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 kidney 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] 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 sites 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. Kidney transplantation is the treatment of choice. See Treatment.
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. Capillary electrophoresis recognizes 2 or 3 conformational isomers of beta-2m in human serum.[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, this is probably not 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.
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
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 daltons. 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 amyloid may accumulate 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 involve individuals who were treated exclusively with 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.
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]
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]
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]
Clinical manifestations of beta-2m amyloidosis almost never appear before a patient has undergone 5 years of dialysis therapy. Unlike other types of amyloids, beta-2m amyloid is confined largely to osteoarticular sites.[12]
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 disorders, such as carpal tunnel syndrome, destructive spondyloarthropathy (DSA), and joint arthropathy, which may show the presence of dialysis-related amyloidosis (DRA), is very high.[13]
Visceral deposits are rare, occur after 10 or more years of dialysis, and tend not to cause symptoms in most cases.
Osteoarticular manifestations can include the following:
Carpal tunnel syndrome
This syndrome is the most common presenting feature. It usually is bilateral and progressive.[11] 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 not all cases of carpal tunnel syndrome in dialysis patients are amyloid related; the syndrome may arise from other causes, such as ischemia.
Flexor tenosynovitis
This disorder is often referred to as trigger finger or trigger thumb. Patients can flex the finger, but with reextension, 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 becomes worse when the patient is in the supine position. Patients often report difficulty dressing.
Spondyloarthropathy
The cervical spine is most often affected, and patients often present with neck and back pain. DSA is a major cause of hospital admissions in long-term dialysis patients, especially in patients who have undergone dialysis 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, patella, acetabulum, and spine. Patients may experience stiffness and/or pain over the affected area.
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 are rare, and patients with systemic involvement generally are asymptomatic. Most individuals with systemic manifestations have undergone dialysis for longer than 10-15 years.
If systemic involvement does occur, 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. Inflammatory symptoms are usually rare and only a few cases with fever or inflammatory arthritis have been reported.[14]
GI involvement
Macroglossia, dysphagia, small bowel ischemia, malabsorption, and pseudo-obstruction can occur because of subepithelial, submucosal, and blood vessel amyloid deposits.[15]
Cardiovascular involvement
Myocardial, pericardial, and cardiac valves may be involved. Beta-2m amyloid deposits have also been identified in small pulmonary arteries and veins.
Genitourinary tract involvement
Renal and bladder calculi containing beta-2m deposits and causing obstruction have been described. Beta-2m amyloid has also been identified in the prostate and the female reproductive tract.
Systemic involvement is rare in beta-2m amyloidosis. Osteoarticular involvement can include the following:
Hoshino et al validated a clinical staging score to measure the severity of dialysis-related amyloidosis (DRA).[16] Elements of the score are as follows:
DRA is staged according to the score as follows:
The diagnosis of beta-2m amyloidosis is established primarily by its clinical appearance on tissue or bone biopsy.
Obtaining a biopsy of the affected bone or synovium, followed by routine hematoxylin and eosin staining, reveals homogeneous eosinophilic material. Amyloid deposits are positive for Congo red staining, showing green birefringence of the amyloid fibrils under polarized light. Specific immunostaining of amyloid deposits by monoclonal anti ̶ beta-2m antibody confirms the diagnosis of beta-2m amyloidosis.
Antisera to amyloid beta-2m are taken up by the Congo red–positive areas, but are not taken up in other types of amyloidosis. On electron microscopy, typically, 8-10 nm wide, nonbranching, curvilinear fibrils are observed in beta-2m amyloidosis.
The reference range of the serum concentration of beta-2m is 1.5-3 mg/L, while in amyloidosis, serum levels can be elevated to values of 50-100 mg/L. However, an increase in beta-2m levels does not confirm the diagnosis of beta-2 amyloidosis, as these levels are usually elevated with low glomerular filtration rates. Hematologic studies frequently reveal a normochromic, normocytic anemia.
Radiologic lesions typically present prior to the onset of pain. Joint erosions (usually involving large joints), lytic and cystic bone lesions (typically juxta-articular), pathologic fractures (most commonly involving the femoral head), spondyloarthropathies (usually involving the cervical area), and vertebral compression fractures may be observed. However, conventional radiography may underestimate the extent of the disease.[17]
Computed tomography (CT) scans reveal amyloid deposits of intermediate attenuation. CT scans can also be used to identify pseudotumors and pseudocystic areas in the juxta-articular bone. Moreover, CT scanning is the best method for detecting small areas of osteolysis in cortical bone or osseous erosion, and it may be helpful in the assessment of the distribution and extent of destructive changes.[17]
Magnetic resonance imaging (MRI) shows characteristic long T1 and short T2 relaxation times, resulting in low to intermediate signal intensity. MRI is helpful in differentiating destructive spondyloarthropathies from inflammatory processes and infections. In evaluating amyloidosis, MRI may provide considerably more information than that obtained from conventional radiographic, CT scan, and sonographic studies.[17]
Ultrasonography is useful in the detection of tendon thickness. Rotator cuff thickness greater than 8mm, thickening of joint capsules (especially of the hip and knee), and retention of synovial fluid may be observed.
Scintigraphy in the diagnosis of beta-2m amyloidosis employs radiolabeled P-component scans, including iodine-123 (123I) serum amyloid P, iodohippurate sodium (131I) beta-2m, and the more natural 111I beta-2m.
The cells surrounding the amyloid deposit take up the circulating tracer, making scintigraphy a useful means of evaluating the total body burden of amyloid. This method has primarily been used in Europe and is not available in North America for diagnosing beta-2m amyloidosis.
Positron emission tomography with fluorodeoxyglucose (PET-FDG), which is able to detect sites of increased inflammatory activity, by detecting the metabolic activity of tissues, measured by glucose uptake, could be a potential tool for early detection of dialysis-related amyloidosis (DRA). A study of 46 dialysis patients with at least one PET scan were compared to a control group of 218 age-matched cases with normal kidney function. PET scans were read in duplicate. Carpal tunnel syndrome was considered a proxy for DRA. A composite “amyloid score” score considered each dialysis year = 1 point; carpal tunnel-DRA = 5 points per site. The prevalence of positive PET was 43.5% in dialysis, 5% in controls (p < 0.0001). PET was positive in 14/15 (93.3%) scans in patients with carpal tunnel. PET sensitivity for detecting DRA was 95% (specificity 64%).[18]
The criterion standard for diagnosis is histologic identification using Congo red and immunohistochemical staining of biopsy specimens or centrifuged synovial fluid sediments. Puncture biopsies are obtained from cystic bone lesions and intra-articularly in synovia. In contrast to other types of amyloidosis, rectal biopsy and subcutaneous fat aspiration are of little value in diagnosing beta-2m amyloidosis. The most common site from which biopsies are obtained is the sternoclavicular joint.
At present, no adequate treatment of beta-2m amyloidosis exists. Medical therapy is limited to symptomatic approaches to ameliorating joint pain and inflammation. Conservative treatment includes physical and occupational therapy. Wrist splints, cervical collars, lumbar corsets, knee braces, and immobilization for spondyloarthropathies often are helpful.
The treatment of joint pain includes the use of the following:
Successful reduction of reduction of osteoarticular pain due to dialysis-related beta-2m amyloidosis has been reported with low-dose doxycycline for up to 1 year.[19]
Surgical intervention may be effective in alleviating pain and restoring function. Procedures include the following:
Unfortunately, orthopedic interventions have high failure rates in dialysis-related amyloidosis (DRA) compared with rates in the general population. If, during the course of a surgery, beta-2m amyloidosis is suspected, then a biopsy should be performed at that time.
In March 2015, the US Food and Drug Administration (FDA) authorized the use of the first device to treat patients with DRA, the Lixelle Beta 2-microglobulin Apheresis Column (Kaneka Corp). During hemodialysis, the patient's blood passes through the device before entering the dialysis filter, and porous cellulose beads in the device bind to and remove beta 2-microglobin. The FDA granted the device a Humanitarian Use Device designation, which is given if the device diagnoses or treats a disease or condition that affects or is found in fewer than 4000 individuals in the United States each year.[20]
Involve rheumatologic, surgical, and transplant consultants early. A nephrologist should care for patients with beta-2m amyloidosis on an ongoing basis.
Kidney transplantation is the treatment of choice for beta-2m amyloidosis. It lowers the blood concentration of beta-2m to the reference range, halting the progression of the disease.
Osteoarticular symptoms, such as joint pain, swelling, and stiffness, disappear within the first week after transplantation. Cystic lesions usually remain unchanged, and regression of amyloid deposits probably does not occur.
Transplantation is not an option for all patients. Some patients on long-term dialysis will have undergone unsuccessful kidney transplantation before they first developed beta-2m amyloidosis; in certain other cases, patients are not suitable candidates.
Although preventive measures are hard to assess, possible ways of preventing, or at least decreasing, the incidence of DRA are the use of the following:
Guidelines from the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) recommend against screening for beta2-microglobulin amyloidosis, including measurement of serum levels of beta2-microglobulin.[24]
High-flux biocompatible polyacrylonitrile and polysulfone membranes have increased middle molecule removal and have thereby enhanced beta-2m removal during HD and hemofiltration.
Online hemodiafiltration has been associated with maximal removal of beta-2m.[21]
The use of ultrapure, sterile, and apyrogenic dialysate may aid in decreasing stimulation and in releasing cytokines. It also may decrease plasma levels of acute-phase proteins.[22]
This was developed to selectively eliminate beta-2m from the circulating blood of patients with DRA. Lixelle treatments reduce the circulating levels of beta-2m and inflammatory cytokines, thereby improving the symptoms of patients with DRA. While this therapy has been used and studied in Japan, it is not currently employed in the United States.[23, 25]
Studies examining the use of laser-beam irradiation to destroy amyloid fibrils of beta-2m fragments have been performed in Japan. This technique has implications for the prevention of amyloid fibril deposition and for the destruction of preformed amyloid deposits.[26]
No medical treatment presently exists to reverse or alter the course of beta-2 amyloidosis. Low-dose steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are symptomatic approaches to ameliorating joint pain and inflammation. Medications used include the following:
Clinical Context: Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is used only in severe cases of joint pain and immobility.
Clinical Context: Triamcinolone decreases inflammation by suppressing the migration of PMN leukocytes and reducing capillary permeability. The drug decreases autoimmune reactions, possibly by suppressing key components of the immune system.
Clinical Context: Capsaicin is derived from plants of the Solanaceae family. It may render skin and joints insensitive to pain by depleting substance P in peripheral sensory neurons.
Topical analgesics penetrate deep for temporary relief of minor, arthritis-associated aches and pains of muscles and joints.
Clinical Context: Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Clinical Context: Sulindac decreases the activity of cyclo-oxygenase and, in turn, inhibits prostaglandin synthesis. Its action results in the decreased formation of inflammatory mediators.
Clinical Context: Naproxen is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of the enzyme cyclo-oxygenase (COX), which results in prostaglandin synthesis.
Clinical Context: Meloxicam decreases COX activity, and this, in turn, inhibits prostaglandin synthesis. These effects decrease the formation of inflammatory mediators.
Clinical Context: Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are indicated initially in small patients, elderly patients, and patients with renal or liver disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with caution, and closely observe the patient's response.
Clinical Context: Flurbiprofen may inhibit COX, thereby, in turn, inhibiting prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.
These agents have analgesic, anti-inflammatory properties and antipyretic activities. Their mechanism of action is not known but may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.