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Clinical Chemistry and Laboratory Medicine (CCLM)

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Volume 43, Issue 10

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Hyperhomocysteinemia and macromolecule modifications in uremic patients

Alessandra F. Perna
  • First Division of Nephrology, School of Medicine, Second University of Naples, Naples, Italy and Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy
  • Other articles by this author:
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/ Rosanna Capasso
  • First Division of Nephrology, School of Medicine, Second University of Naples, Naples, Italy, Department of Biochemistry and Biophysics “F. Cedrangolo”, School of Medicine, Second University of Naples, Naples, Italy and Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy
  • Other articles by this author:
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/ Cinzia Lombardi
  • First Division of Nephrology, School of Medicine, Second University of Naples, Naples, Italy and Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy
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/ Filomena Acanfora
  • First Division of Nephrology, School of Medicine, Second University of Naples, Naples, Italy and Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy
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/ Ersilia Satta
  • First Division of Nephrology, School of Medicine, Second University of Naples, Naples, Italy and Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy
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/ Diego Ingrosso
  • Department of Biochemistry and Biophysics “F. Cedrangolo”, School of Medicine, Second University of Naples, Naples, Italy and Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy
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Published Online: 2011-09-21 | DOI: https://doi.org/10.1515/CCLM.2005.181

Abstract

Hyperhomocysteinemia is present in the majority of well-nourished chronic renal failure and uremic patients. Most observations reported in the literature come from studies carried out in end-stage renal disease patients treated with hemodialysis. The underlying mechanisms of the toxic effects of homocysteine in uremia related to cardiovascular disease and other disturbances are still under scrutiny. As a consequence, macromolecules (i.e., proteins and DNA) have been found to be altered to various extents. One of the mechanisms of homocysteine toxicity is related to the action of its metabolic precursor, S-adenosylhomocysteine, a powerful methyltransferase competitive inhibitor. Disruption of DNA methylation has been demonstrated to occur as a result of hyperhomocysteinemia, and/or is associated with vascular damage. DNA hypomethylation has been found in the mononuclear cell fraction of uremic patients with hyperhomocysteinemia. Proteins are also targets of homocysteine-dependent molecular damage. The formation of oxidative products with free cysteinyl residue thiol groups has been demonstrated to occur in blood. The latter also represents a mechanism for the transport of homocysteine in plasma. In addition, homocysteine thiolactone has been shown to react with free amino groups in proteins to form isopeptide bonds, in particular at the lysine residue level. Another type of isopeptide bond in proteins may result from the deamidation and isomerization of asparaginyl residues, yielding abnormal isoaspartyl residues, which have been demonstrated to be increased in uremic patients. Folate treatment exerts a partial, but significant, homocysteine-lowering effect in uremic patients and has been shown to improve the changes in macromolecules induced by high homocysteine levels. In conclusion, both DNA and proteins are structurally modified in uremia as a consequence of high homocysteine levels. The role of these macromolecule changes in inducing the clinical complications of hyperhomocysteinemia in these patients, although still conjectural in some respects, is at present sustained by several pieces of evidence.

Keywords: DNA methylation; hyperhomocysteinemia; isopeptide bonds; uremia

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About the article

Corresponding author: Alessandra F. Perna, MD, PhD, First Division of Nephrology, School of Medicine and Surgery, S.U.N., via Sergio Pansini 5, 80138 Naples, Italy Phone: +39-081-5666668, Fax: +39-081-5665836,


Published Online: 2011-09-21

Published in Print: 2005-10-01


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 43, Issue 10, Pages 1032–1038, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2005.181.

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