Clinical study

Dialysis arthropathy: Outcome after renal transplantation

β₂-Microglobulin-related (Aβ₂M) amyloidosis is a serious complication in patients on long-term dialysis, and partial unfolding of β₂-microglobulin (β₂-m) is believed to be prerequisite to its assembly into Aβ₂M amyloid fibrils. Many kinds of amyloid-associated molecules (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of Aβ₂M amyloidosis. The formation of Aβ₂M amyloid fibrils in vitro was first observed at low pH (2.0–3.0). Very recently, low concentrations of 2,2,2-trifluoroethanol (TFE) and the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, have been reported to cause the extension of Aβ₂M amyloid fibrils at a neutral pH, inducing partial unfolding of β₂-m and stabilization of the fibrils. Moreover, apoE, GAGs and PGs were found to stabilize Aβ₂M amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Some GAGs, especially heparin enhanced the fibril extension in the presence of TFE at a neutral pH. Some PGs, especially biglycan also induced the polymerization of acid-denatured β₂-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of β₂-m and amyloid fibrils will have significant effects on the deposition of Aβ₂M amyloid fibrils.

Dialysis-related amyloidosis (DRA) is a frequent and serious complication in patients on long-term dialysis. The amyloid has a marked affinity for joint tissues, and carpal tunnel syndrome, polyarthralgia, destructive spondyloarthropathy, and bone cysts are the major clinical manifestations of DRA. β₂-Microglobulin (β₂-m) was identified as the major protein constituent of the amyloid fibrils. Risk factors for the development of DRA include age, duration of dialysis treatment, use of low-flux dialysis membrane, use of low purity dialysate, monocyte chemoattractant protein-1 GG genotype, and apolipoprotein E4 allele, although the retention of β₂-m in the plasma appears to be prerequisite. Clinical therapeutic strategies for DRA include dialysis, medical or surgical therapy, and renal transplantation. Preventive measures have attempted to remove β₂-m from the serum by using high-flux membranes and a β₂-m adsorption column in hemodialysis. Renal transplantation is a radical approach to treating the arthralgias attributed to the amyloid deposits while the regression of dialysi-related amyloid deposits is not identified after successful renal transplantation in many studies. It is necessary to elucidate the pathogenesis of DRA and to establish more effective prevention and therapy in the future.

Beta-2 microglobulin is the most widely studied low-molecular-weight protein in end-stage renal disease. It is known to cause dialysis-related amyloidosis (DRA), by virtue of its retention when renal function fails, its deposition in tissues, its aggregation into fibrils, and its ability to become glycosylated. The onset of DRA may be protracted by the use of noncellulosic membranes, especially when high-volume hemodiafiltration is used in the treatment of renal failure. Adsorptive methods have been developed to improve the removal of beta-2 microglobulin. There seems to be a relative risk reduction in mortality when patients are treated with dialysis membranes that have a higher clearance of beta-2 microglobulin.

β₂-Microglobulin–derived amyloidosis: An update. The present review attempts to summarize recent developments in the field of β₂-microglobulin-derived amyloidosis (Aβ₂m amyloidosis) in patients on chronic dialysis therapy. A key factor in the pathogenesis is the uremic retention of the precursor molecule, β₂-microglobulin (β₂m). However, secondary modifications of the molecule such as limited proteolysis, conformational changes, and the formation of advanced glycation and products have also been described. Finally, in order to explain the striking predilection of the disease for synovial and periarticular structures, a role of local predisposing factors within the synovial membrane (for example, of the particular constituents of the extracellular matrix) must also be postulated. With respect to clinical symptomatology, recent data have confirmed that clinically manifest signs of the amyloidosis represent only the tip of the iceberg, since histologically amyloid deposition is much more widespread. Noninvasive diagnosing of the disease has been advanced by technical changes of the β₂m scintigraphy. Finally, there is accumulating evidence that prevention of the disease not only includes the usage of high-flux synthetic membranes for hemodialysis or hemodiafiltration, but that other factors contribute to the clinical manifestations of amyloidosis such as the dialysate composition and its microbacteriological quality. Such factors, which have changed over the last years as part of general improvements in dialysis care, may explain why the prevalence of the amyloidosis appears to decrease.