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Plasma Protein Aspartyl Damage Is Increased in Hemodialysis Patients: Studies on Causes and Consequences

Alessandra F. Perna^*,, Diego Ingrosso^,, Ersilia Satta^*,, Cinzia Lombardi^*,, Patrizia Galletti^,, Antimo D’Aniello and Natale G. De Santo^*,

*First Division of Nephrology, Department of Biochemistry and Biophysics "F. Cedrangolo," Second University of Naples, School of Medicine, Naples, Italy; Cardiovascular Research Center, School of Medicine, Second University of Naples, Naples, Italy; and the Zoological Station "Anton Dohrn," Naples, Italy

Correspondence to Dr. Alessandra F. Perna, First Division of Nephrology/Department of Pediatrics, Via Pansini 5, 80131 Napoli, Italy. Phone: +39-081-5666650; Fax: +39-081-5666655; E-mail: alessandra.perna{at}unina2.it

Plasma proteins in hemodialysis patients display a significant increase in deamidated/isomerized Asx (asparagine and aspartic acid) content, a marker of protein fatigue damage. This has been linked to the toxic effects of hyperhomocysteinemia in uremic erythrocytes; however, treatment aimed at abating homocysteine levels did not lead to significant reductions in plasma protein damage. The hypothesis that lack of reduction in protein damage could be due to protein increased intrinsic instability, as result of interference with the uremic milieu rather than to hyperhomocysteinemia, was put forward. The deamidated/isomerized Asx content of normal plasma incubated with several uremic toxins for 24 h, 72 h, and 7 d was measured, identifying a group of toxins that were able to elicit this kind of damage. Uremic toxins were also incubated with purified human albumin, and dose-response experiments with the two most toxic agents in terms of protein damage (guanidine and guanidinopropionic acid) were carried out. The effect of the hemodialysis procedure on protein damage was evaluated. For investigating also the consequences of these alterations, human albumin was treated in vitro to produce an increase in deamidated/isomerized Asx residues, and the effects of albumin deamidation on protein binding were evaluated. Among the uremic toxins that are able to elicit protein damage, guanidine produced a dose-dependent increase in protein damage. No difference was found after a hemodialysis session. Deamidated albumin shows normal binding capacity to warfarin, salicylic acid, or diazepam but reduced binding to homocysteine. In conclusion, uremic toxins, especially guanidine, display an ability to induce significant protein damage, which can in turn have functional consequences.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673