Can the Nephrologist Prevent Dialysis-Related Amyloidosis?

Am.erican Journal of Kidney Diseases

IF The National Kidney Foundation The Official Journal of

VOL XVIII, NO 1 , JULY 1991

IN-DEPTH REVIEW

Can the Nephrologist Prevent Dialysis-Related Amyloidosis? Johanna Zingraff, MD, and Tilman Drueke, MD • The pathogenesis of dialysis-related amyloidosis is still poorly understood. Therefore, preventive measures can be proposed at present only on the basis of retrospective studies and hypothetical considerations. Two main solutions may be recommended, namely an effective dialytic removal of .82-microglobulin (.82-M), which is the protein precursor of dialysis amyloid, and the avoidance of bioincompatibility-associated phenomena such as those induced by dialysis membranes and endotoxins. Promising new imaging techniques such as computed tomography (CT) scan, nuclear magnetic resonance (NMR), and scintigraphy with specific tracers for amyloid may be helpful to evaluate the longterm results of different treatment schedules, including various strategies of renal replacement therapy. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Dialysis; uremia; arthropathy; amyloidosis; .82-microglobulin; biocompatibility.

D

IALYSIS-RELATED amyloidosis is a recently recognized form of amyloid deposits in dialysis patients composed by the intact f32microglobulin (f32-M) protein,l,2 as well as by modified f32" M polypeptides. 3 Its main clinical manifestations are joint pain reflecting dialysis arthropathy, and the carpal tunnel syndrome,4.5 the incidence of which increases with the length of time on dialysis treatment. 6 -8 This observation suggests that the dialysis technique plays a pathogenetic role in the occurrence of this syndrome. However, we have recently found that f32-M amyloidosis may exceptionally occur in chronic renal failure before any form of renal replacement therapy.9 This observation favors the hypothesis that the duration of renal insufficiency and subsequent prolonged exposure to high levels of f32" M is also likely to be involved. At the current state of knowledge, our understanding of the precise mechanisms involved in the generation of f32"M amyloid fibrils and in the occurrence of the associated joint lesions, as well of their probable interrelation, is incomplete. In order to deepen our understanding and eventually to achieve treatment and prevention of this syndrome, it is important to gather as much information as possible on potential risk factors. A first attempt would be the reduction or even

avoidance of such favoring conditions. This might induce a lower incidence of f32"M amyloidosis, limit its extension, or delay its onset. A second attempt would consist of the elaboration of noninvasive methods, allowing early and precise diagnosis of this complication, as well as an evaluation of its progression or possible regression by treatment. We have undertaken an analysis of all the factors that have been recently identified or suspected to potentially influence the occurrence or course of dialysis-related arthropathy and f32"M amyloidosis, and a discussion of parallel preventive measures that could be proposed. Moreover, recently developed techniques of noninvasive investigation of f32"M amyloidosis will be discussed. BIOLOGICAL ROLE AND ACTIONS OF !12-M MICROGLOBULIN

The f32"M molecule is the constant light chain of HLA antigens of class I, present on the cell From INSERM Unite 90 and Departement de Neprologie. Hopital Necker. Paris. France. Address reprint requests to Tilman B. Drileke. MD. INSERM Unite 90. Departement de Neprologie. Hopital Necker. 161 rue de Sevres. 75743 Paris Cedex 15. France. © 1991 by the National Kidney Foundation. Inc. 0272-6386/91/1801-0001 $3.00/0

American Journal of Kidney Diseases, Vol XVIII, No 1 (July), 1991: pp 1-11

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surface in all mammalian species. to Elevated plasma {jrM levels reflect an increased turnover of lymphatic cells in a variety of illnesses, including malignancies, aquired immunodeficiency syndrome (AIDS), and rheumatic diseases. to However, by far the highest values of plasma {jr M concentrations are observed in renal failure. The kidney is virtually the sole organ that eliminates this peptide, namely by glomerular filtration, tubular reabsorption, and catabolism. II During chronic renal insufficiency, plasma {jrM increases in parallel with plasma creatinine, and its concentration provides a valuable estimation of renal function. However, in end-stage renal failure, the close relation between plasma creatinine and plasma {jrM no longer exists. The persistance of some residual excretory function of the kidney, together with impaired tubular reabsorption, may allow {jrM to be excreted in the urine in amounts as high as 150 mg/d, ie, near the daily production rate. 12 In uremic patients maintained on regular dialysis therapy, the highest levels of plasma {j2-M are observed in the anuric state, although with a great variability from one patient to another. Moreover, intercurrent infections such as septicemia, peritonitis, and hepatitis may be associated with a transient increase in plasma {j2_M.13,14 Patients with clinical and radiological evidence of {jrM amyloid arthropathy have plasma {j2-M values not different from those in whom no such evidence exists. 15 Even though clinical and x-ray assessment does not allow us to precisely evaluate the degree of severity of amyloid deposition, the question arises as to whether the degree of {jrM retention in plasma is essential for the development of "dialysis-related amyloidosis" or not. Since no case of {j2-M amyloidosis has ever been reported in subjects with normal or only slightly elevated plasma {j2-M levels (ie, < 10 Jl.g/L), it appears reasonable to postulate that at least some degree of retention is required for {jrM amyloid deposition to occur. A question of major interest is the following: Is the {jrM amyloid fibril an innocent bystander in dialysis-related arthropathy, or else does the {jrM protein play an active role in the occurrence of the joint lesions? Recently, exciting new experimental findings have been reported in favor of an active role. Thus, {j2-M has been shown to be capable of directly promoting bone remodeling. An in vivo study in mice has demonstrated

ZINGRAFF AND DROEKE

an increase in the resorption of outer and marrow surfaces of calvarial bone, proximate to the injection site of {j2-M into the subcutaneous tissue overlying the occipital region, as compared with the effect of the injection of the vehicle solution alone. 16 The {j2-M protein appears to be identical to one of the bone-derived growth factors (BDFG) and may modulate the binding of other growth factors or hormones to their receptor, acting as a local regulator of bone cell growth. 17 ,IS In this context, it is interesting to note that cytokineinduced, localized generation of {jrM by cultured osteoblasts has also been recently demonstrated. 19 The growth factor-like activity ascribed to {jrM could be mediated by insulin-like growth factor1 (IGF-l), since in cultured osteoblasts {j2-M enhances the transcription at the gene level and the expression ofIGF-l itself, as well as of its receptor. 20 Since parathyroid hormone (PTH) also increases the transcription and translation of IGF1,21 some similarity may exist between the effects of both polypeptides on the skeleton. However, an active role of {jrM as a bone cell mitogen has been questioned recently.22 Other in vitro experiments demonstrated an inhibitory effect of {jr M on the calcification rate in osteoblast cell cultures.23 The same group reported a preferential collagen binding affinity of {jrM, which was dependent on the concentration of {jrM, as well as on the amount of collagen present in the in vitro preparation. 24 The latter finding may explain the predilection of {jrM amyloid for collagen-rich tissues such as joints. Another recently described effect of {j2-M with potential relevance for the pathogenesis of dialysis arthropathy is its capacity of inducing the synthesis of fibroblast collagenase, similar to the effect of serum amyloid A, thus regulating collagen breakdown. 25 Finally, it has been recognized that {j2-M is identical with thymotaxin, which is a chemotactic protein for bone marrow hematopoietic precursors. 26 Although all the aforementioned actions of {jzM and the clinical relevance of in vitro studies need further confirmation, these findings make a strong case in favor of the possibility that the polypeptide is not an inert molecule, but exerts biological activity on bone and joint tissues, particularly in concentrations as high as those found in end-stage renal failure patients. Moreover, one should remember that the native {j2-M molecule has a {j-pleated configuration and hence can be easily conditioned to form amyloid fibrils, as has

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DIALYSIS-RELATED AMYLOIDOSIS

been demonstrated in vitro either by a precipitation procedure27 or in synovial cell cultures (Y Nakashima, oral communication, II th International Congress of Nephrology, Tokyo, July 1990). Therefore, if one admits that a prolonged and marked elevation of plasma ~rM levels is harmful, an efficient removal of this protein would constitute one ofthe goals to be achieved. .62-M REMOVAL BY RENAL REPLACEMENT THERAPY

The molecular weight of ~rM is 11,800 d. This is clearly above the cut-off level of standard cellulosic membranes. Therefore, no removal of ~r M can be achieved with dialyzers equipped with such low permeable membranes (including Cuprophan, Hemophan [ENKA AG, Wuppertal, Germany], and cellulose acetate), as has been confirmed by several investigations. 28-3o Consequently, the predialysis plasma concentration of ~rM is considerably elevated in patients dialyzed by such membranes, namely in the range of 30 to 50 mg/L. 12 ,15,28-33 In contrast, predialysis plasma ~rM levels are lower in patients regularly dialyzed with highly permeable membranes (Fig 1) such as the polysulfone F_6034,35 and the polyacrylonitrile AN-69 membrane. 28,29,36 During the dialysis session, plasma ~rM concentration remains either stable or even increases using cellulosic membranes,15,29,32,37 whereas the concentration decreases more or less markedly with highly permeable membranes. 29 ,38-41 Highly permeable membranes effectively allow a significant elimination of the molecule,29,38-41 convective transport being more efficient than diffusive mass removal. 40,41 Moreover, the reduction of the extracellular ~rM concentration obtained during dialysis with these membranes (such as polyacrylonitrile AN-69 and polysulfone F-60) is greater than can be accounted for by transmembranous removal alone, indicating concomitant binding of the protein to the membrane. 38 ,42,43 The in vitro adsorption capacity of dialysis membranes for ~rM can be demonstrated by incubation with unlabeled or labeled ~rM.29,44 The greater efficacy ofhemofiltration than of hemodialysis concerning transmembranous ~rM mass transfer is related to the physical characteristics of the former, where convection largely prevails over diffusion. The peritoneal membrane is highly permeable for small proteins. However, during peritoneal

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dialysis convective transport is low, as is dialysate flow rate. Daily ~rM removal in continuous ambulatory peritoneal dialysis (CAPO) patients amounts to approximately 30 to 40 mg. 45 Hence, one should not propose this mode of treatment as the method of choice to promote ~rM elimination, in contrast to a recent suggestion made by others. 46 It is probably not of utmost importance to know whether a given dialysis procedure is able to remove more or less ~2-M from the uremic patient, but above all which amount of the protein should be removed on a weekly basis and to which extent plasma ~2-M should be allowed to increase during the interdialytic interval. Highefficiency, highly permeable purification modules designed to promote convective transport, can remove more than 300 mg of ~rM42,43,47 during a 4-hour session. However, this can only be achieved at the price of high initial plasma ~2-M concentrations, since mass transfer rate "N" depends on this concentration in a linear manner

ZINGRAFF AND DROEKE

4

(N = clearance X concentration). Moreover, thrice weekly dialysis sessions of relatively short duration are probably insufficient to counterbalance the daily i3rM production rate, calculated at approximately 3 mg/kg. 48 The question of whether retention of i3rM, ie, production in excess over elimination, is essential for the pathogenesis of i32-M amyloidosis or whether elevated plasma concentrations per se are harmful in this regard, remains unanswered. We do not know to date if there is a "risk limit" of plasma i32-M below which uremic patients are not exposed to this complication. DOES {12-M GENERATION OCCUR DURING RENAL REPLACEMENT THERAPY?

The question has arisen if enhanced generation or release of i3rM could be induced by the dialysis procedure and if so, whether this could be linked to the use oflow-permeable, so-called bioincompatible membranes,49 in addition to the stimulation of many other acute-phase reactions such as neutropenia and complement activation,5o,51 enhanced production of free oxygen radicals, 52 and stimulation of various cytokines including interleukin (IL)-l, IL-6, and tumor necrosis factor (TNF).53 The plasma i3rM concentration generally increases during hemodialysis sessions with membranes such as Cuprophan, acetate cellulose, or polysulfone F_6. 15 ,29,32,37 However, the apparent increase in plasma i3rM is generally no longer significant when postdialysis plasma values are corrected for the contraction of extracellular volume by ultrafiltration. 43 ,54 In keeping with this, in personal in vitro experiments cellulosic membrane fragments incubated in whole blood failed to induce i32-M synthesis or release,29 whereas such incubation experiments resulted in a significant activation of phagocyte oxidative metabolism, as detected by the increased production of free oxygen radicals. 52 Nevertheless, the negative in vitro findings by our group do not exclude that enhanced generation of i3rM occurs during dialysis, at least under particular conditions. Recently, Zaoui et al 55 have demonstrated that intermittent hemodialysis with Cuprophan membrane led to an increase in i3rM production by peripheral blood mononuclear cells grown in culture. In contrast, no such stimulation occurred when the patients were dialyzed with the non-complementactivating membrane, polymethylmethacrylate

(PMMA). In addition, the i3rM production by such cells incubated with Cuprophan membrane in vitro was higher than when incubated with the biocompatible PMMA or polyacrylonitrile AN69 membrane. It has been hypothesized that bacterial contamination of the dialysis fluid with subsequent transfer of endotoxin fragments across the dialysis membrane could not only lead to the well-known adverse reactions such as fever and malaise, but also to the stimulation of i3rM synthesis and release by leukocytes and mononuclear phagocytes. 56 It is of note that in this work, the incubation of leukocytes or macrophages with the Cuprophan membrane alone did not lead to enhanced i3rM release. On the other hand, the group of Quellhorst et al have reported in a recent preliminary study that in dialysis patients treated with a Cuprophan membrane the predialysis plasma i3rM level decreased by roughly 50% when the usual dialysis fluid was replaced by a sterile dialysis fluid. 35 Our group has recently shown that a transfer of radiolabeled bacterial lipopolysaccharide fragments can be observed across different membranes (including regenerated cellulose) and that the presence of significant amounts of such endotoxins in the dialyzate compartment stimulates IL-l and TNF release from whole blood in the "blood" compartment of an in vitro recirculation dialysis system using the polysulfone F-60 or the polyacrylonitrile AN69 membrane. 57 Finally, preliminary evidence for the clinical relevance of a sterile, pyrogen-free dialysate as to the incidence of the carpal tunnel syndrome has recently been provided. 58 The incidence was significantly lower in patients treated with such an "ultrapure" dialysate (P < 0.008) than in patients dialyzed with conventional dialysis fluid. If one admits the possibility of bacterial lipopolysaccharide transfer across various hemodialysis membranes and a still hypothetical relation with i3z-M amyloidogenesis, then hemofiltration would be the method of choice. Hemofiltration is an entirely sterile procedure, whereas in routine hemodialysis the dialyzate is not sterile and even less pyrogen_free. 35 ,59,60 BIOINCOMPATIBILITY OF THE DIALYSIS MEMBRANE

It has been claimed, but by no means proven, that the adverse reactions induced by the repeated

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exposure of the patients' blood to the artificial surface of dialysis membranes and tubings may contribute to the development of dialysis arthropathy and {j2-M amyloidosis. Therefore, it is at least of theoretical interest to learn more about these reactions and to try to understand their potential impact in the pathogenesis of this syndrome. A great number of studies have been devoted to the various aspects of the so-called bioincompatibility related to the dialysis procedure, and in particular to the dialysis membrane: the acute decrease of polymorphonuclear leukocytes and the activation of the complement system,50,51 the stimulation of phagocyte oxidative metabolism,52 the release of granulocyte components such as proteases,61 the synthesis and release ofIL-l and TNF, which are the main mediators of the acutephase response,53,62-65 and the enhanced production of IL_6. 66 Stimulation of {j2-M production might be added to this list, either due to direct enhancement of {jz-M synthesis by the membrane or mediated by cytokines or interferon gamma. 14,56 The issue is complicated by the fact that most of the "biocompatible" membranes currently under study are also highly permeable and that the capacity of those membranes to clear small to medium size proteins such as the anaphylatoxins C3a and C5a,67 IL-l,62 and {jz-M 42,43 may counterbalance a possible simultaneous production of these molecules. Moreover, with regard to cytokines and acute-phase reactants, the direct responsibility of hemodialysis membranes, ie, their intrinsic property to stimulate their synthesis or release, is not always easy to establish. Some investigators, including ourselves, suggest that enhanced IL-l and {jz-M production is more likely to be the result of endotoxin-induced stimulation than of a direct interaction of blood cells with "bioincompatible" cellulosic membranes. 58,68,69 It would be of interest to investigate the properties of highly permeable, but bioincompatible cellulosic membranes with respect to their effect on cytokines, complement, {j2-M, and other polypeptides in order to differentiate the relative importance ofbioincompatibility and of the clearance of such molecules by various types of dialysis membrane. 7o The possible involvement ofbioincompatibility-induced phenomena in the pathogenesis of dialysis-related amyloidosis will be discussed in the next section. Indirect epidemiologic evidence has been re-

cently provided for a role of the widely used Cuprophane membrane in the development of dialysis arthropathy and the carpal tunnel syndrome associated with {j2-M amyloidosis. Two retrospective studies showed that patients predominantly or exclusively treated with the AN69 polyacrylonitrile membrane had a lower incidence of {j2-M amyloid-related complications than patients mainly or exclusively dialyzed against Cuprophan membranes. 71 ,72 However, another group of investigators could not confirm such findings. 73 The apparent controversy could in part be due to the lack ofuniversal.1Y accepted criteria for the diagnosis of {j2-M amyloid arthropathy, and in part due to patient inhomogeneity. Different diagnostic criteria certainly may yield different percentages of incidence in the same population. 73 Peritoneal dialysis, despite the perfect biocompatibility of the peritoneal membrane, does not protect the patient against the risk of {j2-M amyloidosis. 74-76 This finding suggests the importance of dialysate components such as chemicals and endotoxins in the activation of inflammatory cells. Moreover, plasma {jz-M concentration has been found to increase during peritonitis. 13 FACTORS AND MECHANISMS POTENTIALLY INVOLVED IN THE PATHOGENESIS OF !12-M AMYLOID ARTHROPATHY

Mediators of Inflammatory Response

As mentioned above, we know that exposure of patients' blood to bioincompatible material can induce complement activation, increased cell release of cytokines, of proteses, and of reactive oxygen species, and the hepatic synthesis of acutephase reactants such as serum amyloid A (SAA) and C-reactive protein. The repeated "overproduction" of these substances has been suspected to playa favoring role in the development of dialysis-related amyloidosis. IL-l and free radicals of oxygen are considered to cause injury to articular tissues as demonstrated by studies on cartilaginous slices and synovial fibroblasts. 77 ,78 Even if the direct harmful effect of each substance is not fully established, these inflammatory products can mediate some process deleterious to joints. However, it is presently unclear whether one or more of these mediators may act as an amyloid-enhancing factor or not, or whether they only prepare the terrain for {j2-M amyloid fibrils

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ZINGRAFF AND DRUEKE

to be deposited. At least a disturbed equilibrium between proteases and protease inhibitors could be supposed to induce an alteration of ,82-M structure that might be of importance if proteolysis of ,8rM is required before the formation of amyloid fibrils, in analogy to other types of amyloidosis. 79 Fragments of the ,8rM molecule have been identified in the amyloid deposits of dialysis patients by several investigators,3,8o in contrast to prior findings by others. 2 In our group, structural modifications of ,82-M could be demonstrated when the molecule was exposed to high quantities offree oxygen radicals in vitro. 81 The hypothesis that inflammatory response agents play some role in dialysis-related amyloidosis clearly deserves further investigation. Iron and Aluminum Overload Synovial deposition ofiron 82 and aluminum 83

has been suspected to enhance the occurrence of dialysis arthropathy, but this issue remains controversial. 84 Both metals could damage joint structures by the generation of free oxygen radicals resulting in peroxidation and synovitis. Aluminum intoxication has recently been shown to inhibit superoxide dismutase activity and thereby allow free active oxygen species to exert deleterious effects over a prolonged period of time. 85 The evaluation of the precise role, if any, of aluminum and iron overload in the induction of dialysis-related arthropathy needs to be further investigated. It might be interesting to explore the possible influence of iron overload in patients treated with recombinant human erythropoietin. Since iron overload is efficaciously reduced by erythropoietin therapy, one should expect some effect on the incidence or the severity of ,82-M amyloidosis, if iron is effectively implicated. Hyperparathyroidism

For a long time, erosive azotemic arthropathy has been considered to be part of the spectrum of osteitis fibrosa due to hyperparathyroidism. 86 The x-ray features of the dialysis patients presented in the report by Rubin et al 86 have a great similarity to those of dialysis-related amyloid arthropathy. Others noted the resemblance of destructive spondylarthropathy, apparently due to secondary hyperparathyroidism,87 88 with that observed in long-term dialysis patients and suffering from ,82-M amyloidosis. 4 Whether hyperparathyroidism enhances local ,8z-M production or the transformation of ,8rM into amyloid fibrils 0

remains an open question. Parathyroidectomy has been reported to exert a stabilizing effect on some lesions characteristic of dialysis arthropathy.88 This point clearly merits further study. Age A general consensus exists to consider age as a major determinant of dialysis-related amyloidosis, independently of the duration of dialysis therapy.89,90 Table 1 summarizes the major hypothetical factors involved in the pathogenesis of ,8z-M amyloidosis. NONINVASIVE METHODS OF INVESTIGATION OF DIALYSIS-RELATED AMYLOIDOSIS

Evaluation of different approaches· in the treatment of dialysis-related amyloidosis has been hindered by the lack of ability to define precisely its distribution and its extent in an individual patient. Recently developed scintigraphic tests using either 123I-labeled serum amyloid P component (SAP)91 or 131I-labeled ,8rM92 may be helpful in the ongoing evaluation of therapeutic trials monitoring the burden of amyloid in the tissues of the patients. 93 It should be mentioned that scintigraphy with calcium-seeking tracers such as 99mTc-Iabeled diphosphonates94 yield the same images as those obtained with specific tracers and can perhaps be useful for the follow-up of known articular amyloid deposits. The latter method is less expensive and less hazardous to the patient. Other modem imaging techniques such as computed tomography (CT) scan and nuclear magnetic resonance (NMR) may allow investigators in the near future to distinguish amyloid cystic lesions from bone lacunae of other origin. In addition, they can visualize regions not easily seen by plain radiography, as for instance the occipitocervical junction (Fig 2).95 Using the NMR imaging technique, it is clearly shown that the Table 1. P2-M Amyloidosis: Hypothetical Pathogenic or Enhancing Factors Retention of P2-M Increased production of i12-M Mediators of the inflammatory response (bioincompatibility of dialysis material, endotoxinsj P2-M-mediated bone and joint injury Iron overload Aluminum overload Hyperparathyroidism Aging of the patient

DIALYSIS-RELATED AMYLOIDOSIS

7

Fig 2. Occipitocervical junction (lateral view) in a 51-year-old patient on hemodialysis for more than 22 years. (A) X-ray aspect showing severe spondylarthropathy lesions; (8) NMR imaging (T1-weighted sequence) visualizing the occipitocervical junction with soft tissue masses bulging back into the anterior subarachnoid space.

Fig 3. Lateral view of the left knee of the same hemodialysis patient as in Fig 1. (A) X-ray aspect showing a cystic lesion of the distal part of the femur; (8) NMR imaging (T1-weighted sequence) suggesting invasive amyloid deposition Into subchondral bone with lacuna formation.

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ZINGRAFF AND DRUEKE

cystic lesion is juxta-articular and that synovial material, probably with abundant amyloid substance, invades the subchondral bone (Fig 3). The combined application of these new methods promises to be a valuable tool in the follow-up of the progression or hopefully in the near future of the reversal of amyloid deposition. Using reliable criteria based on these techniques, prospective short-term studies could be performed to investigate the role of dialysis membranes and dialysis fluid quality in the pathogenesis of dialysis amyloidosis. PRACTICAL GUIDELINES IN THE MANAGEMENT OF DIALYSIS-RELATED AMYLOIDOSIS

The administration of antiinflammatory nonsteroidal drugs may induce some initial symptomatic relief of pain, but long-term efficacy is poor. In analogy to the favorable results obtained in amyloid A (AA) amyloidosis associated with familial mediterranean fever, uncontrolled trials of colchicine treatment have been undertaken in single cases of advanced {j2-M amyloidosis, but this therapy has yielded disappointing results. The effect of chronic, low-dose oral glucocorticoid administration has not yet been documented. Such a treatment could be worth studying. Symptoms associated with the carpal tunnel syndrome can be transiently relieved by local glucocorticoid infiltration or more definitely by surgical release of the median nerve. Abundant amyloid deposits infiltrating the synovial structures are frequently found, but are not a constant finding since they are absent in approximately 30% of cases. Recently, a Japanese group has presented a promising report of successful relief of shoulder pain after endoscopic resection of the coracoacromialligament. 96 They obtained evidence of {jzM amyloid deposits in more than 85% of these patients. If confirmed by other groups, such an approach could constitute a breakthrough in the treatment of this type of chronic arthralgias. Prosthetic replacement, especially of weightbearing joints such as the hips and the knees, may be necessary in patients with advanced destructive arthropathy or with a spontaneous fracture of the femoral neck after prior damage by amyloid cysts. Destructive spondylarthropathy, another joint disease frequently associated with {jrM amyloidosis, may lead to severe spondylolisthesis with the risk of spinal cord or nervous

root compression. Orthopedic consolidation including osteosynthetic grafts may be a lifesaving procedure in such cases. Dialysis strategies different from those most frequently used at present are proposed to lower the incidence of dialysis-related amyloidosis, by delaying the onset of this invalidating complication or, if possible, by relieving its symptoms, particularly joint pain and stiffness. Such dialysis strategies are aimed at obtaining two main goals, namely to promote {jrM removal on the one hand and to reduce bioincompatibility-related reactions on the other. Elimination of (jz-M that needs a highly permeable membrane can be achieved by two different ways: (1) adsorption of the protein to the membrane, and (2) transmembranous transport, convective transfer being more effective than diffusive transport. However, the theoretical advantage of hemofiltration over hemodialysis as to the prevention of {jz-M amyloidosis has not yet been demonstrated. As to the bioincompatibility issue, an important role is attributed at present to endotoxin transfer across the dialysis membrane. Preliminary evidence points to a possible benefit of pyrogen-free, "ultrapure" dialysate, which appears to delay the occurrence of amyloid arthropathy. 58 This observation requires confirmation by other long-term studies with large patient groups. Finally, clearly the most efficacious means to stop the progression of dialysis-related amyloidosis is to interrupt the dialysis treatment itself and to restore renal function by a successful renal transplantation. In this case, joint pain generally disappears rapidly and joint function improves. 97 ,98 Whether this amelioration should be ascribed to the effect of high-dose glucocorticoid therapy, the decrease of plasma {j2-M to near normal levels, or other mechanisms is still debated.97 ,99 Radiological lesions of {j2-M amyloidosis do not heal even several years after transplantation. 98 CONCLUSION

As long as reversibility of {j2-M amyloidosis has not undoubtedly been demonstrated, the best therapeutic approaches would consist of those directed to prevention of this complication. However, the pathogenesis of {j2-M amyloid-related arthropathy is incompletely understood. In analogy to other forms of amyloidosis, one should recommend avoidance of accumulation of the

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DIALYSIS-RELATED AMYLOIDOSIS

protein precursor, ie, to promote elimination and to reduce synthesis of ~z-M. Retention of ~z-M appears to be a necessary, although not a sufficient, condition for dialysis amyloidosis to occur. Removal of large quantities of ~z-M also seems important because of the recently acquired awareness that ~2-M may not be an inert molecule, but may exert several biological activities. However, an essential question remains unanswered: How much ~2-M should be removed, and is there a plasma threshold concentration below which deposition of ~2-M amyloid fibrils will not develop? In the particular case of dialysis-related amyloidosis, many systemic and local tissue factors may be potentially important in dete~ining whether amyloid deposition occurs or not. All these hitherto known enhancing factors have been discussed. Special attention has been paid to the phenomena related to bioincompatibility accompanying the dialysis procedure. Reducing all the known enhancing factors as much as pos-

sible should lower the occurrence and extension of ~z-M amyloidosis. A decrease in the incidence of dialysis-related amyloidosis has been attributed, in retrospective epidemiological surveys, to long-term dialysis with the highly permeable, biocompatible polyacrylonitrile AN69 membrane. Although no general consensus exists in this regard, one should provide to the dialysis patient the benefit of the doubt and dialyze him with biocompatible, highly permeable membranes. However, one should take care that the beneficial properties of such membranes are not abolished by the potentially harmful effect of endotoxin backflow. Adequate dialysis strategies including, if feasible, efforts to avoid transmembranous pyrogen transfer, appear particularly indicated for patients who are not suita]jle for kidney transplantation. The latter form of renal replacement therapy is currently the only treatment able to halt the progression of dialysis-related amyloidosis.

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