Pathogenesis of dialysis-related amyloidosis

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beta2-Microglobulin is a major constituent of amyloid fibrils in dialysis-related amyloidosis (DRA), a serious complication leading to bone and joint destruction in long-term haemodialysis patients. However, the molecular pathogenesis of this complication remains unknown. Intact beta2-microglobulin seems an unlikely contributor to the pathogenesis, because no difference in the plasma levels of intact beta2-microglobulin has yet been found between haemodialysis patients with and without this complication. Some investigators have therefore focused on the modification of this molecule. Our studies have revealed a new modification of beta2-microglobulin in amyloid fibrils-the advanced glycation end-products (AGEs) formed by a non-enzymatic reaction between sugar aldose and protein. Our further study has suggested that the interaction of AGE-midified beta2-microglobulin in long-lived amyloid fibrils with monocytes/macrophages gives a plausible explanation for part of the mechanism of bone and joint destruction in DRA.The cause of long-term complications of uraemia are yet to be fully elucidated. It has recently been demonstrated that renal failure is associated with a dramatic elevation of AGEs. A mild rise of AGEs is associated with normal ageing. In uremia, the rise of AGEs is even more marked than in diabetics and is associated with a variety of tissue disorders. AGE accumulation in uraemia does not result from hyperglycemia. Identification of its cause as well as of the involved precursors should contribute to the understanding of uraemic toxcity and open new therapeutic approaches. In course of our recent studies, we propose the hypothesis that AGE generation is enhanced an increased oxidative stress associated with uraemia. Under these conditions, a variety of compounds, both related and unrelated to glucose, may contribute to the advanced glycoxidation of proteins.