Dialysis-Related Beta-2m Amyloidosis

Updated: Feb 03, 2017
  • Author: Anita Basu, MD, FACP; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Practice Essentials

Beta-2 ̶ microglobulin (beta-2m) amyloidosis is a disabling condition that affects patients undergoing long-term hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). [1, 2, 3] Case reports involving patients with near ̶ end-stage renal disease also exist. The condition does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant. Beta-2m amyloidosis evolves predictably over time and is rare in the first few years of HD. (See Etiology.)

Beta-2m is a major constituent of amyloid fibrils. [4] It has been shown that, through accumulation, it invades synovial membranes and osteoarticular sites. As a result, it causes destructive osteoarthropathies, such as carpal tunnel syndrome, flexor tenosynovitis, subchondral bone cysts, and erosions, as well as pathologic fractures. (See Etiology, Prognosis, and Presentation.)

Visceral involvement has been found in different organs, such as the gastrointestinal (GI) tract, heart, and tongue, but overt manifestations are rare. (See Presentation and Workup. The most severe complication involves beta-2m amyloid deposits destroying paravertebral ligaments and intervertebral discs, which can result in paraplegia. Cardiac involvement, with subsequent fatal arrhythmias, and massive GI bleeding have been described.

Symptomatic relief in patients with beta-2m amyloidosis can be provided with analgesic and anti-inflammatory medication, physical and occupational therapy, and surgical procedures. Renal transplantation is the treatment of choice. See Treatment.

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Etiology

Beta-2m is a glycosylated polypeptide with a molecular weight of 11,800 dalton. It makes up the beta chain of the human leukocyte antigen (HLA) class I molecule and has the prominent beta-pleated structure that is characteristic of amyloid fibrils.

Beta-2m is present on the surface of most nucleated cells and in most biologic fluids, including urine and synovial fluid. It circulates as an unbound monomer distributed in the extracellular space and polymerizes to form amyloid deposits in a variety of tissues. Two or 3 conformational isomers of beta-2m are recognized in human serum by capillary electrophoresis. [5]

In the normally functioning kidney, beta-2m is cleared by glomerular filtration and is catabolized in the proximal tubules. Reference range serum levels are 1.5-3 mg/L. In renal failure, impaired renal catabolism causes an increase in synthesis and release of beta-2m, and levels can rise 10- to 60-fold. Retention and accumulation of this type of amyloid protein is presumed to be the main pathogenic process underlying beta-2m amyloidosis.

There is also some suggestion that the dialysis process itself may stimulate beta-2m synthesis, by activation of complements and cytokine production. However, it is unlikely that this is a significant mechanism of dialysis-related amyloidosis (DRA), since the disease is also seen in patients on CAPD and people who have never been on dialysis.

Role of dialysis in amyloidogenesis

Retention of amyloidogenic protein remains a key factor in patients on dialysis. Several factors affecting retention have been implicated, including the following:

  • Type of dialysis membrane
  • Prolonged uremic state and/or decreased diuresis
  • Elevated levels of cytokines
  • Advanced glycation end products
  • Dialysate

Type of dialysis membrane

The healthy kidney can eliminate endogenous end products of metabolism, as well as exogenous toxins that are both large ̶ and small ̶ molecular weight substances. Cuprophan and cellulose acetate membranes previously used in conventional HD have small pores and cannot clear substances with molecular weights higher than 200 dalton. This makes them impermeable to beta-2m, elevating the protein’s serum levels. The newer cellulose triacetate dialyzers and the high-flux synthetic dialyzers remove molecules with a higher molecular weight and do a better job of removing beta-2m.

High cut-off, high-flux dialysis and online hemodiafiltration have been shown to be superior to previously used HD membranes in the removal of beta-2m, possibly decreasing beta-2 amyloidosis.

Beta-2m amyloidosis has also been described in patients receiving long-term CAPD, despite the permeability characteristics of the peritoneal membrane. Clearance of middle molecules is better, however, making CAPD a more biocompatible mode of treatment.

Nonetheless, data are conflicting. Some report the prevalence of beta-2m amyloidosis in patients on long-term CAPD as comparable to the prevalence in patients on HD. Other data show that plasma levels of beta-2m are lower in patients on CAPD, suggesting that accumulation of amyloid may occur more slowly. Some of this may also be related to residual renal function. Results of long-term studies are needed.

Prolonged uremic state and/or decreased diuresis

Membranes with poor biocompatibility cannot completely explain increases in beta-2m, because several reports note individuals who were treated exclusively by CAPD. Cases have also been described in patients with chronic renal failure who have not yet started dialysis. Inadequate diuresis and prolonged uremia are suggested contributing factors.

Elevated levels of cytokines

Dialysis is an inflammatory stimulus, inducing cytokine production and complement activation. The released cytokines, including interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6), are thought to stimulate the synthesis and release of beta-2m by macrophages and/or augment the expression of HLA class I antigens, increasing beta-2m expression.

Advanced glycation end products

Following the identification of advanced glycation end products (AGEs) in beta-2m amyloid deposits, the role of AGE has been the focus of much research. [6]

AGEs make up a heterogeneous group of compounds formed by nonenzymatic glycation and oxidative reactions between reducing sugars, lipids, and protein amino groups.

HD and peritoneal dialysis are ineffective in removing these low–molecular weight compounds from circulation.

As AGE-modified beta-2m accumulates, chemotaxis is enhanced, stimulating macrophages to release proinflammatory cytokines, as well as interfering with collagen synthesis. It has been suggested that the interaction of AGE-modified beta-2m with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of DRA, is mediated by the receptor for AGEs, or RAGE.

RAGEs are central binding sites for AGEs formed in vivo. [7] AGE beta-2m/MP/RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of patients on long-term HD. This inflammatory response may ultimately lead to bone and joint destruction.

Oxidation of beta-2m may enhance amyloid deposition. Studies suggest that increased oxidative stress during HD and exposure of beta-2m to hydroxyl radicals stimulate the autoxidation of unstable molecules, leading to augmented AGE production.

Dialysate

Acetate and/or bacterial lipopolysaccharide (endotoxin) may enter the blood via the dialyzer and stimulate the release of cytokines, inducing beta-2m production.

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Epidemiology

The incidence of DRA in the United States is not known; however, past studies have suggested an incidence of greater than 95% in patients who have been on dialysis for more than 15 years.

Some European studies have suggested that DRA can be seen in as many as 20% of patients after 2-4 years of HD and in 100% after 13 years of HD. Again, however, the overall incidence and prevalence of beta-2m amyloidosis are not clear. Moreover, most studies have focused on HD-associated amyloidosis and were performed before high-flux dialyzer use became commonplace.

There is some mention in the literature that the incidence and prevalence of beta-2m amyloidosis are less in CAPD than in HD (because of residual renal function). Other studies, however, suggest that there is no significant difference in incidence or prevalence. [8]

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Prognosis

The prognosis of beta-2m amyloidosis depends on the duration of dialysis, the age of the patient, the age of the patient at the start of dialysis, and the type of dialysis membrane that is being used. Ultimately, residual renal function is probably the best determinant of beta-2m levels in HD patients and may supersede enhanced convective clearance by hemodiafiltration. [9]

Morbidity and mortality

Patients receiving long-term dialysis can experience disabling musculoskeletal complications. [10] For individuals who are able to undergo renal transplantation, progression of the disease can be halted, but regression is unlikely. Rarely, submucosal bowel deposits have resulted in massive GI bleeding.

Case reports also exist of severe pulmonary hypertension and heart failure due to beta-2m amyloid deposits in the interstitium and/or vasculature of the cardiovascular system.

Studies in Japan have suggested that most patients with carpal tunnel syndrome associated with beta-2m amyloid deposits have undergone HD for 10 years or more. In one study, up to 50% of patients developed this complication after 20 years, and the percentage was even higher after 25 years. [11]

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