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      Positive Acute-Phase Inflammatory Markers in Different Stages of Chronic Kidney Disease

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          Abstract

          Background: An elevated serum level of acute-phase inflammatory markers is associated with an increased risk of cardiovascular disease. We hypothesized that elevated acute-phase inflammatory markers are directly associated with the different stages of chronic kidney disease (CKD). Methods: We evaluated the relationship between serum levels of high-sensitivity C-reactive protein (hsCRP) and α<sub>1</sub>-acid glycoprotein (α<sub>1</sub>-AGP), as well as the renal function in 224 adult patients with CKD (mean age 56.6 years, 46% male, and 40% diabetics), stratified according to the glomerular filtration rate (GFR) (based on the National Kidney Foundation/Kidney Dialysis Outcomes Quality Initiatives), and in 94 hemodialysis patients. Results: The mean hsCRP was 8.2 ± 12.1 mg/l, and hsCRP levels were >5 mg/l in 44.4% of the patients; α<sub>1</sub>-AGP levels were >125 mg/dl in 33.3% of the patients. Mean hsCRP and α<sub>1</sub>-AGP were significantly higher in more severe stages of CKD. A weak inverse relationship was found between GFR and serum hsCRP (r = –0.2205; p = 0.0006) and between GFR and serum α<sub>1</sub>-AGP (r = –0.3266; p < 0.0001). There was a correlation between hsCRP and α<sub>1</sub>-AGP (r = 0.3417; p < 0.0001). No significant differences were detected between patients with CKD and those undergoing hemodialysis concerning hsCRP (8.2 ± 12.1 vs. 6.8 ± 7.4 mg/l; p = 0.2980) and α<sub>1</sub>-AGP (116.3 ± 42.5 vs. 117.2 ± 37.9 mg/dl; p = 0.8590). However, the level of hsCRP was significantly reduced in hemodialysis patients compared with patients with stage 5 predialytic disease (12.1 ± 13.9 to 6.8 ± 7.4 mg/l; p = 0.005). More patients with stage 5 predialytic CKD had an elevated hsCRP serum level compared with patients on hemodialysis (64.7 vs. 37.9%; χ<sup>2</sup> = 6.230, p < 0.01). Conclusions: Approximately 50% of patients with CKD – even in the early phase of renal failure – exhibit an activated acute-phase response, which is closely related to the stages of CKD. Hemodialysis may partially correct the inflammatory process present in the immediate predialysis phase of CKD.

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          Most cited references 17

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          Clinical epidemiology of cardiovascular disease in chronic renal disease.

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            The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.

            Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.
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              Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD).

              This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization. Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is. Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group. Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels. Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2006
                April 2006
                05 April 2006
                : 26
                : 1
                : 59-66
                Affiliations
                Nephrology Service, Hospital das Clínicas da FMUSP, and Hospital Beneficência Portuguesa, São Paulo, Brazil
                Article
                91806 Am J Nephrol 2006;26:59–66
                10.1159/000091806
                16508248
                © 2006 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: 3, Tables: 2, References: 37, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/91806
                Categories
                Original Report: Laboratory Investigation

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