Effect of Dialysis Membrane and Patient's Age on Signs of Dialysis-Related Amyloidosis. The Working Party on Dialysis Amyloidosis

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest. (Int J Artif Organs 2001; 24: 695-725)

Uremic toxicity: present state of the art.

Serum amyloid A (SAA): an acute phase protein and apolipoprotein.

In beta(2)-microglobulin-related (Abeta2M) amyloidosis, partial unfolding of beta(2)-microglobulin (beta2-m) is believed to be prerequisite to its assembly into Abeta2M amyloid fibrils in vivo. Although low pH or 2,2,2-trifluoroethanol at a low concentration has been reported to induce partial unfolding of beta2-m and subsequent amyloid fibril formation in vitro, factors that induce them under near physiological conditions have not been determined. Using fluorescence spectroscopy with thioflavin T, circular dichroism spectroscopy, and electron microscopy, we here show that at low concentrations, sodium dodecyl sulfate (SDS) converts natively folded beta2-m monomers into partially folded, alpha-helix-containing conformers. Surprisingly, this results in the extension of Abeta2M amyloid fibrils at neutral pH, which could be explained basically by a first-order kinetic model. At low concentrations, SDS also stabilized the fibrils at neutral pH. These SDS effects were concentration-dependent and maximal at approximately 0.5 mM, around the critical micelle concentration of SDS (0.67 mM). As the concentration of SDS was increased above 1 mM, the alpha-helix content of beta2-m rose to approximately 10%, while the beta-sheet content decreased to approximately 20%, a change paralleled by a complete cessation of fibril extension and the destabilization of the fibrils. Detergents of other classes had no significant effect on the extension of fibrils. These findings are consistent with the hypothesis that in vivo, specific factors (e.g., phospholipids) that affect the conformation and stability of beta2-m and amyloid fibrils will have significant effects on the kinetics of Abeta2M fibril formation.

Low Concentrations of Sodium Dodecyl Sulfate Induce the Extension of β2-Microglobulin-Related Amyloid Fibrils at a Neutral pH†

In addition to being a marker of disease, the homogeneous immunoglobulins found in monoclonal plasma cell disorders may produce signs and symptoms related to the presence of increased amounts of a single protein with certain structural and functional characteristics Monoclonal immunoglobulin deposition disease of either the amyloid or nonamyloid types may occur in the course of clinical myeloma or be associated with a more limited monoclonal proliferative disorder similar to that previously characterized as monoclonal gammopathy of uncertain significance (MGUS) Their occurrence in the setting of a limited clonal expression converts the outcome of the process from benign to fatal due to the deposition of the clonal products in vital organs The tendency to deposit appears to be a property of the chemical structure of the Ig polypeptide involved and the way it is processed, either in the course of its synthesis and secretion or during its passage through blood vessels and tissue parenchyma

Mechanisms of Disease: Monoclonal Immunoglobulin Deposition: Amyloidosis, Light Chain Deposition Disease, and Light and Heavy Chain Deposition Disease

Significant amounts of glycosaminoglycans (GAGs) were found in amyloid fibril preparations. Using two-dimensional electrophoresis to fractionate GAG mixtures, we quantified and identified for the first time the GAGs of the fibrils from carpal synovium of patients with amyloid associated with chronic hemodialysis. The total GAG content was small, but the GAG distribution (high relative content of chondroitin sulfate and hyaluronic acid and lack of the other GAGs) was unique, unlike that for the other amyloid fibril preparations. The amyloid-rich heart, liver, and spleen tissues, as well as the fibrils isolated from these tissues of patients with systemic forms (primary amyloid and secondary amyloid) of amyloid disease, were also analyzed for GAGs. Fibrils from heart tissue of a patient with primary amyloidosis, now examined for the first time, contained four major GAGs (chondroitin sulfate, dermatan sulfate, hyaluronic acid, and heparan sulfate).

H. Ohishi

Papers

Glycosaminoglycans of the hemodialysis-associated carpal synovial amyloid and of amyloid-rich tissues and fibrils of heart, liver, and spleen.

Myocardial chondroitin sulfates D and E in a case of acute carbon monoxide poisoning.

The glycosaminoglycan composition of human tracheas and the changes observed during aging and in disease

The carbohydrate composition of human serum amyloid P component.

Glycosaminoglycan content in neonatal rat aortic smooth muscle cell cultures