Pathogenesis of dialysis-related amyloidosis

β -微球蛋白是透析相关性淀粉样变性（DRA）中淀粉样蛋白原纤维的主要成分，这是长期血液透析患者导致骨和关节破坏的严重并发症。然而，这种并发症的分子发病机制尚不清楚。完整β -微球蛋白似乎不太可能是致病的原因，因为在有和没有这种并发症的血液透析患者之间，血浆中完整β -微球蛋白的水平尚未发现差异。因此，一些研究人员专注于对这种分子进行修饰。我们的研究揭示了淀粉样蛋白纤维中β 2微球蛋白的一种新修饰——糖醛糖和蛋白质之间的非酶反应形成的晚期糖基化终产物（AGEs）。我们进一步的研究表明，长寿命淀粉样蛋白原纤维中age修饰的β -微球蛋白与单核/巨噬细胞的相互作用可能解释了DRA中骨骼和关节破坏的部分机制。尿毒症长期并发症的原因尚未完全阐明。最近有研究表明，肾功能衰竭与AGEs的急剧升高有关。AGEs的轻微上升与正常衰老有关。在尿毒症中，AGEs的升高甚至比糖尿病患者更为明显，并且与多种组织紊乱有关。尿毒症中AGE的积累不是由高血糖引起的。确定其原因以及相关的前体应有助于了解尿毒症毒性和开辟新的治疗方法。在我们最近的研究过程中，我们提出了一个假设，即与尿毒症相关的氧化应激增加会促进AGE的产生。在这些条件下，各种化合物，包括与葡萄糖相关的和不相关的，都可能促进蛋白质的糖氧化。

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.