Molecular variants of β2-microglobulin in renal insufficiency

Abstract

Many patients with renal insufficiency treated by dialysis for more than 10 years have tissue deposits of amyloid material containing polymerized beta 2-microglobulin (beta 2m). The mechanisms of beta 2m polymerization and degradation remain unknown. In biological fluids (serum and urine) from haemodialysis patients and in dialysis fluids from patients treated by chronic ambulatory peritoneal dialysis (CAPD), we have characterized different molecular forms of beta 2m, including proteolytic split products. beta 2m isoforms of pI 5.7, 5.3 and 4.5-5.0 were isolated from urine and CAPD fluid. The pI 5.3 beta 2m, but not the other forms, was recovered both as monomers and as dimers. Such dimers were also detected in serum from patients but not from healthy controls. pI 5.3 and 5.7 beta 2m isoforms were found to be nearly identical by mass spectrometry and by their amino acid sequences. The amino acid sequence of the 43 N-terminal amino acids of beta 2m of pI 5.0 showed identity with the corresponding region of pI 5.7 beta 2m. Fragments recovered from CAPD fluid were similar to proteolytic fragments generated from pure pI 5.7 beta 2m by incubation in mouse ascitic fluid at acidic pH. Furthermore, pure pI 5.7 beta 2m was converted into more acidic forms of 12 kDa upon incubation in mouse ascitic fluid at acid pH. beta 2m dimers found in serum may represent a precursor of amyloid fibrils.

Discovery and Validation of a Biomarker Model (PRESERVE) Predictive of Renal Outcomes After Liver Transplantation

“…Trefoil factor‐3 and thrombomodulin have been reported as sensitive markers of early and reversible renal injury . β‐2 microglobulin is the light chain of major histocompatibility complex expressed on all nucleated cells and, like α‐1 microglobulin and cystatin C, is filtered by the glomerulus and reabsorbed/catabolized by the proximal tubule . Similar to our findings, a recent nontransplant study found associations between β‐2 microglobulin, cystatin C, and future CKD, even in patients with baseline eGFR >60 mL/min/1.73 m 2 .…”

K3 Fragment of Amyloidogenic β2-Microglobulin Forms Ion Channels: Implication for Dialysis Related Amyloidosis

“…Apart from the large amount of β 2 m fibrils, amyloid plaques isolated from DRA patients contain proteolytic β 2 m fragments 5, 6, 11, 61–66. These fragments can act as seeds accelerating amyloid aggregation 11, 12, 14.…”

The Relationship between Pentosidine and Hemodialysis- Related Connective Tissue Disorders

“…Therefore, it is hypothesized that native β2m undergoes some modifications, becoming a modified β2m with possible more amyloidogenesis. Several novel β2ms have been found, one being acidic β2m [2, 3, 4, 5]. Among them, β2m modified with advanced glycation end products (AGEs) have been reported to be involved in the pathogenesis of DRA [6 , 7].…”