of distinct T helper lymphocyte subsets (Th1/2) with polarised cytokine production has opened up new fields in immunobiology. Of the several alternative methods of monitoring cytokine production, flow cytometric analysis of intracellular staining has distinct advantages and pitfalls. It allows high throughput of samples and multiparameter characterisation of cytokine production on a single cell basis without the need for prolonged in vitro culture and cloning. However, these methods may cause important changes in cell surface phenotype which can make interpretation difficult.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2005
                October 2005
                15 June 2005
                : 101
                : 2
                : c100-c108
                Affiliations
                Department of Pediatric Nephrology, Poznan´ University of Medical Sciences, Poznan´, Poland
                Article
                86348 Nephron Clin Pract 2005;101:c100–c108
                10.1159/000086348
                15956803
                © 2005 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.

                Page count
                Figures: 8, Tables: 2, References: 41, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86348
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