eMedicine Specialties > Nephrology > The Kidney in Systemic Diseases

Amyloidosis, Beta2M (Dialysis-Related)

Author: Anita Basu, MD, Assistant Professor of Medicine, University of Mississippi School of Medicine; Staff Nephrologist, GV (Sonny) Montgomery Veterans Affairs Medical Center
Coauthor(s): Carol A Bogdan, MD, Consulting Staff, Coastal Cancer Center, Myrtle Beach, SC; Reynaldo Matute, MD, Clinical Assistant Professor, Department of Internal Medicine, Division of Nephrology, New York Medical College
Contributor Information and Disclosures

Updated: Feb 22, 2008

Introduction

Background

Beta-2-microglobulin amyloidosis is a disabling condition that affects patients undergoing long-term hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Case reports involving patients with near end-stage renal disease also exist. It does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant.

Beta-2-microglobulin is a major constituent of amyloid fibrils. Its accumulation has been shown to invade synovial membranes and osteoarticular sites, causing destructive osteoarthropathies, such as carpal tunnel syndrome, flexor tenosynovitis, subchondral bone cysts, and erosions, as well as pathologic fractures.

Visceral involvement has been found in different organs, such as the gastrointestinal tract, heart, and tongue, but overt manifestations are rare.

Pathophysiology

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

In the normally functioning kidney, beta-2-microglobulin 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 a release of beta-2-microglobulin, and levels can increase 10- to 60-fold. Retention and accumulation of this type of amyloid protein is presumed to be the main pathogenic process underlying beta-2-microglobulin amyloidosis. There is also some suggestion that the dialysis process itself may stimulate beta-2-microglobulin 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.

Frequency

United States

The incidence of DRA in the United States is not known; however, past studies have suggested an incidence of greater than 95% in patients 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. However, again, the overall incidence and prevalence of beta-2-microglobulin amyloidosis are not clear. 

Most studies have focused on HD-associated amyloidosis and have been done before high-flux dialyzer use became commonplace.

There is some mention in the literature that the incidence and the prevalence in CAPD are less than in HD (because of residual renal function), while other European studies suggest that there is no significant difference in both the incidence and the prevalence.

Beta-2-microglobulin amyloidosis evolves predictably over time and is rare in the first few years of HD.

International

Studies in Japan suggest that most patients with carpal tunnel syndrome associated with beta-2-microglobulin 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.

Mortality/Morbidity

Patients receiving long-term dialysis can experience disabling musculoskeletal complications. For individuals who are able to undergo renal transplant, progression of the disease can be halted, but regression is unlikely. Rarely, submucosal bowel deposits have resulted in massive GI bleeding. Case reports of severe pulmonary hypertension and heart failure due to beta-2-microglobulin amyloid deposits in the interstitium and/or vasculature of the cardiovascular system also exist.

Race

No data comparing the incidence of disease in different groups exist.

Sex

The sex of the individual does not seem to influence risk.

Age

The incidence correlates with the increased age of the individual and the time on dialysis.

Clinical

History

Clinical manifestations almost never appear before 5 years of dialysis therapy. Unlike other types of amyloidosis, beta-2-microglobulin amyloid is confined largely to osteoarticular sites. Visceral deposits are rare, occur after 10 or more years of dialysis, and tend not to cause symptoms in most cases. Patients often present with a characteristic triad of carpal tunnel syndrome, shoulder pain, and flexor tenosynovitis in the hands.

• Osteoarticular manifestations  
  • Carpal tunnel syndrome: This syndrome is the most common presenting feature. It usually is bilateral and progressive. Patients report numbness, paresthesias, pain, and swelling in the region of the distal median nerve. Pain usually is worse during dialysis and at night. Progression to contraction of the hand and atrophy of the muscles can occur. However, it is important to remember that all cases of carpal tunnel in dialysis patients are not amyloid related and that other causes like ischemia may be the cause of carpal tunnel syndrome.
  • Flexor tenosynovitis: This disorder is often referred to as trigger finger or trigger thumb. Patients can flex the finger, but, with re-extension, the patient may feel a painful snap that refers to the dorsum of the hand.
  • Scapulohumeral arthropathy: Amyloid may deposit in and around the rotator cuff, resulting in shoulder pain that is worse while in the supine position. Patients often report difficulties dressing.
  • Spondyloarthropathy: The cervical spine is most often affected, and patients often present with neck and back pain.
  • Bone cysts: Thin-walled bone cysts are common and are most frequently found in the carpal bones. They are also observed in the femoral heads, humerus, acetabulum, and spine. Patients may experience stiffness and/or pain over the affected area.
  • Pathologic fractures: Fractures can develop in bones weakened by bone cysts. The femoral neck is most commonly involved. Patients may experience a sudden onset of leg pain while walking.
• Systemic manifestations: Most individuals with systemic manifestations have undergone dialysis for longer than 10-15 years, and they generally are asymptomatic.
  • GI involvement: Macroglossia, dysphagia, small bowel ischemia, malabsorption, and pseudoobstruction can occur because of subepithelial, submucosal, and blood vessel amyloid deposits.
  • Cardiovascular involvement: Myocardial, pericardial, and cardiac valves may be involved. Beta-2-microglobulin amyloid deposits have also been identified in small pulmonary arteries and veins.
  • Genitourinary tract: Renal and bladder calculi containing beta-2-microglobulin deposits causing obstruction have been described. Beta-2-microglobulin amyloid has also been identified in the prostate and the female reproductive tract.

Physical

The most common physical findings include carpal tunnel syndrome, musculoskeletal deformities, bone cysts, lytic bone lesions, and pathologic fractures caused by amyloid deposition within joints, intervertebral discs, and tendon sheaths. Systemic manifestations are rare.

• Osteoarticular involvement
  • Carpal tunnel syndrome: Patients experience weakness and atrophy of the thenar muscle, along with decreased strength in abduction, opposition, and flexion of the thumb.
  • Flexor tenosynovitis: Amyloid deposits may result in prominence of the tendons of the hands on extension. Patients often experience decreased digital mobility and soft tissue swelling over flexor tendon sheaths.
  • Scapulohumeral arthropathy: Deposits in and around the rotator cuff may cause soft tissue thickening around the shoulder, referred to as the shoulder pad sign. The patient's capacity to abduct or internally rotate the arm is limited.
  • Spondyloarthropathy: Paravertebral ligaments and intervertebral discs may be destroyed or dislocated, resulting in spinal cord impingement or paraplegia.
  • Bone cysts: Cysts grow in size and number in the wrist, humeral head, hip, and patella. As cysts enlarge, soft tissue swelling and swollen joints with subsequent spontaneous tendon rupture and pathologic fracture may occur. Cysts do not regress with renal transplantation.
• Systemic manifestations: If systemic involvement occurs, small, localized deposits are observed around blood vessels and in the mucosa of the GI tract, heart, lungs, and genitourinary tract. In rare cases, fatal GI hemorrhages, cardiac arrhythmias, and renal vein thromboses have occurred.

Causes

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

• 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-2-microglobulin, elevating its 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-2-microglobulin.
  • High cut-off high-flux dialysis and online hemodiafiltration have been shown to be superior in the removal of beta-2-microglobulin, possibly decreasing beta-2 amyloidosis.
  • Beta-2-microglobulin 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, making CAPD a more biocompatible mode of treatment. However, data are conflicting. Some report the prevalence of beta-2-microglobulin amyloidosis in patients on long-term CAPD as comparable to the prevalence in patients on HD. Other data show that plasma levels of beta-2-microglobulin 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: Poor biocompatibility of membranes cannot completely explain beta-2-microglobulin because several reports note individuals 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-2-microglobulin by macrophages and/or augment the expression of HLA class I antigens, which increases beta-2-microglobulin expression.
• Advanced glycation end products
  • Following the identification of advanced glycation end products (AGE) in beta-2-microglobulin amyloid deposits, the role of AGE has been the focus of much research.
    • AGE is a heterogeneous group of carbohydrate molecules formed by nonenzymatic glycation and oxidative reactions between reducing sugars and protein amino groups. HD and peritoneal dialysis both are ineffective in removing these low–molecular weight proteins from circulation. As AGE-modified beta-2-microglobulin 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-beta-2-microglobulin with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of DRA, is mediated by the receptor for AGEs or RAGE.
    • RAGE is a central binding site for AGEs formed in vivo. AGE-beta-2-microglobulin-MP-RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of patients on long-term HD, a process that may ultimately lead to bone and joint destruction.
  • Oxidation of beta-2-microglobulin may also enhance amyloid deposition. Studies suggest that increased oxidative stress during HD and exposure of beta-2-microglobulin 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-2-microglobulin production.

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