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      Leptin and Serum Erythropoietin in Hemodialyzed and Peritoneally Dialyzed Uremic Patients during rHuEPO Therapy

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          Abstract

          Leptin produced by fat cell has an unanticipated role in hematopoietic system development. We examined the relationships between leptinemia and requirements of erythropoietin (Epo), endogenous Epo levels as well as markers of inflammation: C-reactive protein, tumor necrosis factor α (TNFα) and interleukin-1 (IL-1) in rHuEPO-treated patients maintained on chronic hemodialyses or peritoneal dialyses. The studies were performed on 51 chronically hemodialyzed patients, 20 of them did not receive rHuEPO, 31 subjects received rHuEPO, and 22 patients on CAPD, 13 of them did not receive rHuEPO, 9 subjects were given rHuEPO. In hemodialyzed patients (Epo and Non-Epo group) leptin levels were significantly higher when compared to CAPD patients (Epo and Non-Epo group, respectively). Leptin in peritoneal fluid was significantly higher in the Non-Epo group. In ultrafiltrate, leptin levels were below the detection limit of 0.5 ng/ml. Epo levels in the HD + Epo group were significantly lower than in the HD + Non-Epo group and CAPD + Epo group. TNFα and IL-1 concentrations were significantly lower in both groups of CAPD patients when compared to respective HD groups. Treatment with rHuEPO resulted in nonsignificant decline in serum leptin (p = 0.07 in HD and p = 0.08 in CAPD) and significant leptin loss in peritoneal fluid. It may be of clinical relevance in dialyzed patients. In both groups of Epo-treated patients, positive physiological correlation between leptinemia and BMI disappeared. Leptin levels do not correlate with rHuEPO requirements and serum Epo in dialyzed patients.

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          Most cited references 5

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          Design and synthesis of multi-haem proteins.

          A water-soluble, 62-residue, di-alpha-helical peptide has been synthesized which accommodates two bis-histidyl haem groups. The peptide assembles into a four-helix dimer with 2-fold symmetry and four parallel haems that closely resemble native haems in their spectral and electrochemical properties, including haem-haem redox interaction. This protein is an essential intermediate in the synthesis of molecular 'maquettes', a novel class of simplified versions of the metalloproteins involved in redox catalysis and in energy conversion in respiratory and photosynthetic electron transfer.
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            A role for leptin and its cognate receptor in hematopoiesis.

            Hematopoiesis entails the production of multiple blood cell lineages throughout the lifespan of the organism. This is accomplished by the regulated expansion and differentiation of hematopoietic precursors that originate from self-renewing hematopoietic stem cells. Studies of lineage commitment and proliferation have shown that the cytokine family of growth factors plays an important role in hematopoietic differentiation. However, in hematopoiesis, as in most self-renewing biological systems, the molecules that regulate the stem cells directly remain largely unknown. In this study, we have undertaken a search for novel cytokines that may influence the fate of hematopoietic stem cells. We have cloned three splice variants of a novel cytokine receptor from human hematopoietic stem cells expressing the CD34 antigen, one of which is identical to the leptin receptor. Expression analysis revealed that the leptin receptor is expressed in both human and murine hematopoietic stem cell populations, and that leptin is expressed by hematopoietic stroma. We show that leptin provides a proliferative signal in hematopoietic cells. Importantly, we demonstrate that leptin provides a proliferative signal in BAF-3 cells and increases the proliferation of hematopoietic stem cell populations. The proliferative effects of leptin seem to be at the level of a multilineage progenitor, as shown by increased myelopoiesis, erythropoiesis and lymphopoiesis. Analysis of db/db mice, in which the leptin receptor is truncated, revealed that the steady-state levels of peripheral blood B cells and CD4-expressing T cells were dramatically reduced, demonstrating that the leptin pathway plays an essential role in lymphopoiesis. Colony assays performed using marrow from db/db and wild-type mice indicated that db/db marrow has a deficit in lymphopoietic progenitors; furthermore, db/db mice are unable to fully recover the lymphopoietic population following irradiation insult, and although the levels of peripheral blood erythrocytes are normal in db/db mice, spleen erythrocyte production is severely compromized. We have discovered that leptin and its cognate receptor constitute a novel hematopoietic pathway that is required for normal lymphopoiesis. This pathway seems to act at the level of the hematopoietic stem/progenitor cell, and may well also impact upon erythropoiesis, particularly in anemic states that may require output from the spleen. These findings offer a new perspective on the role of the fat cell in hematopoiesis.
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              Low leptin gene expression and hyperleptinemia in chronic renal failure.

              The ob gene product leptin is thought to be a key regulator of food intake and body weight. Patients having advanced chronic renal failure (CRF) have markedly higher serum leptin levels. It is not known whether the increase in leptin levels in CRF is caused by a decreased plasma clearance and/or increased production. In the present study serum leptin levels and glomerular filtration rate (GFR) were measured in 219 patients having various degrees of renal failure. In addition, serum leptin levels, C-reactive protein (CRP), body composition (by dual-energy x-ray absorptiometry) and ob gene expression (by in situ hybridization histochemistry) were determined in 15 patients with advanced CRF. Seven of the patients were re-evaluated following 12 months of peritoneal dialysis (PD) treatment. Serum leptin levels correlated negatively to GFR (r = -0.26; P 25 mg/liter than in 10 patients with CRP < 25 mg/liter. Following 12 months of PD, the amount of body fat increased by 30% while the ob gene expression remained unchanged. The present study shows a correlation between serum leptin levels and GFR, and our results suggest that elevated leptin levels, due to a decreased plasma clearance, down-regulate the expression of the ob gene. We also found that an ongoing inflammation stimulates ob gene expression in patients with CRF. Therefore, it is suggested that the hyperleptinemia induced feedback inhibition of ob gene expression is overcome by inflammatory cytokines.
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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
                2000
                June 2000
                30 June 2000
                : 20
                : 3
                : 180-186
                Affiliations
                Departments of aNephrology and Internal Medicine, and bGynecological Endocrinology, Białystok University School of Medicine, Białystok, Poland
                Article
                13581 Am J Nephrol 2000;20:180–186
                10.1159/000013581
                10878398
                © 2000 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: 1, References: 26, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/13581
                Categories
                Clinical Study

                Cardiovascular Medicine, Nephrology

                Erythropoietin, Cytokines, PTH, Hemodialysis, Peritoneal dialysis, Leptin

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