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Clinical Chemistry 51: 1177-1184, 2005. First published May 12, 2005; 10.1373/clinchem.2005.049544
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Right arrow Proteomics and Protein Markers
(Clinical Chemistry. 2005;51:1177-1184.)
© 2005 American Association for Clinical Chemistry, Inc.

Proteomics and Protein Markers

Quantification of Cleaved ß2-Microglobulin in Serum from Patients Undergoing Chronic Hemodialysis

Dorthe B. Corlin1, Jette W. Sen1,2, Søren Ladefoged3, Grethe Bjerregaard Lund4, Mogens H. Nissen5 and Niels H.H. Heegaard1,a

1 Department of Autoimmunology, Statens Serum Institut, Copenhagen, Denmark.
Departments of2 Clinical Biochemistry and3 Nephrology, Rigshospitalet, Copenhagen, Denmark.
4 Dialysis Unit, Department of Medicine, Storstrømmens Sygehus Nykøbing F, Nykøbing, Denmark.
5 Institute of Medical Anatomy, University of Copenhagen, Copenhagen, Denmark.

aAddress correspondence to this author at:, Statens Serum Institut, Bldg. 81, Room 536, Artillerivej 5, DK-2300 Copenhagen S, Denmark. Fax 45-32683876; e-mail nhe{at}ssi.dk.

Background: Patients on chronic hemodialysis are prone to develop amyloid deposits of misfolded ß2-microglobulin (ß2M) in osteoarticular tissues. ß2M with various deletions/truncations and chemical modifications has been found together with structurally intact ß2M in extracts of ß2M amyloid fibrils. The state of the circulating population of ß2M molecules has not been characterized previously with high-resolution methods.

Methods: We used immunoaffinity–liquid chromatography–mass spectrometry analysis of serum samples to examine whether structurally modified ß2M is generated in the circulation. In addition, we developed an immunoassay for the quantification of a cleaved ß2M variant in biological fluids based on novel monoclonal antibodies and applied this assay to patient and control sera.

Results: A specific alteration compatible with the generation of lysine-58–cleaved and truncated ß2M ({Delta}K58-ß2M) was found in the sera of many (20%–40%) dialysis patients but not in control sera or sera from patients with cerebral amyloidosis (Alzheimer disease). Applied to patient sera, specific immunoassays revealed that dialysis, as expected, significantly lowered the total ß2M concentration, but the concentrations of {Delta}K58-ß2M remained unchanged after dialysis. The results also show that patients dialyzed with less biocompatible membranes have higher serum concentrations of cleaved ß2M (mean, 8.5, 1.8, and 0.7 mg/L in cuprophane membrane-dialyzed, polysulfone membrane-dialyzed, and control sera, respectively).

Conclusions: This study for the first time demonstrates and assigns the structure of a specific ß2M variant in sera from dialysis patients. Because this variant is conformationally unstable in vitro, it may be involved in in vivo amyloidogenesis.




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