Dialysis-Related Amyloidosis: His...
DIALYSIS-RELATED AMYLOIDOSIS                                            81
The prevalence of DRA in dialysis patients incr...
82                                                 Danesh and Ho
ing from loss of range of motion to severe limiting pain....
DIALYSIS-RELATED AMYLOIDOSIS                                                   83
with cervical involvement (C4–C6 vertebr...
84                                                                  Danesh and Ho
(69, 76). Amyloid deposition has also be...
DIALYSIS-RELATED AMYLOIDOSIS                                                                     85
47. Di Raimondo CR, Ca...
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Dialysis-Related Amyloidosis: History and Clinical Manifestations


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Dialysis-Related Amyloidosis: History and Clinical Manifestations

  1. 1. 2 MICROGLOBULIN AND AMYLOIDOSIS IN CHRONIC DIALYSIS PATIENTS Dialysis-Related Amyloidosis: History and Clinical Manifestations Farhad Danesh* and Louisa T. Ho† *Division of Nephrology/Hypertension, Northwestern University Medical School, Chicago, and †Evanston Hospital, Evanston, Illinois ABSTRACT Dialysis-related amyloidosis (DRA) or 2-microglobulin amy- amyloid fibrils in various joint and osteoarticular surfaces leads loidosis (A 2M) is a unique type of amyloidosis that has been to the clinical complaints and findings typical of this disorder. described in individuals with both long-standing chronic renal However, a visceral form with systemic organ involvement has disease and end-stage renal disease (ESRD). It has been associ- also been described. Despite advances in the understanding of ated with serious complications that significantly add to the mor- this disorder and in the delivery of dialysis, the ability to alter the bidity of long-term dialysis patients. The deposition of 2M in incidence of DRA and its course remains uncertain. Dialysis-related amyloidosis (DRA), also referred to Warren and Otiendo (11), after the first substantial num- as 2-microglobulin amyloidosis (A 2M), is a unique bers of hemodialysis patients had been successfully type of amyloidosis affecting patients with end-stage re- maintained on of dialysis. The increased incidence of nal disease (ESRD). This condition is defined as a dis- CTS in dialysis patients was initially considered to be a abling disease in which the accumulation of amyloid consequence of vascular access placement. These au- fibrils consisting of 2M deposits lead to bone and joint thors (followed by others) emphasized the role of angio- destruction. A variety of osteoarticular complications access in developing CTS in dialysis patients (12, 13). have been associated with 2M amyloid deposition in Contemporaneously, an erosive arthropathy affecting pe- patients on long-term dialysis, including carpal tunnel ripheral joints in chronic hemodialysis patients was also syndrome (CTS), chronic arthropathy, cystic bone le- reported (14). A constellation of symptoms began to be sions, destructive osteoarthropathy, and pathologic frac- defined, with the appearance of CTS preceding or ac- tures (1–4). A systemic form of DRA with extra-articular companying complaints of joint stiffening and pain. deposition of 2M amyloid has been largely documented In 1978 Kenzora (15) reported the presence of amy- in patients on long-term dialysis (5–7). The serious clini- loid deposits in tissues obtained from carpal tunnel bi- cal problems associated with A 2M constitute a major opsy specimens of long-term hemodialysis patients. In cause of morbidity in long-term dialysis patients, though the same year, Assenat et al. (16) reported the association few cases of death associated with A 2M have been between amyloid deposits and the presence of CTS and reported (8, 9). Although DRA was initially reported in scapulohumeral arthritis. Their observation was widely patients on long-term hemodialysis, it has also been confirmed, and amyloid deposits in the transverse carpal noted in patients on continuous ambulatory peritoneal ligament or finger flexor synovium are now considered a dialysis (CAPD) and even in patients with chronic renal prominent finding in long-term dialysis patients under- insufficiency who have never been dialyzed (10). going surgery for CTS (17, 18). In 1985 Gejyo et al. (19) In this review article we summarize clinical features of identified a novel protein, 2-microglobulin, as the pri- this serious and debilitating complication. We also dis- mary component of the amyloid protein in DRA. The cuss the differential diagnosis of A 2M from other rheu- clinical significance of 2M amyloid deposition, how- matic disorders in dialysis patients. ever, still remains elusive. In various studies, virtually all patients on hemodialysis for more than 7–9 years were Historical Background and Risk Factors found to have such deposits (20, 21). Moreover, post- The first observation that the incidence of CTS was mortem studies have demonstrated some degree of amy- increased in hemodialysis patients was made in 1975 by loid deposition in almost 100% of patients examined (14). However, not all patients reported clinical symp- tomatology. Therefore it seems that the presence of 2M Address correspondence to: Farhad Danesh, MD, North- amyloid, although necessary, may not alone be sufficient western University Medical School, Division of Nephrology/ Hypertension, 303 East Chicago Ave., Searle Building 10/ to cause symptoms associated with DRA. 465, Chicago, IL 60611-3008. Clinical and radiologic manifestations of DRA de- Seminars in Dialysis—Vol 14, No 2 (March/April) 2001 pp. velop relatively late in the course of dialysis, on average 80–85 510 years after the initiation of dialytic therapy (22, 23). 80
  2. 2. DIALYSIS-RELATED AMYLOIDOSIS 81 The prevalence of DRA in dialysis patients increases tions include paresthesias of the palmar surface of the with length of survival. In some reports, up to 65% of thumb, forefinger, third, and medial half of the fourth patients dialyzed for more than 10 years were affected fingers. Due to variable nerve innervation, the distribu- with DRA (24). Age at the time of initiation of dialysis tion of pain and sensory deficits can be variable, some- appears to be another major risk factor for developing times involving the entire palmar surface of the hand. DRA, with older patients developing DRA more fre- Discomfort is often worse at night and worse with ac- quently and much earlier in the course of therapy than tivities that impinge on the nerve, as with frequent flex- younger patients (25, 26). ion or extension at the wrist. DRA was initially described in patients dialyzed with Physical examination is often unhelpful early in the cuprophane membranes. The role of cuprophane mem- course of CTS; however, as the disease progresses there brane in the pathogenesis of DRA has been a topic of may be objective findings such as diminished pin-prick discussion for many years. Various studies have ad- sensation in the median nerve distribution or loss of the dressed the question of whether the use of high-flux syn- thenar eminence with weakness of the thumb and fore- thetic membranes decreases the prevalence of A 2M (24, finger. Tests to elicit evidence of nerve compression 27). The kinetic studies on 2M clearance during hemo- have relatively low sensitivities and specificities. The dialysis and hemofiltration have shown a reduction in Hoffman–Tinel test involves eliciting pain by tapping the serum 2M concentration during treatment sessions with median nerve at the wrist. The Phalen test attempts to high-flux synthetic membranes through adsorption, dif- elicit symptoms with maintenance of the wrist in the fusion, or convection. Such a reduction was not seen flexed position for 30–60 sec. Some studies report a with the use of cuprophane membranes (28). However, range of 50–70% for the sensitivity of these tests and despite their differences in 2M clearance, a recent 10- 40–70% for the specificity. year retrospective analysis failed to show a significant The diagnosis of CTS is predominantly a clinical one difference in the development of DRA (24). Further- based upon history and physical findings. However, more, A 2M is now recognized as an entity that can be nerve conduction studies can be useful in the diagnosis found in not only hemodialysis patients, but also perito- of CTS and can demonstrate slow conduction velocities neal dialysis patients and in patients with long-standing of the median nerve in involved patients. Unfortunately chronic renal disease even before the initiation of dialy- nerve conduction studies are a relatively weak screening sis treatment (10). Some reports suggest that there may measure, with a high rate of false negativity, even in be an equal incidence of 2M disease in both hemodi- significant disease states. alysis and peritoneal dialysis patients, while others sug- Radiologically the joint spaces are preserved and show gest that the incidence and progression are far greater in no evidence of the focal joint space narrowing suggestive hemodialysis patients (29, 30). Clearly studies looking at of osteoarthritis. The soft tissues may show a focal nodu- the incidence of disease in peritoneal versus hemodialy- lar asymmetric pattern of swelling, reflecting 2M amy- sis have been limited due to the shorter average duration loid deposition. In the juxta-articular bone, the most of peritoneal dialysis in patients. characteristic change is the presence of cystlike bone Schwalbe et al. (31) recently reported a dramatic de- defects. These bone defects are located predominantly in crease in prevalence of DRA in their hemodialysis pa- the carpal bones, but may also affect the radioulnar end tients. They concluded that the most likely factors ac- as well as the proximal end of the metacarpal bones. In counting for the marked decrease in 2M amyloid preva- contrast to the small carpal cysts corresponding to a nor- lence in their center were changes of the dialysate mal variant, these bone cysts characteristic of DRA in- composition and the purity of water. The use of reverse crease both in size and in diameter, often exceeding a osmosis and bicarbonate dialysate instead of acetate in diameter of 5 mm (35). this study was also correlated with the lower incidence of On magnetic resonance imaging (MRI), cystic lesions A 2M (31). associated with DRA show a relatively low signal inten- sity both on T1- and T2-weighted images (36). Amyloid deposition can therefore be differentiated from other eti- Clinical Manifestations ologies (inflammatory masses, chronic synovitis, brown tumors of hyperparathyroidism, and true carpal cysts), all Carpal Tunnel Syndrome of which show a bright signal on T2-weighted images. Treatment, much as in other etiologies of CTS, typi- Carpal tunnel syndrome is a characteristic, although cally initially involves the use of conservative therapies, not pathognomonic, clinical manifestation of DRA. including pain relief with nonsteroidals and other medi- Clinical manifestations of CTS usually develop after cations and splinting of the wrists. CTS associated with more than 5 years of dialysis (22, 23). The reported DRA, however, is progressive and surgical intervention prevalence of CTS varies widely depending on the study, may be required. Optimal relief of symptoms is more and ranges from 9 to 73% (24, 32, 33). Spertini et al. (35) variably achieved than in other populations and recur- observed that the prevalence of CTS was 5% in patients rence of symptoms is more frequent. on dialysis for less than 4 years and 26% in those treated for more than 4 years. In patients treated with cupro- phane membranes, a prevalence as high as 100% has Chronic Arthropathy been reported (34). Clinical manifestations of CTS result from entrapment Chronic arthralgias are a prominent feature of DRA. of the median nerve at the wrist. Typically manifesta- They usually occur bilaterally, with the symptoms rang-
  3. 3. 82 Danesh and Ho ing from loss of range of motion to severe limiting pain. followed chronologically, these lesions multiply and They predominantly involve the shoulder, knees, hips, grow in size. They can be found in the acetabulum, ra- and the long bones of the skeletal system. Shoulder pain dius, tibia, and femoral head. Eventual fracture with its was noted in all patients described by van Ypersele et al. corresponding morbidity can occur. These cystic lesions (35), and in 14 of 15 patients described by Munoz- are sometimes confused with the brown tumors of sec- Gomez et al. (37). Shoulder arthralgias should be care- ondary hyperparathyroidism. However, the cystic lesions fully differentiated from destructive spondyloarthropa- of dialysis-associated amyloidosis more commonly af- thies associated with DRA (see below). Shoulder arthral- fect periarticular surfaces. Amyloid bone cysts may lead gias usually coincide with the presence of symptoms to pathologic fractures (47, 48). Pathologic fractures of associated with CTS, and is the initial symptom in 25– long bones such as the femoral neck are serious compli- 50% of cases (24, 35). The pain is frequently, but not cations that may require surgical repair. They usually completely, relieved by rest. MRI of the shoulder may occur at the site of large cysts or multiple small radio- reveal thickening of the rotator tendons leading to a lucencies (49). Amyloid cyst in the body of C2 has been chronic impingement of the acromiocoracoid arch on the reported to cause crush fracture with spinal cord com- thickened rotator cuff, and synovitis of the shoulder joint pression (50). or subacromial bursitis. Thickened rotator cuff tendons can also be seen by ultrasonography (38). The majority of recent studies stressed the prominent Destructive Spondyloarthropathy role of 2M amyloid deposition in the development of chronic arthropathy associated with DRA. However, it is In 1984 Kuntz et al. (51) reported the development of still uncertain whether amyloid deposits are the sole cul- erosive lesions of the spine in the absence of microbial prits (39). Typically, early deposition of 2M amyloid infection in 10 patients on long-term hemodialysis, and occurs at the site of cartilage surfaces, extending to in- coined the term “destructive spondyloarthropathy” volve the joints and tendons later in the disease. The (DSA). The course of DSA is unpredictable but is gen- resulting inflammation and erosion of joints and sur- erally progressive (52). The prevalence of DSA increases rounding structures leads to the clinical manifestations of with the cumulative years on dialysis. Some reports in DRA arthropathy. The corresponding pathology consists the late 1980s estimated the prevalence of DSA in pa- of synovitis to erosion and destruction of the affected tients with more than 10 years on dialysis to be as high bones and joints. Joint effusion, although uncommon, as 40% (53). The clinical symptoms range from asymp- may also be a part of this process. Aspiration demon- tomatic lesions to myelopathy or radiculopathy associ- strates a serous, occasionally hemorrhagic fluid, and ated with pain and stiffness of the spine. These lesions 2M amyloid deposits may be found in synovial frag- are frequently associated with cervical and lumbar pain, ments (40). and in a few cases may cause spinal cord compression. A Chronic joint swelling is another important feature of few cases of fatal cervical spondyloarthropathy associ- chronic arthropathy associated with DRA. The shoul- ated with 2M have also been reported in the literature ders, knees, wrists, finger joints, elbows, and ankles may (8, 9) (Fig. 1). Radiologically DSA is characterized by be affected. Knee involvement may lead to the develop- discovertebral destruction and disc space narrowing, ment of poplyteal cyst (41). Capsulosynovial swelling with cysts in the adjacent vertebral end plates, and with- caused by the deposition of amyloid generally precedes out significant osteophytosis (51). Flexion views of the the development of 2M amyloid bone cysts (41, 42). cervical spine may show instability by ligamentous lax- The joint effusions are usually paucicellular (43), and ity at the same or adjacent levels. Subluxation or lithesis cell count ranges from 80 to 1100 white blood cells/ml is common. The spine is affected in the cervical, lumbar, (44). 2M amyloid can be demonstrated in the synovium and thoracic levels in a ratio of approximately 85:10:5, or the synovial fluid by Congo red and immunostaining (45, 46). Radiologic examination of the affected joints may show erosion of surfaces of the joint capsule and articular narrowing. The erosive changes most com- monly occur at the metacarpophalangeal joints, but can also involve other larger joints. Correlation between ra- diologic findings and clinical symptoms has not been found. Scapulohumeral periarthritis may present in the same way as a bursitis. Surgical exploration might dem- onstrate swelling, inflammation, and thickening of the tendon sheath and surrounding bursa. Bone Cysts and Pathologic Fractures The development of subchondral bone cysts and/or articular erosions are a pathognomonic finding of DRA. FIG. 1. Fatal cervical spondyloarthropathy in a hemodialysis patient. They are not true cysts, but rather eroded cavities. Ra- MRI shows a soft tissue mass (amyloidoma) lateral to the cervico- diologic examination late in DRA often demonstrates occipital hinge (black arrow) and destructive lesions of the cervical multiple cystic bone lesions in the long bones. When vertebrae (white arrow) (8).
  4. 4. DIALYSIS-RELATED AMYLOIDOSIS 83 with cervical involvement (C4–C6 vertebrae) being the have a low incidence and to occur late in the course of most common (54, 55). Diagnosis is not difficult if the the disease (62). However, at least in one series, a his- frequency of DSA in patients with ESRD is appreciated. tologically confirmed systemic form of 2M amyloid The radiologic differential diagnosis includes vertebral was found in 53% of patients on long-term dialysis (63). osteomyelitis. The visceral form of 2M amyloid has been mainly In addition to cervical spine films, MRI, bone scan, documented in patients who have been on dialysis for and needle biopsy have been employed to confirm the more than 10 years. A literature review of autopsy re- diagnosis of DSA and exclude osteomyelitis. On MRI, ports of visceral A 2M showed the heart as the most spondyloarthropathy shows decreased signal intensity in frequently involved organ, followed by the gastrointes- the affected disc on T2-weighted image sequences. This tinal system (64). is in contrast to osteomyelitis, which shows increased Two types of 2M amyloid deposits have been iden- signal intensity on T2-weighted sequences (56). tified: vascular deposits and interstitial deposits (6). It is 2M amyloid may also involve the atlanto-occipital of interest that in the osteoarticular form, 2M amyloid is joint (57–59). Rousselin et al. (59) used MRI to study the predominantly deposited in the interstitium and rarely in upper cervical spine and found abnormal periodontoid the vascular walls. In contrast, in the visceral form, 2M soft tissue masses (“pseudotumors” or “amyloidomas”) amyloid is generally deposited in blood vessels, espe- in 7 of 25 patients (28%) who had received hemodialysis cially as subendothelial nodules bulging into the vessels for 10 years or more. Four of the seven patients with lumen (64). These nodular deposits may result in isch- amyloidomas also had destructive spondyloarthropathies emia of the tissues supplied by those vessels and occa- of the lower cervical spine, with associated neck pain; sionally may lead to perforation of the viscera (65). none had evidence of spinal cord compression or radic- Deposition of 2M amyloid in the cardiovascular sys- ulopathy. Five of these seven patients had undergone tem is usually of no clinical significance. However, 2M carpal tunnel surgery, and 2M amyloid was demon- deposits replacing the left ventricular myocardium and strated in histologic examination of the surgical speci- the interventricular septum resulting in fatal congestive mens. MRI screening of hemodialysis patients in other stud- heart failure have been reported (66, 67). 2M amyloid ies has also shown a high prevalence of amyloidomas in deposition in the mitral valve with subsequent mitral the cervico-occipital hinge (60). Such lesions are usually valve insufficiency, in addition to pulmonary hyperten- asymptomatic and may result in severe neurologic in- sion, and right ventricular failure have also been de- volvement which may even be fatal (8) (Fig. 2). There- scribed (68). fore early detection of these lesions is important, and Systemic deposits of 2M amyloid in the gastrointes- MRI of the cervical area in patients who have undergone tinal tract may lead to significant morbidity. Subepithe- hemodialysis for more than 7 years with minimal symp- lial 2M amyloid deposits may cause nodular enlarge- toms or as a screening tool has been suggested (60, 61). ment of the tongue with dysphagia, dysphonia, and dys- Extreme caution should be exercised in patients with guesia (69–71). Diffuse submucosal deposits have been associated with macroglossia and odynophagia (72). 2M amyloid-associated lesions in the cervico-occipital hinge during procedures that require manipulation of the Gastric ulcers, hemorrhage, small bowel obstruction, and cervical region (8). small bowel perforation have been reported in associa- tion with 2M amyloid deposits in the lamina submucosa and lamina muscularis of the stomach (65), and in lamina Systemic (Visceral) A 2M muscularis propia and in small and medium-size blood vessels of the small intestine (73–75). It is now evident that 2M amyloid is deposited not Other visceral deposition of 2M amyloid includes only in osteoarticular tissues but also in a wide variety of larger masses of 2M amyloid, particularly in the sub- extra-articular tissues. The visceral form is believed to cutaneous tissues, and especially in the gluteal region FIG. 2. Involvement of the atlantoaxial joint with pseudotumors (amyloidomas), and/or de- structive spondyloarthropathy may lead to spinal cord compression and cervical myelopathy.
  5. 5. 84 Danesh and Ho (69, 76). Amyloid deposition has also been observed in amyloidosis in patients undergoing long-term hemodialysis. Arthritis Rheum 28:1052–1058, 1985 the skin within papillary and reticular layers, around hair 19. Gejyo F, Yamada T, Odani S, Nakagawa Y, Arakawa M, Shirahama T, follicles, and in the sweat glands and blood vessels. We Cohen AS, Schmid K: A new form of amyloid protein associated with chronic hemodialysis was identified as 2-microglobulin. Biochem Biophys recently described a patient with systemic involvement Res Commun 129:701–706, 1985 of 2M amyloid deposits, including the spleen (8). The 20. Noel L, Zingraff J, Bardin T: Tissue distribution of dialysis amyloidosis. Clin spleen, commonly involved in other forms of amyloid- Nephrol 27:175, 1987 21. Koch K: Dialysis related amyloidosis. Kidney Int 41:1416, 1992 osis, was not involved in any of the previously reported 22. Munoz-Gomez J, Gomez-Perez R, Llopart-Buisan E, Sole-Argues M: Clini- cases. The cause of this splenic “resistance” is not clear. cal picture of the amyloid arthropathy in patients with chronic renal failure maintained on hemodialysis using cellulose membranes. Ann Rheum Dis 46:573–579, 1987 Conclusion 23. Bardin T, Zingraff J, Shirahama T, Noel LH, Droz D, Voisin MC, Drueke T, Dryll A, Skinner M, Cohen AS: Hemodialysis associated amyloidosis and 2-microglobulin: clinical and immunohistochemical study. Am J Med 83: DRA is a major complication of chronic renal failure 419–424, 1987 and long-term renal replacement therapy. The most im- 24. Bardin T: Arthropathies of hemodialyzed patients. Rev Praticien 38:1555– 1557, 1988 portant risk factors for developing DRA are age at the 25. Spiegel DM, Sprague SM: Serum amyloid P component: a predictor of time of initiation of dialysis, duration of chronic renal clinical 2-microglobulin amyloidosis. Am J Kidney Dis 19:427–432, 1992 failure, and cumulative years on dialysis. Carpal tunnel 26. van Ypersele de Strihou C, Jadoul M, Malghem J, Maldague B, Jamart J: Working Party on Dialysis Amyloidosis: effect of dialysis membrane and the syndrome and chronic arthropathy are the most prevalent patient’s age on signs of dialysis-related amyloidosis. Kidney Int 39:1012– clinical manifestations of DRA. Cervical spondyloar- 1019, 1991 27. Brunner FP, Brynger H, Elrich JHH, Fassbinder W, Geerlings W, Rizzoni G, thropathy is a debilitating complication of DRA. Neck Selwood NH, Tufveson G, Wing AJ: Case control study on dialysis arthrop- pain in a long-term dialysis patient should alert the ne- athy: the influence of two different dialysis membranes. Data from the EDTA phrologist to the possible presence of dialysis-related registry. Nephrol Dial Transplant 5:432–436, 1990 28. Floege J, Granolieras C, Bingel M, Deschodt G, Branger B, Oules R, Koch spondyloarthropathy. 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