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      Pathophysiology of Cyclosporine-Induced Nephrotoxicity in Humans: A Role for Nitric Oxide?

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          Abstract

          Background: The causes for the nephrotoxicity of cyclosporine A (CsA) have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed. Methods: We studied prostaglandin metabolites, endothelin and nitric oxide in kidney transplant patients receiving their first CsA dose. Prostaglandin metabolites in the urine and endothelin and nitric oxide (NO<sub>2</sub>/NO<sub>3</sub>) in urine and plasma were measured in 14 patients before and 3 and 6 h after oral ingestion of CsA (10 mg/kg b.w.). Clearances for inulin and p-aminohippuric acid (PAH) were measured before and in two separate 3-hour periods after CsA. Blood pressure, heart rate, and CsA blood levels were also determined. Results: Clearances of inulin and PAH decreased progressively after CsA dosage while renal vascular resistance increased. Nitric oxide plasma levels decreased in nearly all patients from 21.0 ± 2.8 to 19.1 ± 2.6 (p = 0.003) and then rose slightly to 19.5 ± 2.5 µmol/l (p = 0.1) 3 and 6 h after CsA ingestion, respectively. Urinary excretion of NO<sub>2</sub>/NO<sub>3</sub> decreased nonsignificantly from 269 ± 38.8 to 259 ± 27.7 and 254 ± 41.6 µmol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E<sub>2</sub> and 6-keto-prostaglandin F<sub>1α</sub> excretion rate declined significantly [from 1,187 ± 254 to 1,186 ± 351 and 730 ± 148 pg/min (p = 0.27 and 0.02) and from 697 ± 115 to 645 ± 134 and 508 ± 58.2 pg/min (p = 0.34 and 0.05)]. Urinary thromboxane B<sub>2</sub> and plasma and urinary endothelin first increased and then decreased nonsignificantly. Mean arterial pressure rose from 107 ± 2.5 to 110 ± 2.6 and 114 ± 3.4 mm Hg (p = 0.1 and 0.05). Conclusion: The pathophysiology of CsA-induced acute renal vasoconstriction involves several different mechanisms including a decrease of the vasodilating prostaglandins E<sub>2</sub> and 6-keto-prostaglandin F<sub>1α</sub> and possibly nitric oxide.

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          Author and article information

          Journal
          KBR
          Kidney Blood Press Res
          10.1159/issn.1420-4096
          Kidney and Blood Pressure Research
          S. Karger AG
          1420-4096
          1423-0143
          2001
          2001
          29 June 2001
          : 24
          : 2
          : 111-115
          Affiliations
          aFunktionsbereich Nephrologie, Medizinische Klinik IV und bKlinik für Urologie, Klinikum der J.W.-Goethe-Universität, Frankfurt am Main, Deutschland
          Article
          54216 Kidney Blood Press Res 2001;24:111–115
          10.1159/000054216
          11435743
          © 2001 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: 4, Tables: 2, References: 19, Pages: 5
          Product
          Self URI (application/pdf): https://www.karger.com/Article/Pdf/54216
          Categories
          Original Paper

          Cardiovascular Medicine, Nephrology

          Nephrotoxicity, Cyclosporine, Prostaglandins, Nitric oxide

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