Amyloidosis, Beta2M (Dialysis-Related) Clinical Presentation

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.^[6] Patients often present with a characteristic triad of carpal tunnel syndrome, shoulder pain, and flexor tenosynovitis in the hands. The rate of surgery for osteoarticular disorder, such as CTS, DSA, and joint arthropathy, which may show the presence of DRA is also very high.^[7] Visceral deposits are rare, occur after 10 or more years of dialysis, and tend not to cause symptoms in most cases.

Osteoarticular manifestations may include the following:

• Carpal tunnel syndrome: This syndrome is the most common presenting feature. It usually is bilateral and progressive.^[8] 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. Destructive spondyloarthropathy (DSA) is a major cause of hospital admissions in long-term dialysis patients, especially in those treated for 30 years or more.
• 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.^[9]
• 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.

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.^[6] 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.

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.^[10]
    • 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.^[11] 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.