From the Guidelines
Dialysis-related amyloidosis (A2M) is a serious complication affecting patients with end-stage renal disease, characterized by amyloid deposits with 2-microglobulin fibrils, and can cause significant morbidity, particularly joint pain and immobility, as reported in the K/DOQI clinical practice guidelines 1. The clinical manifestations of A2M include:
- Carpal tunnel syndrome
- Spondyloarthropathies
- Hemarthrosis
- Joint pain and immobility These symptoms can appear over the course of years, between 2 and 10 years after the start of dialysis in the majority of patients, with 90% of patients having pathological evidence of A2M at 5 years 1. The pathophysiology of the disease is not clear, but most experts agree that the accumulation of 2-microglobulin over time is important, with serum levels in dialysis patients being 15 to 30 times greater than normal 1. The diagnosis of A2M is particularly difficult to diagnose clinically due to nonspecific symptoms and the possibility of patients having the disease pathologically without manifesting clinical symptoms 1. Given the potential for significant morbidity, it is essential to monitor patients with end-stage renal disease for signs and symptoms of A2M and to consider the potential benefits and risks of different dialysis modalities, such as hemodialysis and peritoneal dialysis, in the context of A2M risk 1.
From the Research
Alpha-2 Macroglobulin (A2M) Overview
- A2M is an abundant plasma protein with a structure and function similar to alpha-macroglobulins 2
- It is also produced in the brain, where it binds multiple extracellular ligands and is internalized by neurons and astrocytes 2
- A2M has been localized to diffuse amyloid plaques in the brain of Alzheimer's disease (AD) patients and binds soluble beta-amyloid, mediating its degradation 2
Association with Alzheimer's Disease
- Genetic evidence suggests that A2M is one of the two confirmed late-onset AD genes 2
- DNA polymorphisms in the A2M gene associated with AD result in significantly increased accumulation of amyloid plaques in AD brains 2, 3
- Inheritance of a deletion in the A2M gene confers increased risk for AD 3
- A2M concentration in blood is significantly associated with cerebrospinal fluid markers of neuronal injury in preclinical AD 4
Functions and Regulation
- A2M is a broad-spectrum protease inhibitor that can stabilize and facilitate the clearance of the Alzheimer's disease-associated amyloid beta peptide 5
- A2M can influence the signaling of cytokines and growth factors, including neurotrophins 5
- The functions of A2M are uniquely regulated by hypochlorite, an oxidant generated during inflammation 5
- A2M also has roles in switching proteolysis towards small substrates, facilitating cell migration, and binding cytokines, growth factors, and damaged extracellular proteins 6