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      Inflammatory Markers and Platelet Aggregation Tests as Predictors of Hemoglobin and Endogenous Erythropoietin Levels in Hemodialysis Patients

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          Abstract

          Background/Aims: Chronic inflammation is a common cause of severe anemia and hyporesponsiveness to recombinant erythropoietin (EPO) therapy in maintenance hemodialysis (HD) patients. We compared various acute-phase markers and ex vivo platelet aggregation tests in relation to clinical conditions in order to find factors predictive of hemoglobin (Hb) and endogenous EPO levels in a cross-section of clinically stable HD patients. Methods: In 100 subjects, pre-HD blood levels of C-reactive protein (CRP), α<sub>1</sub>-acid-glycoprotein (AGP), α<sub>1</sub>-antitrypsin (AT), immunoglobulin (Ig) M and G (by nephelometry), antigens of endothelial von Willebrand factor (vWF), type 1 plasminogen activator inhibitor and thrombomodulin, interleukin-6, lipoprotein(a) [Lp(a)] and EPO (by ELISA), and albumin, fibrinogen, iron metabolism indices, thyroid-stimulating hormone, phosphorus, parathormone, total cholesterol, triglycerides, viral hepatitis B/C markers, liver enzyme, and aluminium were determined. Platelet aggregations in response to ristocetin (RIPA), adenosine diphosphate, and collagen were measured in whole blood (electric impedance method) and platelet-rich plasma (optical aggregometry). Results: Hb levels inversely correlated with IgM, Lp(a), soluble vWF antigen, phosphorus, and all platelet aggregations in whole blood, but not in platelet-rich plasma. HD duration and triglycerides were positive correlates of anemia. In a multivariable analysis, increased IgM, short HD duration, increased Lp(a) and enhanced whole blood RIPA (in descending order of significance) were independent predictors of low Hb levels. In 51 patients not treated with recombinant EPO, serum levels of this hormone inversely correlated with whole blood RIPA, AT, age, vWF antigen, AGP, and positively with viral hepatitis marker. Anemia and EPO levels were not affected by gender, body mass index, cause of renal failure, residual renal function, HD dose, protein catabolic rate, use of different heparins or dialysate buffers, ACE inhibitor therapy, and parathyroid or thyroid function. In additional 10 patients, single HD session resulted in an increase in IgM levels associated with a fall in total lymphocyte counts. Conclusion: Subclinical inflammation is an important determinant of anemia in maintenance HD patients. Increased serum IgM reflecting a microinflammatory effect of HD procedures, enhanced whole blood RIPA as a surrogate of vascular endothelial damage, and Lp(a) as its promoter could be markers of such impaired erythropoiesis.

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          Most cited references 6

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          A potential basis for the thrombotic risks associated with lipoprotein(a).

          Lipoprotein(a) (Lp(a)) has been strongly linked with atherosclerosis and is an independent risk factor for myocardial infarction. Distinguishing Lp(a) from other low-density lipoprotein particles is its content of a unique apoprotein, apo(a). The recently described sequence of apo(a) indicates a remarkable homology with plasminogen, the zymogen of the primary thrombolytic enzyme, plasmin. Lp(a) may contain 37 or more disulphide-looped kringle structures, which are 75-85% identical to the fourth kringle of plasminogen. Plasminogen receptors are widely distributed on blood cells and are present at extremely high density on endothelial cells. These receptors promote thrombolysis by accelerating plasminogen activation and protecting plasmin from inhibition. If, by molecular mimicry, Lp(a) competes with plasminogen for receptors, then thrombolysis would be inhibited and thrombosis promoted. Here we provide support for such a mechanism being responsible for the thrombotic risks associated with elevated Lp(a) by demonstrating that Lp(a) inhibits plasminogen binding to cells.
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            Role of cytokines in the response to erythropoietin in hemodialysis patients.

            Cytokines are regulatory factors of erythropoiesis, especially in pathologic conditions. Even though a relevant role for a deranged cytokine production in the pathogenesis of dialysis anemia has been suggested, no data are available that analyze the role of cytokines in the key therapeutic issue of the needs of erythropoietin. The aim of the present study in hemodialysis patients was, therefore, to examine the relationship between the dose of recombinant human erythropoietin (EPO) and the production of cytokines by peripheral blood mononuclear cells (PBMC). After the exclusion of subjects with major active causes of EPO resistance, data from 34 hemodialysis patients were available for analysis. Cytokine levels were measured in the supernatants of stimulated [with bacterial lipopolysaccharide and interferon gamma (IFN-gamma)] and unstimulated PBMC. Mean yearly values of hematocrit, hemoglobin, transferrin saturation, ferritin, parathormone (PTH) and aluminum levels and EPO doses (U/kg/week) were calculated. For analysis, the 34 patients were divided according to their cutoff requirements for EPO: patients with requirements of EPO > or = 60 U/kg/week (group A1, 26 subjects) versus EPO or = 100 U/kg/week (group A2, 18 subjects) versus <100 U/kg/week (group B2, 16 subjects). A significant direct correlation between interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) production values and EPO doses was found (P = 0.039 and P = 0.02 respectively). On the other hand, there was a significantly negative correlation between interleukin-12 (IL-12) production values and EPO doses (P = 0.029). Patients of groups A1 and A2 had spontaneously higher tumor necrosis factor-alpha (TNF-alpha) and lower IL-12 and IFNgamma production compared to patients from groups B1 and B2. Our data disclose a previously undescribed pattern of cytokine alteration that is relevant to determine increased needs of EPO in hemodialysis patients. The present results have potential applicability in designing strategies to improve EPO resistance.
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              Apo(a)-isoform size, nutritional status and inflammatory markers in chronic renal failure.

              Atherosclerotic cardiovascular disease and malnutrition are widely recognized as leading causes of the increased morbidity and mortality observed in uremic patients. Levels of lipoprotein (a) [Lp(a)], an established cardiovascular risk factor, are elevated in uremic patients. Moreover, low serum albumin levels indicating malnutrition have been associated with elevated plasma Lp(a) levels in dialysis patients. However, serum albumin levels are also influenced by an inflammatory reaction. The present study was undertaken to further investigate the relationship between Lp(a), inflammation and malnutrition in patients with chronic renal failure (CRF) prior to the initiation of renal replacement therapy, and to investigate the potential relation between these factors and apo(a)-isoform size, an important determinant of plasma Lp(a) levels. A total of 83 patients (mean age 52 +/- 1 year) with terminal (creatinine clearance 9 +/- 1 ml/min) CRF were cross sectionally investigated. In addition to lipid parameters and apo(a)-isoform size, C-reactive protein (CRP), nutritional parameters including serum levels of albumin and body composition (dual energy x-ray absorptiometry), as well as a subjective global assessment (SGA) and the prevalence of cardiovascular disease (CVD) were evaluated. Malnourished patients (N = 39) had a significantly (P < 0.05) higher median plasma Lp(a) level (19.5 mg/dl) as compared to 44 well-nourished patients, (11.7 mg/dl). No difference was found for other lipid or lipoprotein parameters. A significant relationship was found between CRP and plasma Lp(a), whereas no significant relation was observed between plasma Lp(a) and serum albumin levels. The apo(a)-isoform distribution was similar among malnourished and well-nourished patients. There was no difference in nutritional parameters when comparing patients with small- and large-size apo(a) isoforms. However, a subgroup of patients (12%) with no detectable apo(a)-bands and low Lp(a) levels had significantly higher lean body mass. The present study demonstrates elevated plasma Lp(a) levels in CRF patients with signs of malnutrition, even though no direct relationships between plasma Lp(a) levels and various nutritional parameters were observed. The observed relationship between Lp(a) and CRP suggests that inflammatory factors, more prevalent in patients with malnutrition, may contribute to the Lp(a) increase in malnourished CRF.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2002
                August 2002
                15 July 2002
                : 91
                : 4
                : 671-681
                Affiliations
                Department of Nephrology and Internal Medicine, Medical Academy, Białystok, Poland
                Article
                65030 Nephron 2002;91:671–681
                10.1159/000065030
                12138272
                © 2002 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: 2, Tables: 5, References: 37, Pages: 11
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65030
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