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Dialysis-related amyloidosis

Dialysis-related amyloidosis
Literature review current through: Jan 2024.
This topic last updated: Oct 19, 2023.

INTRODUCTION — Dialysis-related amyloidosis (DRA) is a disabling disease characterized by accumulation and tissue deposition of amyloid fibrils consisting of beta2-microglobulin (beta2-m) in the bone, periarticular structures, and viscera of patients with end-stage kidney disease [1-8]. Beta2-m is a component of the major histocompatibility complex that is present on cell surfaces and is normally cleared by glomerular filtration, with subsequent reabsorption and catabolism in proximal tubules. Clearance declines in patients with reduced kidney function, which leads to plasma accumulation and slow tissue deposition.

The prevalence of DRA in patients on hemodialysis has decreased with the use of high-flux biocompatible membranes, which provide better clearance of beta2-m and are less likely to induce reactive inflammation. (See 'Epidemiology' below.)

However, even modern kidney replacement therapies can be associated with retention of beta2-m. An overview of DRA is presented in this topic review. Other bone diseases and other complications associated with kidney disease are discussed elsewhere.

(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

(See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

Other forms of amyloidosis are also discussed elsewhere.

(See "Overview of amyloidosis".)

EPIDEMIOLOGY

Prevalence — The exact prevalence of DRA is unknown since biopsy, the definitive diagnostic test, is rarely performed [9] (see 'Diagnosis' below). The tissue deposition of amyloid that is detected histologically occurs much earlier than any clinical or radiographic manifestation of the disease. A postmortem study found that the proportion of patients on hemodialysis who had joint amyloid deposition was 21, 33, 50, 90, and 100 percent in those with a dialysis duration of <2 years, 2 to 4 years, 4 to 7 years, 7 to 13 years, and >13 years, respectively [10]. By comparison, another study reported that the proportion of patients on hemodialysis needing surgery for carpal tunnel syndrome (CTS; a surrogate for DRA) was 0, 50, and almost 100 percent in those with a dialysis duration of 5 years, 14 years, and 20 years, respectively [2,11]. However, these data were largely obtained during periods when hemodialysis was performed with low-flux, cellulose-derived dialysis membranes that were impermeable to beta2-microglobulin (beta2-m).

Globally, the prevalence of DRA declined as low-flux dialysis membranes were replaced by high-flux dialyzer membranes that have a higher clearance of beta2-m [7]. As an example, in one study of over 200,000 patients on hemodialysis from Japan, the incidence of CTS declined by almost one-half between 1998 and 2010 [12]. Another observational study of Japanese patients on hemodialysis reported that higher beta2-m clearance and lower serum beta2-m levels were associated with longer intervals from the start of dialysis to surgery for CTS [13]. However, DRA remains relatively common, especially among older patients on long-term dialysis. In two studies of patients with a mean age >60 years who were on hemodialysis for more than approximately 10 years, the prevalence of DRA ranged from 21 to 28 percent [14-16].

The incidence of DRA in patients on peritoneal dialysis is less clear. Some observations suggest that peritoneal dialysis is associated with a similar risk of developing DRA as with hemodialysis [17].

Risk factors — Risk factors for DRA include the following [18,19]:

Older age and increased dialysis vintage

Use of low-flux dialysis membranes

Use of bioincompatible dialysis membrane

Lack of residual kidney function

These risk factors are discussed below:

Older age and dialysis vintage – Older age and increased dialysis vintage are closely associated with DRA [19,20]. Virtually all studies have demonstrated increasing prevalence with time on dialysis [2,7,15].

Low-flux dialysis membrane – DRA is more common among patients who undergo low-flux dialysis compared with high-flux dialysis [7,20-22]. This is suggested by the following studies:

One multicenter study that included 221 patients who were receiving hemodialysis for more than five years found that, among patients >60 years of age at the start of dialysis, the likelihood of developing amyloid bone disease was five times higher with low-flux compared with high-flux membranes (figure 1) [20].

In a retrospective study, clinically evident DRA was compared among 89 patients on hemodialysis for at least 10 years and treated exclusively with low-flux, bioincompatible cellulose membranes; low-flux, intermediately biocompatible polysulfone (PMMA) membranes; or high-flux, highly biocompatible polysulfone (AN69) membranes [22]. Clinical symptoms of DRA were most pronounced in the low-flux, bioincompatible cellulose membrane group and least pronounced in the high-flux, highly biocompatible membrane group.

One report compared patients on dialysis treated with a polyamide high-flux membrane with those treated with low-flux dialyzers; those on the high-flux membrane had lower beta2-m concentrations [23].

A cross-sectional study of 147 patients who had been undergoing hemodialysis for >10 years and had a confirmed diagnosis of CTS (which is one of the two most common manifestations of DRA) reported that the combined use of high-flux dialyzer membranes and ultrapure dialysis fluid resulted in delayed onset of CTS [15].

The mechanisms by which high-flux dialysis membranes decrease DRA include improved dialysis clearance of beta2-m [24-29] and, possibly, better preservation of residual kidney function, which improves overall clearance [15,30,31]. Clearance of beta2-m by low-flux dialysis membranes is poor because the molecular weight of beta2-m (11,800 Da) is greater than the cut-off level of the membrane porosity. The more permeable membranes have an intrinsically greater rate of convective transport (although diffusion is limited by the size of the beta2-m molecule) and also may bind beta2-m directly [24-29].

Bioincompatible dialysis membrane – DRA appears to be more common among patients who are dialyzed using a bioincompatible dialysis membrane than among those who are dialyzed using a highly biocompatible membrane [20,22,32]. As examples:

In one study (cited above), in which DRA was compared among patients on dialysis who used low-flux, bioincompatible cellulose membranes and low-flux, intermediately biocompatible polysulfone (PMMA) membranes versus high-flux, highly biocompatible polysulfone (AN69) membranes, the biocompatibility of the dialysis membrane appeared to be an independent determinant of the risk for developing DRA [22].

In a trial in which 159 new patients on hemodialysis were randomly assigned to either a low-flux biocompatible or low-flux bioincompatible membrane, plasma beta2-m levels rose over time in both groups but the increase above baseline was less among patients treated with biocompatible membranes compared with those treated with bioincompatible membranes (2.6 versus 11.1 mg/L) [32]. This beneficial effect was independent of the influence of residual kidney function and increased progressively over time.

However, in some studies, the prevalence of DRA was not higher among patients treated with cuprophane hemodialysis membranes compared with those treated with AN69 membranes [33,34].

Lack of residual kidney function – The loss of even a minimal degree of residual kidney function is sufficient to decrease clearance and catabolism of beta2-m, thereby promoting the development of DRA. In one study, the plasma beta2-m concentrations were twice as high in patients on hemodialysis with a glomerular filtration rate (GFR) <1 mL/min than in those with a GFR of 4 to 5 mL/min [35]. As noted above, some studies suggest that high-flux membranes or ultrapure dialysis fluid preserve residual kidney function better than low-flux cellulosic membranes and thereby facilitate better overall clearance of beta2-m [15,30,31].

PATHOGENESIS — In contrast to fragments of immunoglobulin light chains in primary amyloidosis and serum amyloid A in secondary amyloidosis, the amyloid protein in DRA is composed primarily of beta2-microglobulin (beta2-m) [2,36,37]. DRA occurs because of increased tissue deposition of beta2-m (due to reduced kidney clearance and, possibly, to increased production) in a uremic milieu that appears to favor amyloid formation.

Reduced clearance of beta2-m – The major underlying cause of DRA is the inability of patients with end-stage kidney disease to adequately clear beta2-m, even with modern, high-flux hemodialysis and/or convective therapies. This is because continuous generation of beta2-m far exceeds its removal by these dialysis modalities. As an example, assuming steady beta2-m generation in a 70 kg anuric individual, net yearly beta2-m retention is 111, 97, 77, 53, and 51 grams with low-flux conventional hemodialysis, high-flux dialysis, short daily hemodialysis, nocturnal hemodialysis, and short daily hemofiltration, respectively [7].

In peritoneal dialysis, there is relatively small removal of beta2-m due to the overall slow rate of convective transport and dialysate flow rate, despite the peritoneal membrane being highly permeable to small proteins. In one study, clearance was significantly higher with high-flux hemodialysis versus peritoneal dialysis (29 versus 6 liters/week per 1.73 m2) [17]. However, residual kidney function is generally higher among patients undergoing peritoneal dialysis compared with hemodialysis; this may increase overall clearance of beta2-m. (See 'Risk factors' above.)

Increased production of beta2-m – In addition to decreased clearance of beta2-m, the dialysis procedure itself (particularly via exposure to bioincompatible membranes) may mildly stimulate intradialytic beta2-m production. This was suggested by in vitro experiments that demonstrated increased beta2-m production by cultured peripheral blood monocytes obtained from patients on hemodialysis after dialysis with a cuprophane membrane but not by monocytes from patients dialyzed with the more biocompatible, non-complement-activating polymethylmethacrylate membrane [21].

Two mechanisms may contribute to the bioincompatible membrane-induced stimulation of beta2-m synthesis: contact of the cells with the membrane and activation of late complement components [38]. It is also possible that dialysate contaminated with endotoxin stimulates the release of beta2-m from leukocytes and monocytes [39].

However, observational data suggest that intradialytic generation of beta2-m may not be a significant underlying factor in DRA [40,41]:

Serum levels of beta2-m are similar or higher in patients treated with peritoneal dialysis as with hemodialysis.

Rarely, DRA has developed in patients who have never undergone hemodialysis.

Amyloid formation – Although sustained increase in serum beta2-m concentration is a prerequisite for the formation of beta2-m amyloid fibrils, the exact mechanism of amyloidogenesis in patients on dialysis remains unclear. Studies have shown that elevation of circulating beta2-m levels is not the only cause of DRA [42], and other substances, such as glycosaminoglycans, proteoglycans, apolipoprotein E, and serum amyloid P component, may be involved with amyloidogenesis in patients on long-term dialysis [43]. These molecules are thought to stabilize the amyloid fibrils and inhibit their depolymerization. Moreover, at a neutral pH, lysophospholipids and nonesterified fatty acids accelerate amyloid fibril formation from beta2-m monomer and extension of amyloid fibrils in vitro and may enhance the amyloid deposition in vivo [43,44].

Glycosylated beta2-m, a modified microglobulin resulting from the activity of 3-deoxyglucose, has been found in amyloid deposits as advanced glycation end products [45]. Since 3-deoxyglucose is present at increased levels in the serum of patients with advanced chronic kidney disease, including those on dialysis [46], the modification of beta2-m may occur more readily in kidney failure. In addition, clearance of glycosylated beta2-m by dialysis membranes is lower than that of native beta2-m [47]. The presence of glycosylated beta2-m in amyloid deposits may further enhance the development of these lesions by both stimulating the secretion of cytokines and acting as a chemoattractant and an apoptosis-delaying agent for monocytes [48-50].

Mechanism of injury – The mechanisms by which beta2-m amyloid deposition causes tissue injury are incompletely understood. Reactive inflammation may play a role, as suggested by observations that beta2-m amyloid lesions are associated with a marked influx of activated macrophages expressing cytokines, such as interleukin-1, tumor necrosis factor-alpha, and transforming growth factor-beta [51]. These macrophages appear to be unable to adequately phagocytose deposited beta2-m [52]. Beta2-m also may cause bone destruction by directly stimulating formation of osteoclasts [53].

CLINICAL FEATURES — The clinical sequalae of DRA are due to the tissue deposition of beta2-microglobulin (beta2-m) amyloid, particularly in bone, articular cartilage, synovium, muscle, tendons, and ligaments [54-56].

Clinical manifestations — The clinical manifestations of DRA typically occur after a period of five years or longer on dialysis and are discussed below.

Shoulder pain — Shoulder pain is one of the most common manifestations of DRA and is due to scapulohumeral periarthritis and rotator cuff infiltration by amyloid [1-3,57]. The shoulder pain related to scapulohumeral periarthritis is usually bilateral and typically is localized to the anterolateral aspect. Abduction may elicit pain, and patients may have limited range of motion, which worsens when patients are in a supine position, particularly at night or when undergoing dialysis treatments. This pain often improves when the patient sits or stands up [9,58].

Carpal tunnel syndrome — Carpal tunnel syndrome (CTS) is another common manifestation of DRA [1-3,57]. Numbness and dysesthesias in the distribution of the median nerve are caused by beta2-m amyloid deposition in the carpal tunnel. In more severe cases, motor involvement can lead to complaints of weakness or clumsiness when using the hands. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis", section on 'Clinical features'.)

CTS symptoms are typically bilateral, but if unilateral, they tend to occur more commonly on the side of a functioning vascular dialysis access [9,59]. Carpal tunnel symptoms may worsen during dialysis due in part to steal syndrome [9,60].

Trigger finger — Trigger-finger (flexor tenosynovitis) manifestations of DRA occur most frequently after the onset of CTS, and often involve multiple fingers [61]. Catching or locking of fingers during flexion is caused by amyloid deposition along flexor tendons. In more severe cases, the finger(s) may become locked in flexion. (See "Trigger finger (stenosing flexor tenosynovitis)", section on 'Presentation' and "Trigger finger (stenosing flexor tenosynovitis)", section on 'Diagnosis'.)

Spinal pain — Patients may experience neck or back pain related to involvement of the spine by a destructive spondyloarthropathy [62]. Neck pain due to cervical spine involvement is more common than back pain. When it occurs, back pain due to destructive spondyloarthropathy is usually in the lumbar region. Infrequently, in patients who have undergone dialysis for 20 years or longer, epidural deposition of beta2-m amyloid may compress the spinal cord, causing quadriparesis or quadriplegia [63-66].

Bone fracture — Patients may present with bone fractures sustained after minimal trauma (ie, pathologic fractures), particularly of the femoral neck, as a result of bone cysts [67]. Bone cysts occur most commonly in the carpal bones but may also occur in the femoral neck, phalanges of the hands, humeral head, acetabulum, tibial plateau, and distal radius.

Other manifestations — Other clinical manifestations of DRA are uncommon, but those that do occur are most often related to the gastrointestinal tract [9].

Gastrointestinal – Gastrointestinal bleeding, ischemic or infarcted bowel with perforation, and pseudo-obstruction with gastric or colonic dilation have all been described [68-75]. Patients may exhibit macroglossia and describe difficulty swallowing or pain with swallowing [76,77]. The colon is the most frequently involved site of the gastrointestinal tract, but other sites of beta2-m amyloid deposition include the tongue, esophagus, stomach, and small intestine [78-81].

Cardiac, pulmonary, and skin – Congestive heart failure and/or mitral regurgitation may occur due to cardiac deposition of beta2-m amyloid. Cardiac, pulmonary, and cutaneous involvement with DRA have been described infrequently [57,68,76,82].

Physical examination — The shoulders and hands are the most common sites of abnormal physical examination findings in patients with DRA.

Shoulder findings – The shoulders of patients with significant scapulohumeral periarthritis appear hypertrophied because of deposition of amyloid between muscles and tendons of the rotator cuff ("shoulder pad sign") (picture 1) [83,84]. The coracoacromial ligament and bicipital tendon may be tender to palpation.

Hand findings – CTS is suggested by weakness and possibly atrophy of the muscles of the thenar eminence and by decreased sensation in the thumb and index, middle, and ring fingers. These sensory deficits typically spare the thenar eminence. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis", section on 'Examination'.)

The pathognomonic "guitar string" sign in the palm refers to prominent flexor tendons that are apparent upon full or partial extension of the fingers [85]. The "guitar string" sign in a patient with either shoulder pain or evidence of CTS strongly suggests DRA.

"Amyloid hand" refers to CTS-associated atrophy of the thenar eminence in conjunction with trigger fingers that have progressed to irreducible flexion contractures (picture 1) [2,84].

Imaging — The preferred radiographic studies for the evaluation DRA vary by clinical presentation and are detailed elsewhere in this topic review (see 'Evaluation' below). Characteristic imaging findings in patients with DRA are as follows:

Conventional radiography may reveal radiolucent lesions or bone cysts, typically in the hand and/or long bones, and frequently with thin sclerotic margins (image 1 and image 2) [2,7]. Bone lesions are often bilateral and are typically found at periarticular sites [86,87]. The bone lesions tend to enlarge more rapidly than the brown tumors of hyperparathyroidism, which are now rare, and usually increase in number and size over time. Plain radiography of the spine also can demonstrate findings of destructive spondyloarthropathy: severe narrowing of intervertebral spaces, vertebral body erosions, and end-plate destruction with minimal osteophyte formation [86,87].

Ultrasonography of the shoulder typically demonstrates increased rotator cuff thickness, deposits with increased echogenicity between the muscles and tendons of the rotator cuff, and a thickened synovial sheath of the long head of the biceps [83,88-90].

Computed tomography (CT) findings of destructive spondyloarthropathy are similar to those of conventional radiography, as described above, but CT better detects osseus erosion and small osteolytic areas, especially in cortical bone [86,87]. CT also is superior to conventional radiography for delineating the extent and severity of destructive spondyloarthropathy [86,87].

Magnetic resonance imaging (MRI) shows intraosseous, periarticular, and soft-tissue lesions, typically with low signal intensity on both T1- and T2-weighted images [86,87,91]. Like CT, MRI can detect bony lesions too small to be seen with plain radiographs. MRI of the shoulder can show supraspinatus and/or subscapularis tendon thickening [92]. Bone lesions usually show moderate enhancement following the administration of gadolinium-based contrast; however, many centers still do not allow patients with end-stage kidney disease to receive even next-generation gadolinium-based contrast agents. (See "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging", section on 'Approach to preventing nephrogenic systemic fibrosis' and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease", section on 'Prevention'.)

DIAGNOSIS

Evaluation

When to suspect the diagnosis – DRA should be suspected in patients who have been on dialysis for five years or longer and develop characteristic clinical features, especially new-onset shoulder pain not associated with trauma, carpal tunnel syndrome (CTS), and/or trigger finger.

Perform a physical examination – Careful physical examination of the patient may suggest the diagnosis of DRA. (See 'Physical examination' above.)

Obtain selected imaging studies – The preferred radiographic studies to evaluate suspected DRA depend on the clinical presentation:

Shoulder pain – We prefer ultrasound for the evaluation of scapulohumeral periarthritis. However, MRI without contrast enhancement also may be used, either for initial evaluation or for patients with equivocal ultrasound findings. (See 'Imaging' above.)

Carpal tunnel syndrome and trigger finger – Plain radiography of both hands, including the wrists, is the preferred imaging study for patients with CTS and/or trigger finger. CTS and trigger finger are generally diagnosed without imaging, and plain radiography does not detect amyloid deposition in the carpal tunnel or along flexor tendons. However, bone cysts observed on these plain radiographs suggest hand involvement by beta2-microglobulin (beta2-m) amyloid. (See 'Carpal tunnel syndrome' above and 'Trigger finger' above and 'Imaging' above.)

For patients with CTS and/or trigger finger who have no findings or equivocal findings on initial plain radiography of the hands, we repeat imaging studies in six months. Because DRA is characterized by multiple bone cysts that enlarge rapidly over time, repeat plain radiographs can be useful in establishing the diagnosis.

Spinal pain – CT of the spine without contrast is the preferred imaging study to evaluate neck or back pain in patients who may have destructive spondyloarthropathy. Normal plain radiographs effectively rule out destructive spondyloarthropathy, but suggestive plain radiographs generally require follow-up with CT. (See 'Imaging' above.)

MRI of the spine without contrast also may be useful as initial or supplemental imaging, especially in the following two settings:

-Suspected spinal cord compression or nerve root impingement (see "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Spinal stenosis')

-Suspected infectious discitis and/or vertebral osteomyelitis (see 'Differential diagnosis' below)

Pathologic fracture – Imaging studies typically obtained for the diagnosis of bone fracture in the general population, usually plain radiography but sometimes CT or MRI, are adequate to evaluate bone lesions characteristic of DRA. However, for patients with suspected DRA who have pathologic fractures in locations other than the spine (eg, the femoral neck), we also obtain plain radiographs of both hands to determine the presence or absence of bone cysts (see 'Establishing the diagnosis' below). Patients with pathologic spine fractures due to DRA do not need hand imaging since they typically have radiographic evidence of destructive spondyloarthropathy.

Diagnostic tests we do not use – The following tests are not useful in the evaluation of DRA:

Abdominal fat pad aspiration.

Measurement of serum beta2-m. Beta2-m levels are elevated among patients on dialysis in the absence of DRA [93,94].

Scintigraphy with radiolabeled beta2-m or serum amyloid P component [95-98], and positron emission tomography with fluorodeoxyglucose (PET-FDG) [99]. Scintigraphy is often unavailable and has not been consistently useful as the results depend upon which specific protein is radiolabeled. PET-FDG remains an investigational imaging modality.

Establishing the diagnosis — DRA is typically a clinical diagnosis based upon the presence of characteristic features in patients who have been on dialysis for an extended period. Tissue biopsy is generally not needed to diagnose DRA.

Generally accepted or validated clinical criteria for the diagnosis of DRA do not exist. We make the diagnosis of DRA in patients who have been on dialysis for ≥5 years and who meet one or both of the following criteria (see 'Evaluation' above):

At least one typical clinical manifestation of DRA (ie, shoulder pain due to scapulohumeral periarthritis, CTS, trigger finger [flexor tenosynovitis], or spinal pain due to destructive spondyloarthropathy) in conjunction with its characteristic findings on imaging

Pathologic fracture accompanied by the presence of bone cyst(s) in the affected bone and, for patients with non-vertebral fracture, bone cysts in one or both hands

Although rarely performed, biopsy is the definitive diagnostic test for beta2-m amyloidosis [5]. The amyloid found in the bone cysts and synovial tissue is similar to other forms of amyloid in its staining properties, with Congo red, and in exhibiting apple-green birefringence under polarized light. In contrast to fragments of immunoglobulin light chains in primary amyloidosis and serum amyloid A in secondary amyloidosis, the amyloid protein in DRA is composed primarily of beta2-m [2,36,37]. (See "Overview of amyloidosis".)

A group in Japan has proposed a clinical set of criteria for the diagnosis of DRA [16]. However, this diagnostic schema has not been validated, and we believe some of the individual criteria lack adequate specificity.

Differential diagnosis — Other conditions besides beta2-m amyloidosis may cause shoulder pain, CTS, and/or back pain in patients with end-stage kidney disease, especially in those who have received dialysis treatment for less than five years:

Calcific periarthritis, caused by hydroxyapatite crystal deposition in periarticular tissue, may cause shoulder pain with associated soft tissue swelling, especially in the setting of elevated serum levels of calcium and/or phosphorus. The presence of radiopaque periarticular calcifications on plain radiographs differentiates calcific periarthritis from the shoulder periarthritis observed in beta2-m amyloidosis. (See "Basic calcium phosphate (BCP) crystal-associated calcific periarthritis (tendinopathy)".)

Subacromial bursitis, bicipital tendinitis, and supraspinatus tendinitis may develop with overuse of the shoulder. These conditions often present with severe shoulder pain at rest that is exacerbated by movement of the affected shoulder and may awaken the individual from sleep. Reflex sympathetic dystrophy syndrome also may present with shoulder pain and limited motion, often associated with or followed by pain, swelling, and stiffness of the ipsilateral hand and wrist with signs and symptoms of vasomotor instability. However, in these conditions, the shoulder does not appear hypertrophied with the appearance of a "shoulder pad."

(See 'Physical examination' above.)

(See "Biceps tendinopathy and tendon rupture".)

(See "Biceps tendinopathy and tendon rupture".)

Septic arthritis of the shoulder, most commonly caused by Staphylococcus aureus in patients receiving hemodialysis, typically causes severe shoulder pain at rest or upon any shoulder movement. This must be diagnosed by shoulder arthrocentesis performed under fluoroscopic or ultrasound guidance with culture of the aspirated synovial fluid. (See "Septic arthritis in adults".)

Patients with chronic kidney disease and renal osteodystrophy may develop shoulder pain due to pathological humeral fractures, which can be diagnosed on plain radiographs. (See "Evaluation of renal osteodystrophy".)

The manifestations of CTS in patients with DRA are similar to those in patients without DRA. However, DRA-associated CTS is more often bilateral [16] and is accompanied by the radiographic and/or physical examination findings of DRA. (See 'Imaging' above and 'Physical examination' above.)

Shoulder pain and CTS may be associated with the underlying disease process that resulted in kidney failure [100]. Examples include the following:

Diabetes mellitus can lead to diabetic cheiroarthropathy, manifest by scapulohumeral periarthritis and CTS with or without trigger finger. Diabetic cheiroarthropathy is accompanied by characteristic physical examination findings and lacks DRA-associated radiographic features. (See "Overview of the musculoskeletal complications of diabetes mellitus", section on 'Shoulder pain' and "Overview of the musculoskeletal complications of diabetes mellitus", section on 'Hand abnormalities'.)

Primary (AL) amyloidosis may result in shoulder periarthritis and CTS. This can be distinguished from beta2-m amyloidosis only by histologic identification of the amyloid subunit protein in tissue.

Systemic lupus erythematosus may lead to shoulder joint inflammation or avascular necrosis of the humeral head causing shoulder pain and also may lead to CTS from median nerve compression by wrist synovitis. Avascular necrosis has characteristic findings on imaging, and wrist synovitis is generally apparent on physical examination. (See "Clinical manifestations and diagnosis of osteonecrosis (avascular necrosis of bone)", section on 'Diagnosis' and "Monoarthritis in adults: Etiology and evaluation", section on 'Physical examination'.)

Infectious discitis and/or vertebral osteomyelitis may share clinical and radiographic features with destructive spondyloarthropathy [86]. Hemodialysis catheter–associated bacteremia is common and may result in spine infections unaccompanied by fever and/or elevated white blood cell count. MRI may be useful in such patients. In contrast to the lesions seen in destructive spondyloarthropathy, infected structures of the spine typically have increased signal intensity on T2-weighted images (see 'Imaging' above) [86]. Biopsy may be necessary in patients with suspected vertebral osteomyelitis to establish a microbiologic and histologic diagnosis. (See "Vertebral osteomyelitis and discitis in adults".)

TREATMENT — There is no specific medical treatment for DRA. However, removal of significant amounts of beta2-microglobulin (beta2-m) may slow progression of the disease. Although this is best accomplished by kidney transplantation (see 'Impact of transplantation' below), changes to the dialysis prescription also can increase the removal of beta2-m.

Dialysis modification — Our approach to dialysis modification depends on dialysis modality.

Hemodialysis – The effective removal of beta2-m by hemodialysis requires the use of newer and more permeable dialysis membranes since cellulose membranes such as cuprophane membranes are impermeable to beta2-m. Increasing the duration and/or frequency of dialysis also increases the clearance of beta2-m.

Optimize the dialysis membrane – For patients on hemodialysis who have DRA, we suggest a biocompatible, high-flux membrane. However, virtually all patients in the United States and other resource-abundant countries are already dialyzed against a biocompatible, high-flux membrane. This recommendation is consistent with 2003 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines [5]. Most [7,15,20-22,24-31], but not all [33,34,101] studies have found that beta2-m level is lower among patients dialyzed with biocompatible high-flux membranes. (See 'Risk factors' above.)

There is limited evidence that the use of super-flux membranes may improve beta2-m clearance even more than with high-flux membranes [102]. However, there are insufficient data upon which to recommend their use.

Intensify dialysis – For patients on hemodialysis who have DRA, we suggest increasing the duration and frequency of dialysis. However, the optimal dialysis prescription for patients with DRA is unknown. Because of the logistics of in-center hemodialysis, and because of the extensive treatment times preferred, nocturnal home hemodialysis is ideal for patients with DRA. An example of an intensified home dialysis regimen for a patient with DRA who uses a low dialysate flow machine (eg, NxStage) is six to eight hours, six days per week.

For patients with DRA who are unable or unwilling to perform home hemodialysis, we increase the duration of in-center, thrice-weekly dialysis sessions and, ideally, we add a fourth weekly treatment as logistics permit. Nocturnal hemodialysis is the preferred in-center option because it allows for longer treatment times (eg, eight hours). If in-center nocturnal hemodialysis is unavailable, we maximize the duration of each daytime dialysis session; though for scheduling and staff reasons, treatment times longer than five hours are usually not feasible.

No high-quality data demonstrate that increased dialysis dose improves or slows the progression of DRA. However, dialysis duration and frequency are important determinants of beta2-m clearance, and increasing the weekly treatment time decreases beta2-m concentrations [103]. Despite substantial clearance, there is still significant retention of beta2-m with conventional three-times-weekly high-flux hemodialysis [7,40,104]. Compared with conventional hemodialysis (performed for four hours, three times per week), nocturnal hemodialysis (performed for eight hours, six nights per week, at low blood- and dialysate-flow rates) is associated with significantly higher clearances of beta2-m (585 versus 127 mg/week) and a greater reduction in plasma beta2-m concentrations (39 versus 21 percent) [105]. Short daily hemodialysis also appears to be associated with enhanced middle-molecule removal compared with that observed with conventional hemodialysis. (See "Short daily hemodialysis".)

Peritoneal dialysis – For patients on peritoneal dialysis who have DRA, we suggest switching to hemodialysis via an arteriovenous fistula or graft. Because of the high risk of serious infection associated with hemodialysis catheters, we do not switch patients on peritoneal dialysis to catheter-based hemodialysis. For patients with DRA who switch to hemodialysis, the preferred hemodialysis regimens are the same as above.

For patients on peritoneal dialysis who do not wish to switch to hemodialysis, we generally do not intensify peritoneal dialysis unless conventional measures of dialysis adequacy are below target (see "Prescribing peritoneal dialysis"). Clearance of beta2-m in patients on peritoneal dialysis depends mainly upon residual kidney function; thus, increasing peritoneal dialysis dose would not be expected to result in meaningful increases in beta2-m removal [106].

No high-quality data demonstrate that switching from peritoneal dialysis to hemodialysis improves or slows the progression of DRA. However, high-flux hemodialysis results in significantly higher clearance of beta2-m compared with peritoneal dialysis (29 versus 6 liters/week per 1.73 m2) [10]. Although the peritoneal membrane is highly permeable to small proteins and has the highest biocompatibility, only a small amount of beta2-m is removed daily with peritoneal dialysis because of slow convective transport and dialysate flow rate. Studies examining dialysis modality and DRA have been limited by the shorter average life-time dialysis duration in patients on peritoneal dialysis and have reported conflicting results. Some studies suggested that the incidence of DRA is similar in patients on hemodialysis and those on peritoneal dialysis [107], while others suggest that its incidence and progression are greater in patients on hemodialysis [96,108].

Other modalities – We do not use hemodiafiltration solely for the treatment of DRA. Significant removal of beta2-m occurs with hemofiltration and hemodiafiltration, although plasma beta2-m levels remain high with these modalities [109-113]. Some [114-116], though not all [117], studies have suggested that the development of clinically significant carpal tunnel syndrome (CTS) occurs less frequently in patients treated with hemodiafiltration and hemofiltration. However, the role of these modalities for the prevention and/or treatment of DRA will remain unclear until more data are available.

Symptom management — Apart from enhancing beta2-m clearance by dialysis or kidney transplantation, treatment of DRA is otherwise palliative. Symptoms of DRA are managed by analgesics, which help to reduce periarticular and bone pain, and by surgery.

Pain control – Our approach to chronic pain in patients on dialysis is detailed elsewhere. (See "Management of chronic pain in advanced chronic kidney disease".)

Surgery – Because DRA may affect surgical management, clinicians referring a patient for surgical evaluation should communicate the diagnosis of DRA directly to the surgical team. Based upon clinical experience, we believe that the following surgical interventions and/or approaches may be beneficial for symptom control:

Arthroscopic or open surgery of the shoulder with removal of synovium infiltrated by amyloid often provides dramatic pain relief [118].

Early surgical correction of CTS is warranted since DRA is a progressive disease [119]. For patients with DRA, carpal tunnel surgery should include debridement of the hypertrophied synovium that is infiltrated by beta2-m amyloid, rather than just transection of the transverse carpal ligament, to relieve median nerve compression more effectively. However, despite surgery, CTS typically recurs within two years and requires multiple repeat surgical decompression procedures over time [9].

Curettage and bone grafting of amyloid cysts in the femoral neck have been successful in relieving hip pain [120] and may prevent pathologic fractures. The grafts were successfully incorporated into the bone defects.

Replacement of a diseased joint with a prosthesis must be considered on an individual basis; when performed, this modality can relieve pain and restore lost mobility [9]. Pathologic fractures of the femoral neck, occurring in bone compromised by beta2-m amyloid deposition, should be treated with total joint arthroplasty, rather than by internal fixation, because of the poor quality of the bone.

No high-quality data have compared the outcomes of surgical procedures to treat DRA-related symptoms with outcomes of the same procedures in patients without DRA.

Other therapies — The role of beta2-m adsorption columns in the treatment of DRA remains undefined. Limited data suggest that beta2-m adsorption columns, which are used predominantly in Japan, are associated with increased beta2-m removal and better improvement in DRA symptoms compared with dialysis alone [121-124]. A survey of 345 Japanese patients on dialysis reported that use of a beta2-m column was associated with improvement of DRA symptoms in over 85 percent of patients [125]. Hypotension and anemia have limited use of this treatment in some patients. Although a beta2-m adsorption column has been approved by the FDA, it is rarely used in the United States.  

Doxycycline has been shown to modulate the formation of beta2-m fibrils in vitro [126]. However, in vivo data suggesting that doxycycline may ameliorate symptoms of DRA are limited to case reports [127,128].

IMPACT OF TRANSPLANTATION — Kidney transplantation is considered the definitive therapy for DRA in patients with end-stage kidney disease. For patients who are undecided about whether to undergo a kidney transplant, DRA may provide incentive.

Successful kidney transplantation reduces plasma beta2-m levels to normal, and joint pain usually resolves soon after the kidney allograft has begun to function [5,129-132]. Over time, after transplantation, the amyloid deposits may also regress. In one study, articular amyloid deposition regressed in eight of nine patients with DRA, as detected by scanning with radiolabeled serum amyloid P component, approximately five years after successful kidney transplantation [132]. By contrast, bone cysts resolve slowly after transplantation, and the destructive spondyloarthropathy may progress [131-133]. DRA symptoms generally recur quickly in patients who restart dialysis after kidney graft failure [131-133].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)

SUMMARY AND RECOMMENDATIONS

Pathogenesis and epidemiology – Among patients with end-stage kidney disease, dialysis-related amyloidosis (DRA) is a disorder caused by the inability to clear beta2-microglobulin (beta2-m), resulting in the deposition of beta2-m amyloid fibrils in bones, joints, and other soft tissues. The incidence of DRA now is much lower than had been reported previously, a trend that correlates with the increased use of high-flux biocompatible dialyzers with enhanced clearance of beta2-m. (See 'Pathogenesis' above and 'Epidemiology' above.)

Clinical manifestations – The clinical manifestations of DRA typically occur after a period of five years or longer on dialysis and include the following (see 'Clinical manifestations' above):

Shoulder pain due to scapulohumeral periarthritis

Carpal tunnel syndrome (CTS)

Trigger finger (flexor tenosynovitis)

Spinal pain due to destructive spondyloarthropathy

Pathologic fractures due to rapidly enlarging bone cysts

Physical examination and imaging – Shoulders and hands are the most common sites of abnormal physical examination findings in patients with DRA. Plain radiography often reveals bone cysts, especially near joints. Ultrasound, computed tomography, and magnetic resonance imaging (MRI) also may demonstrate characteristic findings. (See 'Physical examination' above and 'Imaging' above.)

Diagnosis We make the diagnosis of DRA in patients who have been on dialysis for ≥5 years based upon the presence of typical clinical manifestations and characteristic imaging findings. Although tissue biopsy is generally not needed to diagnose DRA and is rarely performed, biopsy is the definitive diagnostic test for beta2-m amyloidosis. (See 'Diagnosis' above.)

Treatment – There is no specific medical treatment for DRA. However, removal of significant amounts of beta2-m by intensified, high-flux hemodialysis may prevent or slow progression of the disease. For patients with DRA, we modify dialysis and treat symptoms. (See 'Treatment' above.)

Dialysis modification – Our approach to dialysis modification depends on dialysis modality.

-Hemodialysis – For patients on hemodialysis who have DRA, we suggest a biocompatible, high-flux membrane rather than a bioincompatible or low-flux membrane (Grade 2C). However, virtually all patients in the United States and other resource-abundant countries are already dialyzed against a biocompatible, high-flux membrane. For patients on hemodialysis who have DRA, we suggest increasing the duration and frequency of dialysis (Grade 2C). (See 'Dialysis modification' above.)

-Peritoneal dialysis – For patients on peritoneal dialysis who have DRA and who can undergo hemodialysis via an arteriovenous fistula or graft, we suggest switching to hemodialysis (Grade 2C). Because of the high risk of serious infection associated with hemodialysis catheters, we do not switch patients on peritoneal dialysis to catheter-based hemodialysis. (See 'Dialysis modification' above.)

Symptom management – Symptoms of DRA are managed in part by analgesics, which help to reduce periarticular and bone pain. A variety of surgeries also may improve DRA symptoms. Because DRA may affect surgical management, clinicians referring a patient for surgical evaluation should communicate the diagnosis of DRA directly to the surgical team. (See "Management of chronic pain in advanced chronic kidney disease" and 'Symptom management' above.)

Impact of transplantation – Kidney transplantation is the definitive therapy for DRA in patients with end-stage kidney disease. Successful kidney transplantation reduces plasma beta2-m levels to normal, and joint pain usually resolves soon after the kidney allograft has begun to function. (See 'Impact of transplantation' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Robert E Cronin, MD, and William L Henrich, MD, MACP, who contributed to earlier versions of this topic review.

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Topic 1983 Version 33.0

References

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