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      Evidence of Altered Homocysteine Metabolism in Chronic Renal Failure

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          Abstract

          The fasting serum concentrations of total homocysteine and metabolites of transsulfuration (cystathionine, cysteine, methylmalonic acid, 2-methylcitric acid) and remethylation (methionine) were determined by gas chromatography-mass spectrometry in 40 nondialyzed patients with chronic renal disease and in 50 patients with end-stage renal disease requiring chronic maintenance hemodialysis. The nondialyzed patients and 28 of the dialysis patients did not receive additional vitamin supplementations. Twenty-two of the dialysis patients received daily oral vitamin preparations containing 10 mg pyridoxine (vitamin B<sub>6</sub>), 6 µg cyanocobalamin (vitamin B<sub>12</sub>), and 1 mg folic acid. In the nondialyzed patients, linear regression analysis showed positive correlations between serum concentrations of creatinine and total homocysteine (r = 0.68, p < 0.0001), cystathionine (r = 0.73, p < 0.0001), methylmalonic acid (r = 0.77, p < 0.0001), and 2-methylcitric acid (r = 0.81, p < 0.0001). Serum homocysteine was positively correlated with serum concentrations of cystathionine (r = 0.59, p < 0.0001), cysteine (r = 0.69, p = 0.004), methylmalonic acid (r = 0.64, p = 0.0001), and 2-methylcitric acid (r = 0.64, p < 0.0001). There was no significant correlation between serum concentrations of homocysteine and methionine (r = –0.14, p = 0.63). In the hemodialysis patients receiving oral vitamin supplementation, serum homocysteine and cystathionine concentrations were significantly lower than in hemodialysis patients not receiving vitamins (homocysteine 21.8 ± 1.1 vs. 33.2 ± 3.7 µmol/l, p = 0.0004; cystathionine 2,075.9 ± 387.1 vs. 3,171.3 ± 680.2 nmol/l, p = 0.02; mean ± SEM). In summary, our results show increased intermediate products of the transsulfuration pathway, but no increase in remethylation of homocysteine in chronic renal disease, including end-stage renal disease requiring chronic maintenance dialysis.

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          Most cited references 4

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          Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies.

          Patients with cobalamin (vitamin B12) deficiency usually lack many of the classic features of severe megaloblastic anemia; because of the low diagnostic specificity of decreased serum cobalamin levels, demonstrating the deficiency unequivocally is often difficult. We examined the sensitivity of measuring serum concentrations of methylmalonic acid and total homocysteine for diagnosing patients with clear-cut cobalamin deficiency and compared the results with those of patients with clear-cut folate deficiency. Serum metabolites were measured for all patients seen from 1982 to 1989 at two university hospitals who met the criteria for cobalamin and folate deficiency states and for such patients seen from 1968 to 1981 from whom stored sera were available. In all, 406 patients had 434 episodes of cobalamin deficiency and 119 patients had 123 episodes of folate deficiency. Criteria for deficiency states included serum vitamin levels, hematologic and neurologic findings, and responses to therapy. Responses were documented in 97% of cobalamin-deficient patients and 76% of folate-deficient patients. Metabolite levels were measured by modified techniques using capillary-gas chromatography and mass spectrometry. Most of the cobalamin-deficient patients had underlying pernicious anemia; two thirds were blacks or Latinos. Hematocrits were normal in 28% and mean cell volumes in 17%. Of the 434 episodes of cobalamin deficiency, 98.4% of serum methylmalonic acid levels and 95.9% of serum homocysteine levels were elevated (greater than 3 standard deviations above the mean in normal subjects). Only one patient had normal levels of both metabolites. Serum homocysteine levels were increased in 91% of the 123 episodes of folate deficiency. Methylmalonic acid was elevated in 12.2% of the folate-deficient patients; in all but one, the elevation was attributable to renal insufficiency or hypovolemia. For the cobalamin-deficient patients, measuring serum metabolite concentrations proved to be a highly sensitive test of deficiency. We conclude that normal levels of both methylmalonic acid and total homocysteine rule out clinically significant cobalamin deficiency with virtual certainty.
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            Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men

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              Renal uptake and excretion of homocysteine in rats with acute hyperhomocysteinemia.

              Elevated plasma total homocysteine, an independent risk factor for cardiovascular disease, is commonly observed in renal patients. We have previously shown that the kidney is a major site for the removal of plasma homocysteine in the rat. The present investigation was performed to further characterize the capacity of the kidney to handle acute elevations in plasma homocysteine concentrations. Acute hyperhomocysteinemic conditions (4- to 7-fold > controls) in rats were produced by either a primed-continuous infusion of L-homocysteine or exposure to 80:20% nitrous oxide:oxygen, which results in the inhibition of methionine synthase. At physiological homocysteine concentrations, approximately 15% of the arterial plasma homocysteine was removed on passage through the kidney. Renal homocysteine uptake was approximately 85% of the filtered load. The urinary excretion of homocysteine was negligible (<2%). During acute hyperhomocysteinemia produced by the infusion of L-homocysteine, renal homocysteine uptake was increased fourfold and was equivalent to 50% of the infused dose, while urinary excretion remained negligible. Renal homocysteine uptake during nitrous oxide-induced hyperhomocysteinemia increased threefold, with urinary excretion remaining negligible. These results provide strong evidence that the kidney has a significant capacity for metabolizing acute elevations in plasma homocysteine, and support a very limited role for the re-methylation pathway in renal homocysteine metabolism.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                1999
                December 1999
                30 November 1999
                : 83
                : 4
                : 314-322
                Affiliations
                aMedizinische Klinik I, Marienhospital Herne, University of Bochum, bSeveri Med GmbH, Münster, cKfH Dialysis Center, Münster, Germany
                Article
                45423 Nephron 1999;83:314–322
                10.1159/000045423
                10575293
                © 1999 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: 7, Tables: 4, References: 47, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45423
                Categories
                Original Paper

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