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      Atorvastatin Increases Erythropoietin-Stimulating Agent Hyporesponsiveness in Maintenance Hemodialysis Patients: Role of Anti-Inflammation Effects

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          Abstract

          Erythropoietin-stimulating agent (ESA) hyporesponsiveness is aggravated by chronic inflammation in maintenance hemodialysis (MHD) patients. Dyslipidemia is prevalent in MHD patients. Statin therapy has been demonstrated to not only be effective in lowering lipid levels, but also numerous pleiotropic effects including anti-inflammatory, anti-fibrotic and endothelial function improvement. Recently, a retrospective study has shown that statin therapy decreases ESA requirements in MHD patients. We conducted a prospective study to analyze the effect of statin therapy on ESA hyporesponsiveness, and especially emphasized its anti-inflammatory benefits in MHD patients. This prospective study enrolled 30 patients with baseline cholesterol >220 mg/dl. Low-dose atorvastatin (10 mg/day) was prescribed for 12 weeks. We prospectively recorded patients’ biochemistry and hematological profiles, ESA prescription and some inflammatory markers at baseline, 4 weeks and 12 weeks. Statistically significant changes were noted after 4 and 12 weeks of statin therapy for cholesterol (272.5 ± 41.1 to 184.4 ± 37.6 and 196.4 ± 40.2 mg/dl, p < 0.05) and ESA hyporesponsiveness, which demonstrated as erythropoietin to hematocrit ratio (EHR) (129.3 ± 58.2 to 122.3 ± 53.5 and 121.0 ± 53.3 EPO U/Hct/week, p < 0.05). Mean values for proinflammatory cytokines included interleukin-6 and tumor necrotic factor-α levels decreased by 30.8 and 10.6%, respectively. Thus, these data suggest that statin therapy may improve ESA hyporesponsiveness in dialysis patients. This improvement in ESA hyporesponsiveness is associated with the effects of statins on inflammation.

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          Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients.

          J Cheigh, Craig Parker, Lainey Rubin … (1998)
          Low serum albumin and low serum cholesterol levels are among the most consistent predictors of mortality in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Hypoalbuminemia is often interpreted as a marker of poor nutrition, but serum albumin and cholesterol levels can also be low as part of a cytokine-mediated acute-phase reaction to acute or chronic inflammation. Here we report the results from a 900-day prospective study designed to determine whether tumor necrosis factor-alfa (TNF-alpha) and interleukin-6 (IL-6) predict serum albumin and cholesterol levels and mortality in a group of 90 ambulatory, adult hemodialysis patients with no acute infection, hospitalization or surgery, and no known acquired immunodeficiency syndrome (AIDS), malignancy, or liver disease. Measurable levels of TNF-alpha and/or IL-6 were found in 89 of 90 patients. Significant relationships were found between TNF-alpha and IL-6 and the degree of hypoalbuminemia and dyslipoproteinemia. IL-6 was the strongest predictor of mortality in univariate and multivariate analysis, followed by age, albumin level, and body mass index (BMI). Although the cause of hypercytokinemia was not addressed in this study, the data support the view that hypoalbuminemia and hypocholesterolemia are negative acute-phase responses to inflammatory stimuli. These results suggest that efforts to identify the nature of the stimuli for cytokine production and to lower cytokine levels in hemodialysis patients might be effective in improving the survival of patients undergoing hemodialysis.
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            Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients.

            M Tozawa, Shuichi Takishita, Kunitoshi Iseki … (2002)
            Although hypocholesterolemia is common in chronic hemodialysis patients, its effect on survival has not been studied in a large patients population. A cohort of chronic hemodialysis patients (N = 1167) was prospectively followed from January 1991 to January 2001. The survival impact of this cohort, who were divided according to different baseline levels of serum cholesterol, were calculated with the multivariate Cox proportional hazard analysis after adjusting for baseline clinical and laboratory variables. During the study period, 567 (48.6%) patients died. The mean (SD) baseline level of serum cholesterol was 171.0 (40.8) mg/dL and ranged from 76 to 378 mg/dL. The five-year survival rate was highest (0.812) in the subgroup that had a serum cholesterol range of 200 to 219 mg/dL and was lowest (0.608) in the subgroup with serum cholesterol values of or =220 mg/dL. Serum cholesterol was a significant predictor of death with an adjusted hazards ratio (95% confidence interval) was 0.939 (0.891 to 0.989). In a subgroup of patients with serum albumin values > or =4.5 g/dL (N = 128), the adjusted hazards ratio was even greater at 1.370 (1.105 to 1.692). Other than sex, body mass index and serum albumin were significant determinants of baseline levels of serum cholesterol. Hypocholesterolemia was an independent predictor of death in patients on chronic hemodialysis. This impact of hypercholesterolemia on survival was only evident in a subgroup of patients whose serum albumin was more than 4.5 g/dL.
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              Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia.

              Rita S M Shih, R Mohini, D. C. Rao (1993)
              Anemia is common in patients with chronic renal insufficiency and secondary hyperparathyroidism. Erythropoietin therapy is effective, but the dose required varies greatly. One possible determinant of the efficacy of erythropoietin therapy is the extent of marrow fibrosis caused by hyperparathyroidism. We examined the relation between the erythropoietic response to erythropoietin and hyperparathyroidism in a cross-sectional study of 18 patients undergoing hemodialysis who had received erythropoietin therapy for one to three years. In 7 patients (the poor-response group), the dose of intravenous erythropoietin needed to maintain a mean (+/- SD) target hematocrit of 35 +/- 3 percent was > 100 units per kilogram of body weight three times a week, and in 11 patients (the good-response group) it was < or = 100 units per kilogram. In all patients, indexes of the adequacy of dialysis and the extent of hyperparathyroidism and aluminum toxicity were determined monthly, and bone histomorphometry was performed. The mean (+/- SD) dose of erythropoietin required to maintain the target hematocrit was 174 +/- 33 units per kilogram three times a week in the poor-response group and 56 +/- 18 units per kilogram in the good-response group. The mean ages, duration and adequacy of dialysis, increment in hematocrit, iron requirements, and serum concentrations of calcium, phosphate, and aluminum were similar in the two groups. The percentages of osteoid volume and surface, the osteoid thickness, and the stainable aluminum content of bone were similar in the two groups. In contrast, the mean serum parathyroid hormone concentration, the percentages of osteoclastic and eroded bone surfaces, and the degree of marrow fibrosis were greater in the poor-response group than in the good-response group (P = 0.03, P = 0.04, P = 0.009, and P = 0.009, respectively). In patients with uremia, the dose of erythropoietin needed to achieve an adequate hematocrit response may depend on the severity of secondary hyperparathyroidism and the extent of bone marrow fibrosis.
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                Author and article information

                Journal
                Journal ID (publisher-id): AJN
                Journal ID (nlm-ta): Am J Nephrol
                Journal ID (doi): 10.1159/issn.0250-8095
                Title: American Journal of Nephrology
                Publisher: S. Karger AG
                ISSN (Print): 0250-8095
                ISSN (Electronic): 1421-9670
                Publication date Subscription-year: 2009
                Publication date (Print): April 2009
                Publication date (Electronic): 31 October 2008
                Volume: 29
                Issue: 5
                Pages: 392-397
                Affiliations
                Departments of aInternal Medicine, bIntegrated Diagnostics & Therapeutics, National Taiwan University Hospital, College of Medicine, National Taiwan University, and cInternal Medicine, Far-Eastern Memorial Hospital, Pan-Chiao, Taipei, Taiwan
                Article
                Publisher ID: 169658 Other ID: Am J Nephrol 2009;29:392–397
                DOI: 10.1159/000169658
                PubMed ID: 18974640
                SO-VID: 613f25aa-73e6-457d-ad5b-870be792da57
                Copyright © © 2008 S. Karger AG, Basel
                License:

                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.

                History
                Date received : 24 May 2008
                Date accepted : 03 September 2008
                Page count
                Tables: 4, References: 31, Pages: 6
                Categories
                Subject: Original Report: Patient-Oriented, Translational Research

                ScienceOpen disciplines: Cardiovascular Medicine,Nephrology
                Keywords: Inflammation,Dialysis,Statins,Erythropoietin-stimulating agent
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine, Nephrology
                Keywords: Inflammation, Dialysis, Statins, Erythropoietin-stimulating agent

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