β 2 -microglobulin amyloidosis

Amyloid: Int. J. Exp. Clin. Invest. 4, 187-211 (1997)

Review

p 2 -microglobulin amyloidosis Jonathan Kay, M.D.

Department of Internal Medicine, Lahey Hitchcock Medical Center, Burlington, MA, and the Department of Medicine, Harvard Medical School, Boston, MA, USA

Kf.1 I f OKIK P,-microglobulin amyloidosis, dialysis-related amyloidosis, hemodialysis, uremia, advanced gl-vcosylation end products, carpal tunnel syndrome, shoulder periarthritis, bone cysts, destructive spondyloarthropathy, renal transplantation, aminoguanidine

. ~ H H X I . I 7qr~lhs: AP = amyloid-P peptide, AGE = advancedglycosylation endproducts, AGE-P2M = advancedglycosylation endproduct- modijied P2-microglobulin, P2M = p, microglobulin, CAPD = continuous ambulatoty peritoneal dialysis, CT = computed tomography, 30G = 3-deoxyglucosone, DRAQ = dialysis-related amyloidosis questionnaire, HLA = human leukocyte antigen; IGF I = ins1llln-fike grod i jhc tor I, IL-1 = interleukin-I, IL-6 = interleukin-6, LF-L = lactoferrin-like polypeptide, MMP = matrix metalloproternase, ,24RI =

magnerrc resonance imaging, PMMA = polymethylmethaciylate; RACE = receptor fo r advancedg1,vcosylation endproducts. .CAP =serum am),loid P component, TGF-p = transforming growjth factor f i TIMP = tissue inhibitor of metalloproteinuse, TNFa = tumor necrosis factor a

Abstract

@microglobulin (P2M) amyloidosis is a disabling disease that aflects patients with long-term chronic renalfail- ure but not individuals with normal renal function. It is an ideal model for study of the amyloid diseases because a de$ned population is at risk for the development of this condition, its clinical manlfes fations evolve predictably over time, and it ultimately occurs in the majority of patients who have received long-term dialysis therapy. The clinical features ofP2M amyloidosis are reviewed, high- lighting the systemic nature of this disease. The various techniques available to diagnose this condition are described. The pathogenesis of P2M amyloidosis is recon- sidered in light of recently published data regarding advanced glycation end products (AGE). Available and potential treatments for this condition are also discussed.

occurring in patients undergoing hemodialysis in 1975, 15 years after Scribner2 first treated a patient with chronic uremia with intermittent hemodialysis. Amyloid was frst identified in a carpal tunnel biopsy specimen from a patient undergoing hemodialysis by Kenzora’ in 1978. Assenat and colleagues4 reported an association between the carpal tunnel syndrome and a scapulohumeral periarthritis in 1980. In 1985, Gejyo and colleagues5 identified P2M as the protein precursor of the amyloid associated with chronic hemodialysis. Subsequently, a variety of syndromes predominantly involving the musculoskeletal system and occurring in patients with chronic renal failure have been shown to be caused by P2M amyloid deposition. Following the identification of AGE in P2M amyloid deposits by Miyata and co-workers in 19936, a new direction to elucidate the pathogenesis of this condition has been pursued.

Clinical features Historical background

he current understanding of dialysis-associated amyloidosis has evolved over the past two decades. War- T ren and Otieno’ described carpal tunnel syndrome

Patients with P2M amyloidosis commonly display musculoskeletal signs and symptoms. In contrast, although gastrointestinal tract complications have been reported, visceral (32M amyloid deposits usually do not cause symptoms. Sys-

Correspondence Dr Jonathan Kay, Section of Rheumatologq Lahey Hitchcock Medical Center. 41 Mall Road, Burlington, MA 01805 USA Tel 6 17-273-8857 Fax 6 17-273-5249 E-mail Jonathan K a y 2 Lahey Hitchcock org

Submitted March 6. 1997 Revision Accepted Ma) 30, 1997

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Kay

temic involvement by P2M amyloidosis seems to occur less commonly than musculoskeletal involvement. However, the only available data describing the prevalence of signs and symptoms of P2M amyloidosis are derived from several major cross-sectional cohort studies. The true prevalence of P2M amyloidosis has not been established because biopsies have not systematically been performed on sufficient patients undergoing dialysis to determine the actual frequency of musculoskeletal and systemic P2M amyloid deposition.

Musculoskeletal involvement P2M amyloid deposits preferentially in bone, articular

cartilage, synovium, muscle, and ligaments'. Patients with P2M amyloidosis often have a characteristic triad of shoulder pain, carpal tunnel syndrome, and flexor tendon deposits in the hands on presentation. This clinical syndrome is similar to the musculoskeletal complications seen in patients with long-standing diabetes mellitus, including shoulder periarthritis, carpal tunnel syndrome, flexor tenosynovitis, and Dupuytren's contracture of the hands', and suggests the possibility of a common pathogenetic mechanism, such as modification of proteins with AGE9. The clinical and radiographic appearance of amyloid deposits in patients undergoing hemodialysis also resembles many of the findings seen in patients with rheumatoid arthritis, sometimes leading to the misdiagnosis of dialysis-related amyloidosis as rheumatoid arthritis (Table 1).

Laurent and colleaguesI0 described the prevalence of musculoskeletal symptoms associated with dialysis-related amyloidosis in 256 patients on long term hemodialysis. Shoul- der pain developed, in most patients, after 5 years of hemodialysis treatment and occurred more often in patients with carpal tunnel syndrome. As many as 95% of patients with amyloid deposits demonstrated in tissue removed at the time of carpal tunnel release also had shoulder pain. The incidence of carpal tunnel syndrome and shoulder pain increases with longer duration of hemodialysis'0-'2; both are present in most patients who have undergone hemodialysis for longer than 12 years". Among patients receiving hemodialysis for 10 years or longer, the prevalence of shoulder pain, often bilateral, has ranged from 34% to 84%'?-''; the

Table 1. Musculoskeletal manifestations of P2M amyloidosis.

Scapulohumeral periarthritis Carpal tunnel syndrome Flexor tenosynovitis Destructive spondyloarthropathy Cervico-occipital pseudotumor Bone cysts Pathologic fractures

FIGURE 1. Shoulder pad sign in a patient with !32M amyloidosis.

prevalence of carpal tunnel syndrome, also often bilateral, has ranged from 9% to 73%12-''. The wide variation in prevalence observed among these studies probably reflects the heterogeneity of the patient populations examined.

Shoulder periartliritis P2M amyloid deposition in the shoulders of patients

undergoing chronic hemodialysis may produce a scapulohumeral periarthriti~l~. The rotator cuff muscles may be thickened or amyloid may deposit between the muscles and tendons of the rotator cuffz', causing the shoulders to appear hypertrophied with shoulder pads (Figure 1). Depos- its of P2M amyloid in the biceps and supraspinatus tendons and tendon sheaths may predispose these tendons to rup- ture". The subacromial bursa may be thickened and an inflammatory infiltrate may be present within the synovium'3.

Patients receiving long-term hemodialysis often report anterolateral shoulder pain that is worse when they are in a supine position, especially during dialysis treatments and at night, and may improve when they assume a sitting or standing position''. The coracoacromial ligament and sometimes the bicipital groove are tender to palpation. Impingement of the thickened subacromial bursa beneath the acromial process may induce pain and limit range of shoulder motion, especially in abduction. Adhesive capsulitis of the shoulder may be present.

Carpal tunnel syndrome Hand pain and numbness and dysesthesias in the dis-

tribution of the median nerve may occur in chronic hemodialysis as a result of P2M amyloid deposits in the carpal

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Amyloid: Int. J. Exp. Clin Invest. 3, 187-211 (1997)

tunnel?. Symptoms of carpal tunnel syndrome occur more frequently on the side of the longest functioning vascular accessz4. However, bilateral carpal tunnel syndrome has occurred even in patients whose vascular access site is on one side only. Exacerbation of carpal tunnel syndrome symptoms during hemodialysis may result from a fistula-induced arterial steal phenomenon causing ischemia to the median nerve in the narrowed carpal tunnel3.

Flexor tenosynovitis Irreducible flexion contractures of the fingers fi-equently

develop in individuals on hemodialysis when P2M amyloid is deposited along the flexor tendons of the handL3, causing the digital flexor tendons of the hand to adhere to one another?’. These deposits may create a subcutaneous soft tissue mass in the palm (Figure 2). The flexor tendons become prominent when the fmgers are extended. This “gui- tar string sign” in a patient on dialysis with shoulder pain or carpal tunnel syndrome or both is highly suggestive of 132M am? Ioidosisz6.

Spine The axial skeleton is affected less frequently than the

upper extremities. Maruyama and colleagues” found radiographic features characteristic of the destructive spondyloarthropathy associated with dialysis-related amyloidosis in 9. I % of 405 patients. The prevalence ofthis condition is also higher the longer the duration ofhemodialysis28: destructive spondyloarthropathy was present in 13.4% of the I57 patients who had been receiving hemodialysis for longer than 10 years. Kessler and colleague^'^ found a similar prevalence of 14.0% in a cohort of 171 patients from 19 centers in northeastern France who had been receiving hemodialysis for longer than 10 years.

Radiographic features of the destructive spondyloarthropathy2’ that occurs in patients receiving long- term hemodialysis are similar to those seen in infection of the disk space, including narrowing ofthe intervertebral disk spaces and erosions of the vertebral end-plates without appreciable formation of osteophyte. These erosions occur most frequently at the anterosuperior or anteroinferior margins ofthe vertebral bodies, similar to the Romanus lesion of ankylosing spondylitisjO.

The cervical spine is most often affected by destructive spondyloarthropathy; however, similar changes may also occur in the dorsal and lumbar spine”. Radiographic changes of the destructive spondyloarthropathy are usually noted in the lower cervical spine’’. ?’. z9: the disk spaces between the fourth and fifth cervical vertebrae and between the fifth and sixth cervical vertebrae are most frequently involved” (Fig- ure 3). Ohashi and colleagues2* hypothesized that P2M amyloid deposition in intervertebral disks is accelerated by mechanical stress due to the motion of daily life: P2M amy-

loid deposits appear first in the disk spaces between the fourth and fifth cervical vertebrae, between the fifth and sixth cervical vertebrae. and between the sixth and seventh cervical vertebrae where the range of motion is greatest.

Involvement of the upper cervical spine has also been demonstrated3’. Cystic radiolucencies of the first and second cervical vertebral bodies or the odontoid process are the most common radiographic changes seen31. Periodontoid soft tissue masses of 132M amyloid, termed pseudotumors, may occur with destructive changes of the cervico-occipital hinge joint3z. Such a pseudotumor has been reported in a patient on hemodialysis for only 4 yearsi3.

Radiographic changes of the cervico-occipital hinge joint were found in 9 of 23 patients (39%) on hemodialysis for 8 years or longer’l. Periodontoid pseudotumors were identified3‘ by magnetic resonance imaging (MRI) in 7 of 25 patients (28%) treated for 10 years or longer. However, the prevalence of upper cervical spine involvement may be over- estimated because of the small number of patients included in the studies describing these changes. Kessler and col- leagues1’ observed spondyloarthropathy affecting the cervico-occipital hinge joint in only 2 of 171 patients ( 1 YO) receiving hemodialysis for longer than 10 years.

Deposits of 132M amyloid have been demonstrated in paravertebral ligaments and intervertebral disks”, even in the absence of radiographic changes of destructive spondyloarthropathyz8. Postmortem examination of the intervertebral disks of patients who received dialysis for fewer than 5 years revealed small deposits of P2M amyloid almost exclusively in the annulus fibrosus of cervical disks as early as 1 year and 7 months after the initiation of hemo- dialysis28. Patients who underwent dialysis for longer t h s n 5 years had P2M amyloid deposits in lumbar and upper tho- racic disks as well as in cervical disks.

FIGURE 2. Amyloid deposits in the wrist and palm, with irreducible flexion contractures of the fingers, in a patient with P 2 M arnyloidosis. The thenar atrophy reflects the presence of long-standing carpal tunnel syndrome.

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The initial symptom of destructive spondyloarthropathy is pain, typically in the neck when the cervical spine is involved36. However, most patients who have radiographic abnormalities in the cervical spine have no neck pain". Although neurologic compromise occurs infrequently, significant myelopathy has been reported to result from P2M amyloid deposits in the cervical and lumbar spinal canal. Thickening of the dorsal ligaments and ligamentum flavum of the cervical spine has resulted in obstruction of the sub- arachnoid space and spinal cord compressioni7. In three patients who had received long-term hemodialysis, spastic quadriparesis resulted from extradural P2M amyloid deposits compressing the lower cervical spinal Compres- sion of the upper cervical spinal cord by a periodontoid pseudotumor resulted in quadriparesis and death of a 5 1 - year-old woman who had received hemodialysis for 17 years39. P2M amyloid deposition in the intervertebral disks and ligamentum flavum of the lumbar spine has also resulted in compression of the thecal sac and cauda equina".

Bone cysts Cystic bone lesions also develop in patients with P2M

amyloidosis. Subchondral amyloid cysts, most commonly found in the carpal bones", may also occur in the acetabu- lum and in long bones, such as the femoral head or neck, the

FIGURE 3. Lateral cervical spine radiograph of a patient with p2M amyloidosis showing changes characteristic of destructive spondyloarthropathy. The intervertebral disk spaces between the third and fourth cervical vertebrae and between the fifth and sixth cervical vertebrae are narrowed and the vertebral end-plates are eroded without appreciable formation of osteophyte.

humeral head, the distal radius, and the tibia1 plateau. Unlike brown tumors of hyperparathyroidism, these bone cysts typically occur adjacent to joints". On plain radiographs, they appear as well-defined radiolucencies with occasional disruption of the bony cortex but no periosteal reaction" 13.

Cysts vary in size, ranging from 2 to 3 mm diameter in the carpal bones to as large as 40 mm in the a c e t a b u l ~ m ~ ~ . Even in the absence of radiographic features of hyperparathyroidism, these cysts increase in number and enlarge with timeu.

Pathologic fractures Pathologic fractures, especially of the femoral neck, may

occur through areas of bone weakened by amyloid depos- itS45.47 . Patients with femoral neck fractures may experience the sudden onset of intense leg pain, especially when walk- ing48. The prevalence of femoral neck fracture associated with long-term hemodialysis is significantly higher in patients with periosteal P2M deposition on iliac crest bone biopsy specimens than in patients without P2M depositioni9.

Systemic involvement Although P2M amyloid deposits predominantly in

osteoarticular tissue, visceral deposits of P2M amyloid have been identified. Most patients with visceral deposits have undergone hemodialysis for 10 years or longer and also have either carpal tunnel syndrome or arthropathysO. The amount of visceral P2M amyloid deposition increases with longer duration of dialysis50, however, the extent of systemic involvement remains controversial.

Most of the information available about systemic involvement by P2M amyloid is derived from postmortem examination of patients receiving long-term hemodialysis, whereas during life, histologic evidence is acquired only when the clinical consequences of the amyloid deposits require surgical intervention. Thus, the actual extent of asymptomatic visceral P2M amyloid deposition is poorly understood, especially in patients who have undergone dialysis for less than 10 years.

The prevalence of visceral P2M amyloid deposition identified on postmortem examination varies among published reports. In a study of 19 patients, all of whom had osteoarticular P2M amyloid deposits, four also had visceral P2M amyloid deposits that were small and localized to blood vessel walls of heart, lung, liver, duodenum, tongue, prostate, and adrenal glands'. Patients with visceral deposits had received hemodialysis for longer than 13 years. Another study demonstrated visceral P2M amyloid deposits on postmortem examination of 7 patients who had received hemodialysis for 10 years or longer but not in any of 13 patients who had undergone hemodialysis for less than 10 years". Visceral P2M amyloid was deposited mainly

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Amyloid: Int. J Exp. Clin. Invest. 4, 187-211 (1997)

in blood vessel walls; the heart, gastrointestinal tract, and lungs were most frequently involved. In autopsy material from 6 patients with osteoarticular P2M amyloid deposits. visceral P2M amyloid deposits were found only in a 70-year- old woman who had received hemodialysis for 10 years; no visceral P2M amyloid deposits were found in the other 5 patients, although one 58-year-old man had received hemodialysis for longer than 14 years”. Thus, other factors in addition to the duration of dialysis determine the extent of visceral P2M amyloid deposition.

Two types of visceral P2M amyloid deposits have been identified: vascular deposits and interstitial deposits5? (Table 2). In contrast to osteoarticular P2M amyloid, which is deposited predominantly in the interstitium, visceral P2M amyloid is deposited predominantly in blood vessels’O. Vas- cular deposits may be linear, replacing the muscular layer around the circumference of small vessels, or nodular, located beneath the vascular endothelium and protruding into the vessel lumen50. Linear deposits of P2M amyloid in blood vessel walls may result in vascular fragility and bleed-

ischemia of the tissues supplied by those vesselss4 and occasionally result in perforation of viscera52. Interstitial deposits may be focal or difhse (“plate-like”) and can infiltrate visceral smooth m ~ s c l e ~ ’ ~ ~ ~ . Diffuse interstitial P2M amyloid deposits may cause m a l a b ~ o r p t i o n ~ ~ or disturbances of smooth muscle h n c t i ~ n ~ ~ .

inoi l . , nodular deposits occluding vessel lumens may lead to

Gastrointestinal tract Most of the visceral P2M amyloid deposits reported to

cause symptoms during life have been in the gastrointestinal tract. Subepithelial P2M amyloid deposits have caused nodular enlargement of the tongue and difficulty in swal-

caused macroglossia and ~ d y n o p h a g i a ~ ~ . Gastric ulceration has been associated with extensive P2M amyloid deposition in the lamina submucosa and lamina muscularis propria ofthe stomach5‘. P2M amyloid deposition in the lamina muscularis mucosae of the stomach and the walls of small submucosal vessels has resulted in intestinal pseudo-obstruction with gastric dilations7. Hemorrhage has occurred at sites of P2M amyloid deposition in submucosal blood vessels of the duodenum53 and jejunums6. P2M amyloid deposition in small- and medium-sized blood vessels and in the lamina muscularis propia ofthe small intestine has also resulted in small bowel ischemia and perforation’O. c 4 .

Extensive deposition of P2M amyloid in submucosal blood vessels and the lamina muscularis propria of the small and large intestines has resulted in malabsorption and diarrhea’6 and in intestinal pseudo-obstruction6’. P2M amyloid deposition in submucosal blood vessel walls and the muscle layer of the large intestine has resulted in intestinal in far~ t ion~‘ ,~’ -

and p e r f ~ r a t i o n ~ ? . ~ ~ . P2M amyloid deposition in the walls

lowing% 59. , diffuse submucosal P2M amyloid deposits have

of small submucosal blood vessels of the colon has also been associated with intestinal pseudo-obstruction64, 66. 67 .

Thus, systemic deposition of P2M amyloid may result in significant morbidity.

P2M amyloid deposits not causing signs or symptoms have been detected within the walls of small submucosal blood vessels in the rectum of patients undergoing long- term hemodia ly~ i s~~ , 68-70. Rectal biopsy may demonstrate systemic involvement of P2M amyloidosis if the sample includes submucosal tissue55, but it may not yield diagnostic findings, even from patients in whom visceral P2M amyloid deposition subsequently has been demonstrated on postmortem examination, because of sampling error7I.

In the liver, small P2M amyloid deposits have also been observed in the walls of arterioles, small arteries, and veins7.

tion caused by P2M amyloid deposition has not been reported.

47. 50, 5 5 , 56, 71-75 . H owever, clinically evident hepatic dysfunc-

Heart and lungs P2M amyloid deposits have been identified in the myo-

cardium52. 5 3 . 5 5 . 7 1 . 7 5 , endocardiums3, cardiac valves and valve rings7’. 7 6 , and within blood vessel walls in the heart7, 46.47. (O.

T2. 55, 56. 72-74. 76-78 . Campistol and reported two- dimensional echocardiographic evidence of amyloidosis in 12 of 23 patients (52%) who had undergone hemodialysis for 6 years or longer. P2M amyloid deposited in the myocar- dium and mitral valve ring of a patient who had received long-term hemodialysis caused “difficulty seating” a pros- thetic valve in the valve ring during mitral valve replacement surgery7‘.

P2M amyloid deposits have also been described in the walls of small pulmonary blood vessels7. 47 76.

Although most P2M amyloid deposits in the heart and lungs are asymptomatic, severe pulmonary hypertension, right ventricular failure, and low cardiac output developed as a result of P2M amyloid deposited predominantly in the walls of small arteries, arterioles and venules supplying the myo- cardium and of small peripheral pulmonary arteries and veins in a 6 1 -year-old woman who had received hemodialysis for 13 years76.

52. 55. 56,

Genitourinary tract Small deposits of P2M amyloid in the genitourinary tract

have been observed in the kidney5’ 5? 56 71 75 and the urinary bladder52, 7 3 . 79 of patients who had undergone long-term hemodialysis. Two patients, each of whom received a renal allograft from the same donor after having undergone hemodialysis for only 10 and 25 months, had nodular deposits of 132M amyloid within the walls of the transplanted ureters that caused ureteral obstruction 3 months after transplantation*’. Neither of the recipients nor the donor had other evidence of P2M amyloidosis.

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Urinary matrix calculi, which are found in 5% to 7.5% of patients receiving chronic hemodialysis, contain P2M, serum amyloid P component (SAP), and lysozyrne". Congo red-stained sections of these stones reveal the apple-green birefringence that is characteristic of amyloids2.

In the male reproductive tract, both vascular and interstitial deposits have been noted in the prostate7. ' 5 73. 75 and testissz, 5 5 , 7s. In the female reproductive tract, large paren- chymal deposits of P2M amyloid, some with areas of acute and granulomatous inflammation, have been observed in the uterine broad ligament, within blood vessel walls in the broad ligament, and in the myometrium8*.

Nervous system P2M amyloid deposits have been identified in the en-

doneurium, perineurium, and around blood vessels in the epineurium on biopsy of a sural nerve from a 55-year-old woman receiving hemodialysis for 10 yearsg3. She had symptoms of peripheral neuropathy but did not have either carpal tunnel syndrome or arthropathy. P2M amyloid deposits have been found in the walls of blood vessels in the brain of a 59- year-old man who had undergone hemodialysis for 15 years7s.

Endocrine system On postmortem examination of patients who had

received long-term hemodialysis, P2M amyloid deposits have been found in blood vessel walls of the thyroid gland56, 71,

pancreas7', 7 3 , and adrenal glands7. s*. 5 5 . 56. 7s. Diffuse interstitial P2M amyloid deposits also have been found in the parathyroid glands of a 60-year-old man who had received hemodialysis for 11 years5' and in the enlarged left lobe of

the thyroid gland of a 5 1 -year-old man who had undergone hemodialysis for 13 yearss9. However, during life, none of these patients manifested clinical evidence of decreased glan- dular hnction related to the presence of these deposits.

Skin Cutaneous manifestations of P2M amyloidosis occur

infrequently in patients receiving chronic hemodialysis. Biopsies of clinically uninvolved skin from patients undergoing long-term hemodialysis have demonstrated no P2M amyloid deposition, even in patients with amyloid arthropathy and carpal tunnel syndromeS1~ss.72. However, biopsies of hyperpigmented skin lesions from 37 patients who had been receiving hemodialysis for longer than 10 years revealed cutaneous P2M amyloid in 3 patients (8.1%) by light rnicros- copy; amyloid fibrils were detected in skin biopsies from 17 of 30 of these patients (56.7%) using electron microscopy8'. Cutaneous P2M amyloid deposits have also been found on biopsy of lichenoid-appearing papules that developed on the arms and trunk of a 40-year-old man with musculoskeletal manifestations who had undergone hemodialysis for more than 15 yearsg5. Arnyloid was deposited in the dermal papillae, along the dermal-epidermal junction. and around the eccrine ducts and hair follicles.

Subcutaneous amyloidomas also occur in patients with P2M amyloidosis. Large subcutaneous P2M amyloid deposits, occasionally bilateral, have been observed in the gluteal regions of five patientss8, 79. 86-88 and the popliteal fossae of two patient^^^,^^. Each of the patients, who ranged in age from 40 to 76 years and had received hemodialysis for 10 to 18 years, also had carpal tunnel syndrome or arthropathy.

Table 2. Visceral P2M amyloid deposition.

Vascular deposits Interstitial deposits

Tongue Esophagus Stomach Intestine Rectum Liver Spleen Pancreas Brain Heart Lung Thyroid Adrenal glands Kidney Testes Prostate Urinary bladder Uterine broad ligament

Tongue Stomach Intestine Rectum Heart Thyroid Parathyroid gland Kidney Prostate Testes Uterine broad ligament Peripheral nerve Skin

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In summary, P2M amyloid deposits not only in osteoarticular tissue but also in viscera and skin of patients receiving long-term dialysis treatment for chronic renal failure. Deposits of P2M arnyloid outside the musculoskeletal system may also result in significant morbidity, as has been observed in the gastrointestinal tract. Systemic involvement by P2M amyloidosis appears to occur predominantly in patients who have undergone hemodialysis for longer than 10 years. However, systematic postmortem examination of a large number of patients with chronic renal failure will be necessary to determine the actual extent of systemic P2M amyloid deposition.

Effect of age Dialysis arthropathy occurs more commonly in older

patients. Gaucher and colleagues9' reported that most of their patients with dialysis arthropathy were between the ages of 50 and 70 years; most of the patients who were younger than SO years were without clinical evidence of dialysis arthropathy. A European multicenter study" dern- onstrated that advanced age at onset of dialysis correlates

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with the development of carpal tunnel syndrome and radiographic evidence of amyloid bone cysts. The destructive spondyloarthropathy is also more likely to be present in individuals who were older at the onset of h e m ~ d i a l y s i s ” ~ ~ ~ . Signs of dialysis-related amyloidosis appear sooner in patients who are older at the initiation of hemodialysis therapy93.

P,-microglobulin amyloidosis occurring before dialysis

Three cases have been reported in which P2M amyloidosis developed in patients with chronic renal failure who had not yet received dialysis treatment, although almost all of the patients in whom P2M amyloidosis has been demonstrated had undergone hemodialysis or continuous ambula- tory peritoneal dialysis (CAPD). Thus, because P2M amyloidosis occurs in individuals with chronic renal disease who have not yet received dialysis therapy, it is a conse- quence of the duration of uremia and not of the dialysis treatment alone. However, factors related to the dialysis prescription may contribute to the development of P2M amyloidosis.

P2M amyloid was demonstrated in the stemoclavicular joint of a 69-year-old woman with “long-standing renal insufficiency” who also had radiographic evidence of cysts in the carpal bones and knees and of lumbar ~pondyloarthropathy~“. P2M amyloid was also demonstrated in the intervertebral disk between the fifth and sixth cervical vertebrae of a 5 1 -year-old woman in whom renal insufficiency had been present for 17 yearsgs. Radiographs revealed erosive spondyloarthropathy involving the intervertebral disks between the fifth and seventh cervical vertebrae, erosive arthropathy of the right acromioclavicular joint, and cysts in the hands and left femoral neck.

A third case of P2M amyloidosis, developing before chronic hemodialysis, has been reported in a 65-year old man with noninsulin-dependent diabetes mellitus of 30 years’ duration and severe uremia of 1 year’s duration96. Radio- graphs obtained at the onset of hemodialysis demonstrated cystic radiolucencies in the left wrist and erosive spondyloarthropathy involving the intervertebral disks between the fifth and eighth cervical vertebrae. The patient had received only four hemodialysis treatments when he underwent surgical decompression of the left carpal tunnel: P2M amyloid deposits were present in the excised transverse carpal ligament and tenosynovium. The presence of long-standing diabetes mellitus with microvascular complications, in the setting of advanced age, may have accelerated the development of P2M amyloidosis before dialysis treatment in this patient, despite his relatively brief duration of uremia. Advanced glycation end products (AGE), which have been implicated both in the development of diabetic

complications and the aging process9’, may have contrib- uted to the rapid development of P2M amyloidosis in this patient.

P,-microglobulin amyloidosis and diabetes mellitus

If AGE are involved in the pathogenesis of both diabetic complications and P2M amyloidosis, diabetic patients with nephropathy might be expected to experience the manifestations of P2M amyloidosis earlier than nondiabetic patients with renal failure. Because the 5-year survival rate for diabetics with end-stage renal disease (20%) is only half that for nondiabetics (39%), diabetic patients receiving hemodialysis may not live sufficiently long for clinically evident P2M amyloidosis to develop98.

A recent cross-sectional case-control study of diabetic and nondiabetic patients who had undergone hemodialysis for longer than 5 years described the prevalence of radiolu- cent cysts in the carpal bones and of carpal tunnel syndrome to be similar in both groups99. However, each ofthese clinical manifestations may occur in conditions other than P2M amyloidosis, and tissue was not examined for P2M amyloid deposition. Thus, further investigation of the occurrence of P2M amyloidosis in diabetic patients with chronic renal failure is necessary. Additional studies com- paring the prevalence of both periarthritis of the shoulder and flexor tenosynovitis of the hand in diabetic and nondiabetic patients receiving hemodialysis, with histologic con- firmation of P2M amyloid deposition, are needed to elucidate the relationship between these two conditions.

Diagnosis

The diagnosis of dialysis-related amyloidosis is suggested primarily by its clinical appearance. Radiographic findings, such as bone cysts, narrowing of the intervertebral disk space, and vertebral end-plate erosion, serve to cor- roborate the diagnosis. However, histologic identification of P2M amyloid by Congo red and immunohistochemical staining in biopsy specimenP9 or in centrifuged synovial fluid sedimentsIoo remains the gold standard for diagnosis. As with AA amyloid, potassium permanganate pretreatment of tissue sections decreases Congo red

Computed tomography (CT) and MRI Amyloid deposits have distinct MRl characteristics: the

relatively long T1 and short T2 relaxation times result in a low to intermediate signal intensity, between that of fibro- cartilage and that of muscle, on both T1- and T2-weighted images. These signal characteristics distinguish amyloid

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deposits from inflammatory or fluid-filled lesions, which display low signal intensity on TI-weighted images and high signal intensity on T2-weighted imageslO'. On CT scanning, these amyloid deposits have intermediate internal attenua- tion values between 0 and 30 Hounsfield

P2M amyloid deposits that are too small to be seen on conventional radiographs may be evident by CT or MRIIo2. These imaging modalities may demonstrate soft-tissue masses, such as cervico-occipital p~eudotumors~', 34 that are not apparent on plain radiographs. CT or MRI may also show communication of intraosseous amyloid deposits with the joint space'02.

MRI of the spine may differentiate destructive spondyloarthropathy from infectious diskitis and from vertebral osteomyelitis. MRI o f destructive spondyloarthropathy demonstrates low to intermediate signal intensity in the intervertebral disk and adjacent vertebral end plates on both T 1 - and T2-weighted images. These MRI characteristics differ from those observed in infectious diskitis, where there is low signal intensity on T1 -weighted images and high signal intensity on T2-weighted images, and from those seen in vertebral osteomyelitis, where a prevertebral soft tissue mass is often visiblelo3.

Scintigraphic imaging Scintigraphic imaging has been tested as a noninvasive

technique to identify P2M amyloid deposits in patients receiving hemodialysis. Scintigraphy with 99mTc-methylene dip hosp honat e ( 99mTc-MD P) demonstrates increased radiotracer uptake by articular bone and soft tissue around large joints affected by P2M a m y l o i d o ~ i s ~ ~ ~ . Increased radiotracer uptake has been observed at the sites of cystic bone lesions, which are presumed to correlate with intraosseous P2M amyloid depo~its'~'. However, in a study of 17 patients with dialysis arthropathy, 99"'Tc-MDP uptake was not detected in 7 of 16 clinically affected shoulders'04. In another series of 7 patients with P2M amyloidosis who had undergone hemodialysis for 10 years or longer, radiotracer uptake was also increased diffusely throughout the skeleton in 3 patients with marked hyperparathyroidism and in the small joints of the hands in 3 patients at sites of erosive azotemic ~steoarthropathy~~~, which is a complication of long-term hemodialysis that is not associated with P2M amyloid deposition'06. Thus, scintigraphy with 99mT~- MDP in patients receiving hemodialysis is not specific for the diagnosis of P2M amyloidosis.

Whole-body scintigraphic imaging with Iz3I-SAP, which has been used to identify, quantify, and monitor amyloid deposits in patients with AL, AA, and hereditary forms of systemic amylo id~s i s '~~ , has also been used to localize amyloid deposits in patients undergoing hemodialysislo8. Radiotracer uptake was observed in joints in which P2M

amyloid had been demonstrated by biopsy. Although radiotracer uptake was detected in all symptomatic wrists and in 9 of 10 symptomatic knees, it was detected in only 7 of 19 (37%) symptomatic shoulders. The lower sensitivity of 1231-SAP scintigraphy in the shoulder, which is a joint often affected by P2M amyloidosis early in its clinical course, lim- its the utility of this investigational imaging modality as a screening test for this condition.

Scintigraphy with ')'I-P2M, another investigational imaging technique, has detected P2M amyloid deposits in patients receiving long-term hemodialysi~'~~. This radiotracer accumulates in osteoarticular structures, including the shoulders, that are clinically symptomatic and/or demonstrate radiographic changes characteristic of P2M amyloidosis; it does not accumulate in structures where both symptoms and radiographic changes are absent. Histologic examination of tissue obtained from a patient who had been injected with '"I-P2M demonstrated concentration ofthe radioactiv- ity in P2M amyloid deposits and not in surrounding tissues. Further study of this imaging technique is necessary to determine whether it is a sensitive and specific method for detecting P2M amyloid deposits. However, the risks of radiation exposure and of blood-borne infections will limit its use in screening patients for P2M amyloidosis.

Ultrasonography Diagnostic ultrasonography, a noninvasive imaging mo-

dality that involves no exposure to radiation or to blood products, detects changes that are characteristic of P2M amyloidosis in patients undergoing chronic hemodialysis. We have used real-time, high-resolution ultrasonography to evaluate the shoulders of patients chronically hemodialyzed against cuprophane membranes. In comparison to 13 patients with normal renal fimction and no evidence of amyloid, at least one of two ultrasonographic findings was selectively observed in 1 1 of 14 (79%) patients undergoing hemodialysis with clinical and histologic evidence of P2M amyloid: rotator cuffs greater than 8 mm in thickness and echogenic pads between muscle groups of the rotator cuff. These findings were not observed in any patient with normal renal function or in 19 of 20 (95%) patients undergoing hemodialysis without clinical or histologic evidence of P2M amyloidosis. Thus, the presence of at least one of these two findings on ultrasonography of the shoulder provides a relatively sensitive and highly specific noninvasive adjunct to the clinical diagnosis of P2M amyloidosis in the patient undergoing long-term hemodialysisZ1.

Thickening of synovial tissue has also been demonstrated by ultrasonography in the knees of 11 patients receiving hemodialysis. The mean total synovial thickness was 4.7 mm in the 19 knees with suprapatellar effusions compared with 0.3 mm in 18 knees of 9 individuals without knee

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Amyloid: Int. J Exp. Clin. Invest. 4, 187-211 (1997)

symptoms or joint effusions. Patients with amyloid demonstrated in synovial fluid aspirated from the knee had thicker knee joint synovium than the patient without amyloid in synovial fluid, suggesting that increased knee joint synovial thickness correlates with the presence of P2M amyloid in patients undergoing long-term hemodialysis44. Further study is necessary to confirm this observation.

Screening questionnaire We developed a 19-item self-administered questionnaire

to evaluate the effects of dialysis-related amyloidosis on functional status'''. This dialysis-related amyloidosis questionnaire (DRAQ) is a reliable, internally consistent, and valid instrument to assess symptoms and disability associated with P2M amyloidosis. When the DRAQ was administered to 15 patients with dialysis-related amyloidosis and 15 age- matched control subjects who had been on hemodialysis for less than 24 months, a DRAQ score of 30 or more indicated the presence of dialysis-related amyloidosis with a sensitivity of 93% and specificity of 80%. The positive predictive value of a DRAQ score of 30 or more ranged from 2% when the prevalence of P2M amyloidosis was estimated to be 0.5% to 54% when the disease prevalence was estimated to be 20%. The negative predictive value of a DRAQ score of 30 or more was greater than 98% when the disease prevalence was estimated to be 20% or less, suggesting that symptomatic and disabling P2M amyloidosis would be unlikely in individuals with low total DRAQ scores. The DRAQ is sensitive and specific enough to be useful and cost effective in population screening, particularly as the first test in a two- part case-finding strategy utilizing either shoulder ultrasonography or another radiographic technique to further evaluate patients with elevated DRAQ scores.

Abdominal fat pad aspiration Abdominal fat pad aspiration is a sensitive and specific

screening test to diagnosis AL"' and AA amyloidosis and familial amyloid polyneuropathy'I2, but it has not proven to be as useful in screening for P2M amyloidosis. Although Campistol and colleagues" found amyloid deposits by Congo red staining in abdominal fat pad aspirates from 9 of 25 patients (36%) who had received hemodialysis for 6 years or longer, Varga and colleague^"^ found no amyloid deposits in abdominal fat pad aspirates obtained from 30 patients who had undergone hemodialysis for 2 years or longer. Although the patients in both studies were of similar age. only 37% of the patients studied by Varga and associates had carpal tunnel syndrome, whereas 84% of the patients studied by Campistol and colleagues had carpal tunnel syndrome. This suggests that a lower prevalence of P2M amy-

loidosis among the patients studied by Varga and colleagues could have accounted for the absence of amyloid deposits in the abdominal fat pad aspirates obtained from their population.

Constituents of P,-microglobulin amyloid deposits

P2M amyloid deposits contain various macromolecular and cellular constituents. Besides the subunit protein P2M, proteases and protease inhibitors have been demonstrated in and around P2M amyloid deposits. Proteoglycans, glycosaminoglycans, and other proteins that are also present may affect the formation or deposition of P2M amyloid fibrils. The predominant cells infiltrating P2M amyloid deposits are macrophages2*.

P ,-microglobulin P2M was frst described in 1968 by Berggkd and Beam

as a low molecular weight P,-globulin isolated from urine of patients with tubular proteinuria caused by Wilson's disease or chronic cadmium poisoning'I4. In 1985, Gejyo and colleagues identified P2M as the subunit protein in the amyloid associated with chronic hemodialysis'. This nonglycosylated 1 1,800 dalton protein is homologous in sequence"', 'I6 and to the constant (C) region domains of immunoglobulin (Ig) K and h light chains and the y 1 heavy chain of IgG. It is found on the plasma membrane of all nucleated mammalian cells, where it is noncovalently associated with human leukocyte antigen (HLA) Class I molecules118. It is normally present in most biological fluids, including serum, urine, and synovial fluid'19. Serum concentrations range up to 2.7 pg/ml in healthy individuals with normal renal function. P2M is filtered by glomeruli and catabo- lized after proximal tubular reabsorption'20. Serum levels of P2M correlate with serum creatinine levels, and patients undergoing hemodialysis have an 8- to 60-fold elevation in their serum P2M levels1".

Intact monomeric P2M is present in amyloid deposits of patients receiving chronic hemodialysis'. Aggregates of intact P2M, consisting of dimers and tetramers, have also been isolated from amyloid deposits of patients undergoing chronic hemodialysis". I ? ? . The prominent P-pleated sheet structure of P2M permits it to adopt the fibrillar configura- tion of amyloidh8~77. ] I 7 . By electron microscopy, P2M amyloid deposits as nodules composed of short, tightly packed bundles of parallel aggregated fibrils with a curvilinear configurationh8 "

Several modified forms of P2M have also been identi- tied in some amyloid specimens. Sera, plasma ultrafiltrate,

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and amyloid deposits contain isoforms of P2M that migrate to a more acidic position than normal P2M on isoelectric focusing124. Although deamidation of Asn to Asp at residues 17 and 42 has been identified in one such isoform of P2M purified from plasma ultrafiltrate of a patient with carpal tunnel syndrome who had undergone hemodialysis for longer than 15 amino terminal amino acid sequencing of six other such P2M isoforms extracted from amyloid deposits has not demonstrated deamidation of Asn to Asp at residue 1 7Iz6. AGE-modified P2M (AGE-P2M), which constitutes about 10% of the total P2M in the sera and urine of patients receiving long-term hemodialysis, also migrates to a more acidic position than normal P2M on isoelectric focusing and has been demonstrated in P2M amyloid deposits6. P2M that is truncated after the amino terminal Lys-6 has also been identified in amyloid deposits from bone and carpal tunnel synovium and P2M truncated after Lys-19 has been found in amyloid kidney stones but not in osteoarticular amyloid deposit~'~' . While this pattern of fragmentation could represent an artifact generated ex vivo during extraction and isolation of the amyloid fibrils, it might be produced in vivo by limited proteolysis of P2M at the amino terminus by lysine- specific proteases.

Proteases and protease inhibitors By immunostaining, the human neutrophil proteases

elastase and cathepsin GI2* and matrix metalloproteinases (MMP)129 have been demonstrated in and adjacent to P2M amyloid deposits. The MMP that is expressed most promi- nently in P2M amyloid deposits is MMP-I, which can degrade types I, 11, 111, and X In carpal tunnel synovium, MMP-1 is found in hyperplastic synovial lining cells, in fibroblasts beneath the proliferating synovial lining cells, in mesenchymal cells with chondroid metaplasia, and in granulation tissue. MMP- 1 expression correlates with the degree of macrophage infiltration and synovial proliferation but not with the amount of amyloid deposition or duration of hemodialysis. To a lesser degree, MMP-2 is also present in fibroblasts beneath the synovial lining cells and MMP-9 is present in capillary endothelial cells in areas of neovascularization. In the hip joint, MMP-I is expressed by chondrocytes beneath P2M amyloid deposits in articular cartilage, by mesenchymal cells in and around amyloid deposits, and by periosseous fibroblasts and osteoclasts at the interface between subchondral bone and amyloid. These osteoclasts also express MMP-9129. However, although enzymatic activity characteristic of elastase and cathepsin G is associated with fibrils isolated from deposits of P2M amyloid, collagenolytic activity is notlz8.

The presence of protease inhibitors in P2M amyloid deposits may account for the absent collagenolytic activity ofthese MMP. Tissue inhibitors ofmetalloproteinase (TIMP)

have been identified around deposits of P2M a m y l ~ i d ' ~ ~ , I".

TIMP-1 is found in synovial lining cells and in capillary endothelial cells in areas of neovascularization; TIMP-2 is present in fibroblasts beneath the synovial lining cells129. Amyloid P component, which has been reported to inhibit the proteolytic activity of elastase in v i r r ~ ~ ~ l , is found in the interstitial space between P2M amyloid fibrils12'. Anti- thrombin 111, a,-proteinase inhibitor130, and a,-macroglobu- lin130, 132 , are also present in P2M amyloid deposits as well as in surrounding tissue. These molecules may inhibit proteolysis or permit limited proteolysis of P2M at the site of fibril deposition.

Other macromolecules Deposits of dialysis-related amyloid contain macromol-

ecules other than P2M, proteases, and protease inhibitors, which may influence the formation or deposition of P2M amyloid fibrils Ubiquitin, an 8,600 dalton protein that has amyloid enhancing factor activity in a murine model of AA amylo id~s i s l~~ , deposits with P2M amyloid in '35.

Compared with healthy individuals with normal renal hnction, plasma levels of ubiquitin measured by radioimmunoas- say are elevated both in patients with chronic renal failure who have not yet received dialysis therapy and in those who have undergone hemodialysis. This elevation may result from decreased renal clearance of ubiquitin. Plasma ubiquitin concentrations increase with longer duration of hemodialysis and are significantly higher in patients with carpal tunnel syndrome than in those without carpal tunnel syndrome, despite the two groups having similar serum concentrations of P2M13'. Thus, could ubiquitin promote the formation of P2M amyloid in patients with chronic renal failure?

An 85,000 dalton heterodimer protein, with subunit molecular weights ofapproximately 55,000 and 30,000 daltons, has been purified from sera of patients undergoing hemodialysis and identified in P2M amyloid This heterodimer binds the fluorescent dye, thioflavin T. Whereas the 85,000 dalton protein has a novel amino terminal amino acid sequence, the smaller subunit chain of the heterodimer has been identified as the K light chain137. Although the function of the 85,000 dalton heterodimer protein or of K

light chains in P2M amyloid deposits is not known, electron microscopy with double label immunogold staining demonstrates colocalization of amyloid filament immunoreactivity with antibodies to P2M and K light chains137, 13*. The 14,000 dalton human globin P-chain is also associated with P2M amyloid fibrils139.

Proteoglycans and glycosaminoglycans surround the nodules and bundles of P2M amyloid but are not present on the amyloid fibrils t h e m ~ e l v e s ' ~ ~ . Chondroitin sulfate is the major glycosaminoglycan that surrounds P2M amyloid

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Amyloid: Int. J. Exp. Clin. Invest. I, 187-211 (1997)

fibrils1", I d ' ; in contrast, dermatan sulfate and heparan sulfate are the major glycosaminoglycans surrounding AL and AA amyloid fibrilslJO. Nishi and colleagues12' suggested that the proteoglycans and glycosaminoglycans may have a regu- latory effect on the distribution and arrangement of P2M amyloid fibrils.

Cellular constituents Macrophages are the predominant cell type infiltrating

P2M amyloid deposits28, in contrast to AL or AA amyloidosis, where little inflammatory cell infiltration is observed around amyloid In tenosynovial tissue, the macrophage infiltration occurs mainly around blood vessels"'. Immunohistochemical staining reveals these macrophages to express HLA-DR and the CDI 3, CD14, CD33'", and CD68 antigens on their surfaces and to contain 1L-1 P, TNFa'*, and IL-6Id3. Many of these macrophages also express the adhesion molecules LFA-1 (CDl IdCDI S), Mac- 1 (CD 1 1 b/CDl S), and VLA-4 (CD49dlCD29) on their surfaces"'. The degree of inflammatory cell infiltration correlates with the extent of P2M amyloid deposition, with little cellular infiltration around small deposits of P2M amyloid. Electron microscopy provides evidence of phagocytosis of P2M amyloid fibrils by macrophages, with protruded cyto- plasmic processes engulfing amyloid fibrils and phagolysosome-like vacuoles containing amyloid fibrils6*

Multinucleated giant cells, some of which have phago- cytosed amyloid, may be present in areas with significant P2M amyloid depositionz8. Lymphocytes are infrequently detected around P2M amyloid deposits'44.

At the edges of bone cysts containing P2M amyloid, trabecular bone appears eroded with scalloped margins145. Osteoclast activity is slightly increased, whereas no signs of bone regeneration by osteoblasts are evident. Electron microscopy of mesenchymal cells and osteolining cells that have engulfed P2M amyloid fibrils from bone cysts reveals degeneration of the cell membranes and intracellular organs'23. This may represent the rnorphologic correlate of the observation that P2M inhibits calcification of cultured murine os t e~b las t s l~~ .

Pathogenesis

Various factors have been implicated in the pathogenesis of P2M amyloidosis. Retention of the subunit protein P2M by patients with chronic renal failureI2' is presumed to be the basic requirement for the initiation of P2M amyloid deposition. Poor biocompatibility of dialysis membranes has been suggested as a cause of P2M amyloidosis, although it does not completely account for the development of this

condition. AGE-modification of proteins, elevated levels of cytokines, and impaired bone metabolism may promote P2M amyloid deposition.

Elevated concentrations of 0,-microglobulin Because P2M forms amyloid fibrils at high concentra-

t i on~ '~ ' , it has been proposed that the dialysis-related amyloidosis is due to the elevated P2M levels seen among patients undergoing hemodialysis. Levels of P2M in synovial fluid, where P2M amyloid deposition is most prominent, are similar to those in serum148. However, serum levels of P2M in patients with carpal tunnel syndrome caused by amyloidosis are not appreciably higher than levels of P2M in patients without carpal tunnel syndrome who have undergone hemodialysis for an equivalent durationlJ9. Serum P2M levels are comparable for patients of different ages, despite the increased prevalence of dialysis arthropathy among older patientsIs0. Thus, dialysis-related amyloidosis cannot be explained solely on the basis of chronically elevated levels of 132M.

Dialysis membranes The role of the dialysis membrane in the pathogenesis

ofP2M amyloidosis is uncertain. The epidemiologic studies published are limited by small numbers of patients dialyzed exclusively on the newer membranes. In one study, the incidence of carpal tunnel syndrome was greater among patients who had been dialyzed against cellulose-based cuprophane membranes than among those dialyzed exclusively against the polyacrylonitrile membrane AN69I5'. In a larger European multicenter bone cysts, but not carpal tunnel syndrome, were observed more frequently among patients dialyzed against cuprophane membranes than among those dialyzed against AN69. Polyacrylonitrile membranes are considered to be more biocompatible than cuprophane membranes because they induce less intradialytic leukopenia and hypotension and do not activate complement by the alternative pathway to generate the anaphylatoxin C5a1". Thus, it has been proposed that P2M amyloidosis may be caused by dialysis with less biocompatible membranes.

Contact with dialyzer membranes may enhance P2M production by cells. Transcription of P2M mRNA in lymphocytes is stimulated by contact with cuprophane dialyzer membranes; this transcription is stereospecifically inhibited by the soluble carbohydrate L-fucose"'. These lymphocytes express increased amounts of P2M and HLA Class I antigen on their surface. P2M production by peripheral blood mononuclear cells cultured inside hollow fiber dialyzer membranes is higher when cells are incubated with cuprophane mem-

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brane than when cells are incubated with either of the more biocompatible polymethylmethacrylate (PMMA) or AN69 membrane^'^^. P2M production by peripheral blood mononuclear cells in vitro is also increased in cells isolated from patients receiving intermittent hemodialysis with a new cuprophane membrane but not in cells isolated from patients receiving hemodialysis with the more biocompatible PMMA membrane. Incubation of these mononuclear cells with IL- 1 P or C5a further increases P2M produ~ t ion l~~ .

However, P2M amyloidosis is not completely explained by poor biocompatibility of membranes. In a French multicenter study17, the prevalence of dialysis-related arthropathy was similar among patients undergoing dialysis for more than 10 years regardless of whether they had been dialyzed against cuprophane or the more biocompatible AN69 membranes. P2M is not generated during hemodialysis with cuprophane membranes; when corrected for the decrement in extracellular volume (instead ofplasma volume), P2M levels do not increase’55. Serum P2M levels ofpatients on CAPD are comparable to levels of patients on hemodialy~is l~~. Finally, hemodialysis is not necessary for the deposition of P2M amyloid: deposits have been reported in patients with chronic renal failure who had never undergone d i a l y ~ i s ~ ~ - ~ ~ and in patients who had been treated exclusively with CAPD’57.

Advanced glycation end products The predominant form of P2M in amyloid fibrils extracted

from carpal tunnel tissue specimens of patients undergoing hemodialysis is modified with AGE6. AGE have several characteristic properties: they are yellow-brown in color, fluo- resce with emission at 440 nm upon excitation at 370 nm, and covalently crosslink macromolecule^^^^. AGE-modified proteins exhibit enhanced binding to collagen and trap nonglycosylated serum proteins, such as immunoglobulin, albumin, and low-density lipoprotein. AGE-modified proteins are less susceptible to degradation by proteases than are unmodified proteins9, 159. AGE generate reactive oxygen intermediatesI6O. These properties of AGE-modified proteins are presumed to contribute to the development of atherosclerosis and various complications of diabetes mellitus, including nephropathy, neuropathy, retinopathy, and cataracts9, I 6 I .

Post-translational modification of proteins with AGE results from nonenzymatic glycosylation by the Maillard reaction between reducing sugars and free amino groups on proteins (Figure 4). In the first step ofthe Maillard reaction, an a-amino group of the N-terminal amino acid or the E- amino group of lysine reacts with the carbonyl group of a reducing sugar to form a Schiff base. This step is reversible and reaches equilibrium over several hours’62. The Schiff base then undergoes intramolecular rearrangement to form

the more stable Amadori product, reaching equilibrium over 28 days. This second step is also reversible but the Keg is 8.4, favoring Amadori product f ~ r m a t i o n ’ ~ ~ . The Amadori products subsequently undergo a series of irreversible chemical reactions, including dehydration and rearrangement, to form highly reactive carbonyl compounds, such as 3-deoxyglucosone [3-deoxy-D-erythro-hexos-2-ulose] (3- DG)164. Over weeks to years, Amadori products undergo condensation with these carbonyl compounds, with other Amadori products, and with additional reactive amino groups to form AGEI6*.

Glucose concentration and protein half-life, among other variables, determine the extent of Amadori product and, con- sequently, ofAGE formation165. Thus, AGE and their precur- sors accumulate in diabetes mellitus and aging because of increased production. Patients with diabetes mellitus and hyperglycemia have higher concentrations than healthy euglycemic individuals of 3-DG166, AGE-modified plasma

and Amadori products, such as hemoglobin

AGE irreversibly bound to long-lived proteins, such as collagen158 and lens ~ rys t a l l i n l~~ , accumulate with age. Pro- teins with long half-lives, such as amyloid fibril subunit pro- teins6. I7O, are more susceptible to AGE-modification. The accumulation of AGE-modified proteins with age corresponds with the observations that P2M amyloidosis occurs earlier93 and is more prevalentg2 among older patients with chronic renal failure.

The functioning kidney clears AGE-modified proteins better than do dialysis modalities. Thus, AGE accumulate in uremia because of decreased removal. Serum concentrations of AGE-modified low molecular weight (2,000 to 6,000 dalton) proteins are 2 or 3 times lower in nondiabetic individuals with normal renal h c t i o n or with functioning renal allografts than in nondiabetic patients receiving conventional or high- flux hemodialysis or CAPD17’. Additionally, serum levels of the AGE precursor 3-DG are 5 or 6 times lower in nondiabetic individuals with normal renal function than in nondiabetic patients receiving conventional hemodialysis or CAPD1”. The presence of elevated serum levels of 3-DG and AGE- modified low molecular weight proteins in patients with chronic renal failure undergoing hemodialysis or CAPD par- allels the occurrence of P2M amyloidosis in these populations. The absence of elevated serum levels of 3-DG and AGE-modified low molecular weight proteins in nondiabetic patients with hnctioning renal allografts is consistent with the observation that P2M amyloid deposits do not progress, and may even regress, in patients who have undergone successful renal tran~plantationl~~.

AGE-modified proteins are specifically recognized by a receptor present on the surface of mononuclear phagocytes and endothelial cells. This 35,000 dalton receptor for AGE (RAGE) is a member of the immunoglobulin ~ u p e r f a m i l y ~ ~ ~ .

Alc168.

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On mononuclear phagocytes and endothelial cells, a 30,000 dalton lactoferrin-like polypeptide (LF-L) binds noncovalently to the extracellular domain of RAGE, forming a RAGE/LF-L complex that also binds AGE'75.

Binding of AGE-modified proteins to the RAGEILF-L complex on mononuclear phagocytes results in various cellular responses. Cells exposed to AGE-modified proteins may exhibit signs of oxidant The concentrations of reactive oxygen intermediates generated by AGE-modified proteins can activate the transcription factor NF-KB in the promotor of genes encoding cytokines, resulting in enhanced cytokine gene e x p r e ~ s i o n ' ~ ~ . AGE-modified proteins induce the secretion of proinflammatory cytokines, such as interleukin- 1 (IL- l), tumor necrosis factor-a ( T N F c ~ ) ' ~ ~ , and interleukin-6 (IL-6)I8". Binding of soluble AGE-modified proteins to the RAGE/LF-L complex on mononuclear phagocytes initiates monocyte chemotaxis; binding of immobilized AGE to this complex slows the migration of mononuclear phagocytes and may lead to the concentration of mono-

nuclear phagocytes in tissue deposits, such as P2M amyloid deposits, which contain AGE-modified

AGE-modified P2M (AGE- P2M) is present in the sera and urine of patients receiving long-term hemodialysis but not of healthy individuals with normal renal functionb. Pentosidine'* ' , NE-(carboxymethyl)lysine18?, and i rn idaz~ lone '~~ are AGE structures present on AGE-P2M in amyloid deposits of patients who had received long-term hemodialysis. The a-amino group ofthe amino-terminal iso- leucine residue is the primary glycated site on AGE-P2M purified from the urine of patients undergoing hemodialysis; the &-amino groups of lysine residues in at least six positions are additional sites of gIycationlE4.

AGE formation in types I, 11, and I11 collagens (the predominant collagens in osteoarticular tissue) is increased compared with type IV collagen (a collagen found in basement membranes) when each is incubated for 30 days with glucose under identical conditionsIs5. P2M binds readily to immobilized types I, 11,111, and IV collagen in vitro whether

pi + L 'y H \ ,o

1 CH C

CH,OH ,!&- Microglo bulin CH20H

7

( y w 4 NHZ I (CHOHh

Glucose Schiff Base

NH

y 2

'F '

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-I- !H2 -- C = O NH2

CH,OH CH,OH

3-Deoxyglucasone Amadori Product (Carbonyl Compound)

AGE-P,-Microg lo bul in

m

FIGURE 4. Post-translational modification of (12M with AGE. In the first step of the Maillard reaction, an amino group reacts with the carbonyl group of a reducing sugar to form a Schiff base. The Schiff base then undergoes intramolecular rearrangement to form the more stable Amadori product. The Amadori products subsequently undergo a series of irreversible chemical reactions, including dehydration and rearrangement, to form highly reactive carbonyl compounds, such as 3-deoxyglucosone [3-deoxy-D- erythro-hexos-2-ulose] (3-DG). Amadori products ultimately undergo condensation with these carbonyl compounds, with other Amadori products, and with additional reactive amino groups to form AGE, such as pentosidine, Nr-(carboxyrnethy1)lysine (CML), and imidazolone.

lrnidazalone Ho

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the collagen is modified with AGE or unmodifiedlB5. The amount of P2M that binds collagen is dependent on the concentration of either collagen or P2MIa6. However, significantly more P2M binds to immobilized AGE-modified type I collagen than to unmodified type I collagen18s. At the same concentration, more normal (unmodified) P2M binds to immobilized AGE-modified type I collagen than does AGE- P2M. Once bound to AGE-modified type I collagen, normal P2M undergoes AGE modification in sitdX5. These data sup- port the hypothesis that normal P2M binds to AGE-modified collagen, which is probably more abundant in osteoarticular tissue than in visceral basement membranes of older patients with chronic renal failure and that AGE formation subsequently occurs in the bound P2M. Once modified, the AGE-P2M may form cross links with the AGE- modified collagen. These cross-linked AGE-P2M collagens may ultimately be incorporated into deposits of P2M amyloid.

Of the different isoforms of P2M purified from the sera and urine of patients receiving long-term hemodialysis, AGE- P2M appears to be responsible for the observed biologic activity. AGE-P2M, but not normal P2M, enhances both chemotaxis (directed migration) and chemokinesis (random migration) of human monocyteslS7. AGE-P2M, but not normal P2M, induces enhanced oxidant stress and the elabora- tion of reactive oxygen intermediates by monocytesLsx. AGE-P2M might also contribute to the elevation of TNFaIa9, IL-1 IS9, and IL-61y0 levels observed in patients undergoing long-term hemodialysis. AGE-P2M induces synthesis and secretion of TNF-a187,18s, IL-1 P I x 7 , and IL-6Iy1 by macrophages, whereas macrophages incubated with normal P2M secrete much lower amounts of TNF-alS7, IL-1 PlS7, and IL- 6I9l. Neither deamidated P2M nor P2M modified with Amadori products elicits monocyte chemotaxis or induces secretion of TNF-a, 1L- 1 P, or IL-6 significantly more than does normal p2MIy2. The amounts of TNF-a and 1L-lP secreted by macrophages incubated with AGE-P2M are sufficient to induce transcription of collagenase mRNA by cultured human synovial cells and morphologic changes, with the synovial cells becoming dendritic in shapeIs7. Both chemotaxis and synthesis and secretion of TNF-a by monocytes are mediated by interaction between AGE-P2M and RAGEIa8. AGE-P2M-induced secretion of TNF-a by monocytes involves oxidant stress, since release of this cytokine is inhibited in the presence of the antioxidant N - acetylcysteineLa8.

AGE modification of proteins and binding of amyloid precursor proteins to RAGE may also be involved in the pathogenesis of amyloid diseases besides P2M amyloidosis. Immunostaining of hippocampal tissue from patients with Alzheimer’s disease has demonstrated the AGE pyrroline and pentosidine to be associated with amyloid-P peptide (AD) and tau protein in neurofibrillary tangles and senile

plaqueslg3. AGE-modified recombinant human tau protein, when introduced into cultured neuroblastoma cells. results in more synthesis of AP precursor and release of AP by these cells than when they are loaded with nonglycated recombinant human tau RAGE mediates the specific binding of AP to the surface of mouse brain endothelial cells, rat cortical neurons, and the mouse microglial cell line BV-2, although through structural determinants distinct from AGEIy4. RAGE expression is increased on neurons close to AP deposits, and RAGE levels are increased about 2.5-fold in brain of patients with Alzheimer’s disease compared with age-matched Interaction of AP with RAGE induces migration of microglia and accumulation of microglia at deposits of AS, as well as transcription, translation, and secretion of TNFa by m i ~ r o g l i a ’ ~ ~ . The similarity between the RAGE-mediated effects of AGE-P2M and of AP on mononuclear phagocytes suggests that analogous inter- actions between amyloid precursor proteins and RAGE might also occur in other amyloid diseases.

Cytokines The “interleukin hypothesis,” which was proposed by

Henderson and colleagues19s in 1983, states that the recur- rent induction of cytokines during the hemodialysis procedure causes the chronic complications seen among patients undergoing long-term hemodialysis. Elevated levels of cytokines, including IL-1, TNFa, and IL-6, are observed in patients with chronic renal failure receiving hemodia lys i~ ’~~ lye. In addition, TNFa levelsLs9 and IL-6 activityLg0 are elevated in the plasma of uremic patients who have not yet undergone dialysis. P2M amyloidosis, which occurs both in patients undergoing hemodialysis and in individuals not yet exposed to dialysis membranes, may be a complication of chronic renal failure that develops, in part, as a conse- quence of these elevated plasma levels of cytokines.

Various substances to which patients are exposed during the hemodialysis procedure stimulate mononuclear leukocytes to produce cytokines, such as TNFa and IL-1. These substances include acetate in the dialysateLy6, lipopolysaccharide (endotoxin) contaminating the dialy~ate’~’, membrane-derived carbohydratesLy8, and C5a generated by membrane-induced complement activationly9 2oo. In addition. AGE-P2M stimulates mononuclear leukocytes to produce TNFa, IL-1 lSs, and IL-6I9’. Mononuclear cells obtained from carpal tunnel tenosynovium of patients undergoing long-term hemodialysis have spontaneously produced IL- 1 P and IL-6 in tissue culture”’, perhaps in response to stimulation by AGE-P2M.

The elevated levels of cytokines in the plasma of patients with chronic renal failure may induce P2M production. Cytokines, such as interferon-y (IFN y). TNFa, and IL- 1, as well as lipopolysaccharide, stimulate the synthesis and

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release of P2M by macrophages in vitro202. TNFaZo3 and IL- lZo4 each augment the expression of HLA Class I antigens, with a concomitant increase in P2M expression, on the surface of nucleated cells. TNF-a and IL-1 P each may also act synergistically with interferon-y (IFN-y) to increase cell surface expression of HLA Class I antigens on nucleated cells beyond that induced by IFN-)I alone205. Although IL-6, either alone or in combination with IFN-y, has no effect on HLA Class I antigen expression on the surface of nucleated cells’05, IL-6 induces P2M secretion by human hepatoblastoma and hepatoma cells in vitro and may stimulate P2M production by hepatocytes in vivo206.

Hypothetical mechanism for the formation of P2M amyloid deposits

Noncovalently bound P2M is released from the surface of cells that shrink and swell in response to changes in osmotic pressure that occur during hernodialy~is’~~. Because of renal failure, decreased catabolism and decreased excre- tion of P2M result in increased serum levels of free P2M. Circulating P2M then can bind to AGE-modified collagen: the affinity of P2M for types I, 11, and I11 collagens, which occur in osteoarticular tissue, is greater than that for type IV collagen, which is present in basement Once bound to AGE-modified collagen, P2M itself may be modified with AGE in situ. The AGE-P2M then can form crosslinks with the AGE-modified collagen.

The cross-linked AGE-P2M and AGE-modified collagen could trap other constituents of the P2M amyloid deposits, such as amyloid P component and ubiquitin. Ubiquitin may promote the formation of amyloid. Limited proteolysis of the P2M. perhaps regulated by the protease inhibitors that are found in P2M amyloid deposits, might also contribute to the formation of amyloid fibrils. Proteoglycans andor glycosaminoglycans, such as chondroitin sulfate, may regulate the distribution and arrangement ofthese P2M amyloid fibril^'?^.

P,-microglobulin and bone metabolism The amyloid subunit protein P2M may also contribute

to the development of renal osteodystrophy. Various effects of human P2M on bone metabolism have been observed in wtro when physiologic concentrations of P2M have been studied in rodent models ofbone remodeling. P2M has growth factor-like activity and regulates bone formation, as do insulin-like growth factor I (IGF I) and transforming growth factor P (TGF-P)208. P2M stimulates synthesis ofDNA, collagen, and noncollagen proteins by intact fetal rat calvariae and fetal rat osteoblast-enriched cellszoq. This growth-promot- ing activity of P2M is mediated, at least in part, through IGF I but not TGF-P. P2M enhances IGF I binding to fetal rat

osteoblast-enriched cells by increasing IGF I receptor number and IGF I synthesis and secretion208.

The effect of human P2M on proliferation of osteoblasts, as assessed by DNA synthesis and collagen synthesis by cultured tissues, varies depending upon the source of P2M, the concentration of P2M, and the tissue examined. At concentrations comparable to those found in plasma of patients receiving hemodialysis, human P2M stimulates cell proliferation in fetal rat calvarial organ culture, in isolated fetal rat osteoblast-enriched cell culture209, and in isolated human osteoblast-like bone cell culture2’0. However, even at concentrations similar to those found in plasma of patients receiving hemodialysis, P2M purified from plasma of uremic individuals has no effect on cell proliferation in cultures of mouse calvaria-derived osteoblasts2’ I . Furthermore, at lower concentrations, human P2M does not stimulate DNA synthesis in neonatal mouse calvarial organ culture2I2 or in isolated human osteoblast-like bone cell Likewise, at concentrations comparable to those found in plasma of patients receiving hemodialysis, P2M purified from plasma of healthy individuals stimulates collagen synthesis both in fetal rat calvarial organ culture and in isolated fetal rat osteoblast-enriched cell culture209, whereas P2M purified from plasma of uremic individuals has no effect on collagen synthesis in mouse calvaria-derived osteoblast cell culture2”. Based upon these in vitro data, the in V I V O effect of P2M on cell proliferation and collagen synthesis by osteoblasts in patients with chronic renal failure cannot be predicted.

P2M also impairs bone mineralization. P2M inhibits calcification, but not collagen synthesis, in cultures of mouse calvaria-derived osteoblasts2”. P2M also induces calcium efflux in cultures of neonatal mouse calvariae, probably by stimulating bone resorption and uncoupling bone formation from resorption or inhibiting bone formation2I2 2 1 1 . This calcium efflux, which may occur as a result ofthe interaction of P2M with other growth factors, such as IGF I , is directly mediated by IL-1 P but not by prostaglandins213. AGE-P2M induces more IL-1 P production by cultured neonatal mouse calvariae than does normal P2M; this increased IL- 1 p production augments calcium effluxZIJ. Thus, P2M and AGE- P2M may contribute to the development ofthe osteomalacia that is observed in patients with renal osteodystrophy by enhancing synthesis of bone matrix proteins and interfering with bone mineralization.

Additionally, P2M stimulates collagenase synthesis and secretion by rabbit synovial and human skin fibroblasts in vitro”’. IL-1 and TNFa, levels of which are elevated in the circulation of patients with chronic renal failure, also stimulate collagenase production by synovial cells and skin fibro- blasts216. Breakdown of cartilage and bone caused by collagenase, the synthesis of which can be induced by P2M and cytokines, may contribute to the development of bone

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cysts and of the destructive spondyloarthropathy observed in patients with P2M amyloidosis.

Treatment

Presently, no treatment is available to reverse P2M amyloid deposition, Medical therapy of patients with 132M amyloidosis is symptomatic. Surgery may be necessary for patients with large deposits of P2M amyloid. Successful renal transplantation can halt the progression of some manifestations of P2M amyloidosi~l'~. However, in the future, medications that inhibit AGE formation might interfere with the pathogenesis of this condition.

Medical therapy Physical and occupational therapeutic modalities may

lessen the disability associated with musculoskeletal manifestations of P2M amyloidosis. Wrist splints for carpal tunnel syndrome and adaptive devices to assist with activities of daily living are useful. Heat and range-of-motion exer- cises for the shoulder increase mobility. Conservative treatment of cervical destructive spondyloarthropathy consists of immobilization of the neck in a cervical collar27. The intraarticular injection of corticosteroids or the application of 10% hydrocortisone cream to the shoulder using phonophoresis may greatly decrease the pain associated with the shoulder periarthritis of dialysis-related amyloidosis and permit increased shoulder function.

Nonsteroidal anti-inflammatory drugs are usefid in treat- ing symptoms of pain involving multiple joints26. Because of the increased risk of bleeding in patients undergoing dialysis, consideration should be given to the concurrent use of a prostaglandin analogue, such as misoprostol. Joint pain and restriction of motion may improve in patients with P2M amyloidosis who are treated with oral prednisone, up to 8 mgiday, although symptoms recur within 48 hours upon the discontinuation of prednisone2I7. However, the potential risks of corticosteroid-induced bone loss and atherosclerosis limit the use of low-dose prednisone to patients whose P2M amyloidosis has not responded to other forms of medical therapy.

Surgical intervention Carpal tunnel release is indicated for patients who have

symptoms unresponsive to conservative management; however, symptoms may recur after surgery has been performed, requiring re-exploration of the carpal tunnel24. Arthroscopic release of the transverse carpal ligament, performed through a smaller skin incision on the forearm, may yield results similar to those achieved with open carpal tunnel release21s.

Arthroscopic resection of the coracoacromial ligament may provide symptomatic relief of shoulder pain related to deposits of P2M amyloid2'.

If the cervical spine is unstable and neurologic findings progress, surgical fusion of the cervical spine is indi~ated?~. When spinal cord compression is present, a decompressive laminectomy may permit recovery of neurologic function3*

Pathologic fractures through P2M amyloid deposits in the femoral neck should be treated by total hip arthroplasty with a cemented femoral component because of the compro- mised structural integrity of the involved bone2I9. Internal fixation of the femoral neck in patients with bone cysts or pathologic fractures due to P2M amyloid deposition frequently results in migration of the pin or screw and is not recommended220,221. Cystic lesions in the femoral neck of 2.5 cm or more in diameter, where at least half of the surrounding cortex is destroyed, or that cause pain on weight bearing should be treated prophylactically to prevent fracture, either by curettage and bone grafting222 or by total hip arthroplasty22'.

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Choice of dialysis modality The role of dialysis with less biocompatible membranes

in the pathogenesis of P2M amyloidosis is controversial. More biocompatible membranes, such as polyacrylonitrile (AN69), do not necessarily reduce the incidence of dialysis- related amyloidosi~'~. However, the greater reduction in circulating P2M levels achieved with high-flux hemodialysis using more biocompatible membranes, such as polysulfone, compared with conventional hemodialysis using less biocompatible membranes, such as c u ~ r o p h a n e ~ ~ , might lessen the degree to which renal osteodystrophy occurs.

Renal transplantation Serum levels of P2M fall rapidly following successful

renal transplantation224. Patients with P2M amyloidosis who undergo successful renal transplantation experience a marked reduction in joint pain and stiffness following transplanta- tion173, 225-229 . Symptoms usually resolve over a period of several days to 6 m ~ n t h ~ ~ ~ ~ - ~ ~ ~ . Joint pain recurs rapidly in patients who resume hemodialysis because of graft rejec- tionz2*, 229. Although prednisone and other immunosuppressive therapy may contribute to the reduction in joint pain following renal transplantation2I7, pain relief has been sus- tained despite reduction or complete withdrawal of corticos- t e r o i d ~ ' ~ ~ . This suggests that some factor other than immunosuppressive therapy results in the dramatic improvement in symptoms.

Although P2M amyloid deposits detected by Iz3I-la- beled SAP scintigraphy enlarge in patients undergoing he-

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modialysis, these deposits do not progress and may regress in patients who have undergone successful renal transplan- t a t i ~ n ” ~ . Following renal transplantation, subchondral bone cysts do not increase in size or number’73. 226-229 . Although cyst size may decrease, bone cysts do not r e ~ o l v e ” ~ , and P2M amyloid has been detected in osteoarticular structures 10 years after successful renal t r ansp lan ta t i~n~~~ . In patients who resume hemodialysis after graft rejection, bone cysts subsequently increase in number229.

Thus, early renal transplantation in appropriate candi- dates, before significant deposition of P2M amyloid has occurred, may be the most effective preventive measure that is presently available for a condition without a definitive cure. However, although renal transplantation is accompa- nied by improvement in the symptoms of P2M amyloidosis and no further enlargement of P2M amyloid bone cysts, it does not stop the development of all manifestations of 132M amyloidosis. Despite successful renal transplantation, destructive cervical spondyloarthropathy progresses with further disk space narrowing and an increase in the size of vertebral end plate erosionszz8.

Aminoguanidine Although there is presently no effective therapy for

(32M amyloidosis other than symptomatic treatment of complications, future treatment strategies directed toward inhibition of AGE formation might interfere with the pathogenesis of this condition. The nucleophilic hydrazine derivative aminoguanidine hydrochloride reacts with Amadori products and Amadori-derived compounds, such as 3-DG, and inhibits formation of AGE before irreversible protein cross-linking occurs231. When administered to streptozotocin-induced diabetic rats, aminoguanidine prevents or delays the occurrence of r e t i n ~ p a t h y ~ ~ ~ , nephropathy’3’ ‘j4, and n e ~ r o p a t h y ~ ~ ~ . Additionally, it prevents the formation of AGE and hyperglycemia-induced collagen cross-linking in arterial wall connective tissue of alloxan- induced diabetic The ability of aminoguanidine to delay the development of nephropathy is being studied in phase 111 clinical trials in patients with type I and type I1 diabetes mellitus2-”.

Aminoguanidine is well absorbed from the gastrointestinal Approximately 80% of the orally administered dose is excreted in the urine by individuals with normal renal function; in individuals with impaired renal function, the clearance of aminoguanidine is directly proportional to the glomerular filtration rate. Patients undergoing chronic hemodialysis tolerate the oral administration of aminoguanidine with minimal, if any, side effects. Aminoguanidine may be administered orally three times weekly after hemodialysis and is effectively removed from plasma by hemodialysis. Clinical trials of aminoguanidine in

patients with chronic renal failure will be necessary to determine whether this compound can halt or delay the development of P2M amyloidosis.

Future directions for study

Further study of the epidemiology of P2M amyloidosis is needed. The prevalence of P2M amyloidosis should be estimated in a large population ofpatients with chronic renal failure using reliable and specific noninvasive diagnostic methods. Although the musculoskeletal manifestations of p2M amyloidosis have been well characterized, additional investigation is necessary to determine the actual extent of visceral involvement by this condition. This information will help to predict which patients are at risk for the complications associated with visceral P2M amyloid deposition.

The occurrence of P2M amyloidosis in diabetic patients with chronic renal failure also requires further investigation. Because diabetic patients receiving hemodialysis may not live long enough for clinically evident P2M amyloidosis to develop, shoulder ultrasonography or scintigraphic imaging with 1231-serum amyloid P component might be employed to detect the appearance of early, asymptomatic deposits of P2M amyloid.

Medical therapy must be developed to prevent the occurrence of P2M amyloidosis and permit regression of amyloid deposits. At present, no preventive intervention exists other than for renal transplantation, which only stabilizes many of the existing signs and symptoms of this disease and might delay further amyloid deposition. Because AGE appear to play a pivotal role in the development ofthis condition, a trial of aminoguanidine in patients with chronic renal failure is warranted to determine whether this drug can interfere with the clinical manifestations of this disease.

A predictive test would be useful to help decide which patients would benefit most from a treatment to prevent the development of P2M amyloid. It might be used to determine the optimal timing of renal transplantation. However, based upon the current understanding of the pathogenesis of P2M amyloidosis, neither the total serum P2M level nor the circulating AGE-P2M level is a promising candidate for such a test . Further investigation of the mechanism by which P2M amyloidosis develops is necessary and may also shed light upon the pathogenesis of the other amyloid disorders.

Summary

P2M amyloidosis is a complication ofchronic renal failure that has been recognized mostly in patients receiving long-term hemodialysis. The clinical features of this condi-

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tion are particularly evident in the musculoskeletal system: patients with P2M amyloidosis typically present with the triad of shoulder periarthritis, carpal tunnel syndrome, and flexor tenosynovitis of the hands. Other musculoskeletal manifestations of P2M amyloidosis include destructive spondyloarthropathy, cervico-occipital pseudotumors, bone cysts, and pathologic fractures. Visceral and cutaneous deposits of P2M also occur and may cause clinical symptoms.

The pathogenesis of P2M amyloidosis is not entirely understood. Important factors may include elevated levels of P2M, limitedproteolytic cleavage of P2M, modification of P2M and other proteins with AGE, and elevated circulating levels of proinflammatory cytokines. The type of dialysis membrane used may affect P2M production and clearance and, by generating C5a through activation of the alternative complement pathway, cytokine production.

At present, only renal transplantation may slow or halt the progression of P2M amyloidosis. Medical therapies may decrease pain associated with this condition but do not alter the disease course. Surgical procedures may be used to remove large deposits of P2M amyloid and to replace joints that have been damaged by these deposits. Future treatment strategies might address biologic processes involved in the pathogenesis of P2M amyloidosis, such as AGE modification of proteins, to prevent progression and permit regression of this disabling complication that affects patients with chronic renal failure.

References

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β 2 -microglobulin amyloidosis

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