MOLECULAR VARIANTS OF BETA(2)-MICROGLOBULIN IN RENAL-INSUFFICIENCY

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(2)m) The mechanisms of beta(2)m 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(2)m, including proteolytic split products. beta(2)m isoforms of pI 5.7, 5.3 and 4.5-5.0 were isolated from urine and CAPD fluid. The pI 5.3 beta(2)m, 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(2)m 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(2)m of pI 5.0 showed identity with the corresponding region of pI 5.7 beta(2)m. Fragments recovered from CAPD fluid were similar to proteolytic fragments generated from pure pI 5.7 beta(2)m by incubation in mouse ascitic fluid at acidic pH. Furthermore, pure pI 5.7 beta(2)m was converted into more acidic forms of 12 kDa upon incubation in mouse ascitic fluid at acid pH. beta(2)m dimers found in serum may represent a precursor of amyloid fibrils.