Dialysis-related amyloidosis: pathogenesis focusing on AGE modification.

Dialysis-related amyloidosis (DRA) is a serious complication in long-term dialysis patients, and presents with carpal tunnel syndrome, cystic bone lesions, destructive spondylarthropathy, diffuse arthritis and periarthritis, systemic organ involvement, and dialysis-related spinal canal stenosis (DSCS). Recently a new concept of DSCS has been proposed that includes both destructive spondylarthropathy and myeloradiculopathy induced by extradural thickness. beta(2)-microglobulin (beta(2)M) amyloid was demonstrated to be modified with advanced glycation end products (AGEs) such as imidazolone, N(epsilon)-(carboxymethyl)lysine (CML), and pentosidine. Imidazolone is a reaction product of arginine residue in proteins with 3-deoxyglucosone (3-DG), which is markedly accumulated in uremic serum. Imidazolone is generated under nonoxidative conditions, while CML and pentosidine are formed by oxidative processes. Immunoelectron microscopy demonstrated that AGEs were localized not only in dialysis amyloid but also in nonamyloid collagenous structures, supporting the hypothesis that AGE modification of collagen might have pathogenic relevance in the deposition of beta(2)M on collagen. Serum levels of AGEs are increased in uremic patients. The dimeric form of beta(2)M in the dialysate and urine of uremic patients is more susceptible to imidazolone modification as observed in dialysis amyloid. However, the major component of dialysis amyloid is a native form of beta(2)M, while AGE-modified beta(2)M and truncated beta(2)M are the minor components. Thus I propose that 3-DG and the other dicarbonyl compounds accumulating in uremic serum promote the modification of beta(2)M with AGEs mainly after deposition of beta(2)M as amyloid. For the prevention and treatment of DRA, beta(2)M should be efficiently eliminated from circulating blood by kidney transplantation, hemodialysis, or hemodiafiltration using high-flux membranes and an adsorbent (Lixelle) column.