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      Renal Transplantation in Patients with Fabry Disease

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          Abstract

          Anderson-Fabry disease (AFd) is a rare X-linked disorder characterized by deficiency of α-galactosidase A that leads to systemic accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and visceral tissues, including the kidney. End-stage renal failure is a common manifestation in hemizygous males that often occurs by the third to fourth decade of life. Usually transplanted patients exhibit improvement in clinical symptoms of the disease, probably related to the production of α-galactosidase A from the grafted kidney, but mainly related to the increase in Gb3 clearance by the functioning kidney, and increased survival of red cells due to the correction of the uremic status with an evident decrease in the production of Gb3 depending from hemolysis. Several Fabry patients with successful kidney graft survived for 10–15 years and died for cardiovascular complications related to the metabolic disease. The loss of grafted kidney is due to rejection, thrombosis or sepsis. An important issue considering renal transplantation in AFd is the recurrence of the disease in the kidney graft; however, no evidence regarding this possibility has occurred up to now. We report herein the ultrastructural study of the urinary sediment of a 35-year-old male Fabry patient with a severe clinical form of the disease with progression to ESRF at age 29, and submitted to renal transplantation at 33 years. Ultrastructural findings of the urinary sediment documented several cells, probably tubular epithelial cells, with typical accumulation of myelinic bodies resulting from intracellular storage of neutral glycosphingolipids. This morphological evidence arises the problem of the possible recurrence of AFd in the kidney graft in patients with severe phenotype of the metabolic disease.

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          Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.

          Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb(3); also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified alpha-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered alpha-gal A, (ii) to assess the pharmacokinetics of i.v.-administered alpha-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb(3). alpha-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified alpha-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of alpha-gal A, nine of the 10 patients had significantly reduced Gb(3) levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of alpha-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb(3) burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.
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            Renal transplantation in congenital and metabolic diseases. A report from the ASC/NIH renal transplant registry

            (1975)
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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
              June 2002
              03 June 2002
              : 91
              : 2
              : 348-351
              Affiliations
              aUO Nefrologia e Dialisi, bAnatomia Patologica, Vimercate, cAnatomia Patologica, Istituto di Scienze Biomediche, Ospedale Sacco, Università di Milano, dDipartimento di Medicina Interna, Università di Pisa, and eIstituto Neurologico C. Besta, Milano, Italia
              Article
              58419 Nephron 2002;91:348–351
              10.1159/000058419
              12053080
              © 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, References: 18, Pages: 4
              Product
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/58419
              Categories
              Short Communication

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