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Hemodialysis |
Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany
Address correspondence to Dr. Gerhard Lonnemann, Gemeinschaftspraxis, Eickenhof 15, D-30851 Langenhagen, Germany. Phone: +49-511-7865621; Fax: +49-511-7865625; E-mail: GLonnemann{at}t-online.de
Abstract
ABSTRACT. The available data on the pathophysiology of ß2-microglobulin amyloidosis (ß2mA) suggest that this progressive disease associated with end-stage renal failure develops in several consecutive phases. First, declining kidney function leads to retention of ß2 microglobulin (ß2m) and its deposition preferentially in the synovial tissue of bigger joints such as wrists, shoulders, and hips. Second, at the site of deposition, formation of unique amyloid fibrils, whose major component is ß2m, takes place. Deposition and fibril formation occur in the absence of modification of ß2mA by advanced glycoxidation end products and also in the absence of a local inflammatory response. It is later, in the third phase, that advanced glycoxidation end product modification of ß2m induces a local inflammatory response by attracting macrophages chemotactically and by stimulating these cells to produce and release proinflammatory cytokines. In addition, unmodified ß2m itself induces inflammatory activities such as upregulation of cyclooxygenase-2 and metalloproteinase-1. The severity of the local inflammation seems to determine the degree of the destructive processes in tissue and bone accompanying ß2mA.
Measures to slow down progression of ß2-microglobulin amyloidosis (ß2mA) in patients in terminal renal failure are high-flux hemodialysis, hemodiafiltration, and hemofiltration with highly permeable synthetic membranes, which have been shown to reduce circulating levels of ß2-microglobulin (ß2m) by approximately 20% to 30%. In addition, the use of these synthetic high-flux membranes may be beneficial for two reasons: they induce less complement, and they adsorb bacterial pyrogens derived from contaminated dialysate. Less complement activation and the absence of pyrogens reduce dialysis-dependent preactivation of circulating mononuclear cells to a minimum and thereby may also reduce severity of local inflammation and tissue destruction at the site of ß2mA deposits. This concept is supported by clinical studies demonstrating that the use of ultrapure dialysate and/or synthetic dialyzer membranes with pyrogen-adsorbing capability reduces the incidence and severity of complications of ß2mA.
Pathogenesis of ß2mA
End-stage renal failure is associated with the development of a unique type of amyloidosis that may lead to complications such as carpal tunnel syndrome (CTS) and the formation of bone cysts with the consequence of bone destruction and an increased risk of bone fractures. Even though the pathogenesis of this dialysis-related amyloidosis is still not fully understood, it seems justified to separate several phases of development: the retention of ß2m as a result of renal failure; its deposition in joints, synovia, cartilage, and bones and subsequent formation of ß2m-positive amyloid fibrils; and a later stage characterized by local inflammation with secondary destructive processes.
Deposition of ß2m and Formation of Amyloid Fibrils
ß2m is a middle molecule with a molecular weight of 11800 Da, which is produced by all cells expressing the major histocompatibility class I. ß2m is almost exclusively removed by the normal kidney. After glomerular filtration, ß2m is reabsorbed and catabolized in the proximal tubule. With declining kidney function, ß2m blood levels increase and high concentrations of circulating ß2m lead to deposition of this molecule in various tissues, predominantly in the synovia of bigger joints. There are preferential sites of ß2m deposition. The reason that certain joints, e.g., the wrists and hips, are preferred is unknown.
At the site of deposition of ß2m, nonbranching, characteristic curved or linear amyloid fibrils arranged in bundles or nodules, whose major component is ß2m, are formed. The mechanism of formation of the fibrils is still a matter of debate. From in vitro studies, one can conclude that the unaltered ß2m molecule is able to form fibrils, and most in vivo studies show the whole, intact ß2m molecule to be the major subunit of this type of amyloid (1,2). There is, however, work by Linke et al. (3) suggesting that at least one cleavage product of ß2m, a truncated peptide with a shortened amino acid terminal, is present in ß2mA deposits. On the basis of these findings, the authors suggested that proteolysis of the intact ß2m molecule that would increase the hydrophobicity of the remnant molecule might be required for ß2m fibril formation. This theory remains controversial because other investigators could not confirm the described observation (4). Also, the importance of 
2-macroglobulin, which acts as an antiprotease, of extracellular matrix components such as glycosaminoglycans, and of an acidic form of ß2m ("novel" ß2m) remain uncertain with respect to deposition of ß2m at preferential sites and to formation of ß2m fibrils (5–7). Finally, the modification of ß2m by advanced glycoxidation end products (AGE) has been proposed as an important factor in the pathogenesis of ß2m amyloidosis (8). However, the AGE modification of ß2m is unlikely to play a role in the deposition of ß2m or the formation of fibrils. On the basis of the histologic findings of a prospective postmortem study, Garbar et al. (9) proposed that the deposition of ß2m and the formation of ß2m amyloid fibrils occur in the absence of infiltrating monocytes/macrophages or a local inflammatory response. It is in later phases of development that ß2m-amyloid deposits stain positive for AGE. At the same time, infiltrates of macrophages around the amyloid deposits can be observed. Similarly, an immunohistologic study on periarticular tissue obtained during routine joint surgery or from autopsy specimens of chronic hemodialysis patients demonstrated that positive staining for AGE and cellular infiltrates (mainly macrophages) were restricted to patients with advanced deposits of ß2m amyloid, and in the vicinity of early ß2mA deposits no cellular infiltrates could be demonstrated (10).
How does deposition of ß2m and formation of fibrils lead to severe tissue damage? Although massive deposits of ß2mA in the wrists may cause CTS simply by compression of the nervus medianus, there is often severe tissue damage in the absence of massive amyloid deposits. A local inflammatory response induced at the site of ß2mA deposition seems to be more important in the development of tissue destruction. Mechanisms and factors involved in the induction of local inflammation are discussed in the following paragraphs.
Importance of AGE-Modified ß2m
The findings of the above-mentioned pathology studies are in agreement with the results of experimental studies of Miyata et al. (8) suggesting that AGE-modified ß2mA chemotactically attracts circulating monocytes and by binding to their AGE-receptor induces the production and release of proinflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor- (TNF-). On the basis of these observations, AGE modification of ß2m amyloid seems to play a key role in the induction of local inflammation mediated by cytokines, which then leads to matrix degradation, bone resorption, and formation of bone cysts. A more recent work demonstrated the presence of all types of transforming growth factor-ß (TGF-ß types 1, 2, and 3) and their specific receptors in infiltrating macrophages and lining synovial cells around amyloid deposits (11). In the same paper, the authors described cell culture experiments in which human macrophages were stimulated with unmodified ß2m as well as AGE-ß2m. AGE-ß2m induced TNF-, IL-1 receptor antagonist, and TGF-ß in macrophages, whereas unmodified ß2m had no cytokine-inducing activity. Taken together, the studies discussed in this paragraph suggest that AGE-ß2m induces more inflammatory activity than unmodified ß2m.
Inflammatory Activities of Unmodified ß2m
Recent publications, however, have suggested that unmodified ß2m also may contribute to inflammatory processes at the site of ß2m amyloid deposition. Migita et al. (12) demonstrated in cultured human synovial cells that ß2m induces transcription of mRNA specific for cyclooxygenase-2 (COX-2) as well as the production of the COX-2 protein. In contrast to COX-1, which is a household enzyme involved in the physiologic production of prostaglandins, COX-2 is induced by proinflammatory cytokines (e.g., TNF-) and acts as a regulatory enzyme in the biosynthesis of excessive prostaglandin production, which plays a critical role in inflammatory processes. According to this study, unmodified ß2m can intensify inflammation via prostaglandin synthesis, at least under in vitro conditions.
Another study investigated the influence of ß2m (unmodified ß2m and AGE-ß2m) on the induction of metalloproteinases in human synovial fibroblasts in culture (13). Metalloproteinase-1 (MMP-1) degrades interstitial collagens with the consequence of destruction of articular cartilage and subchondral bone. The biologic activity of MMP-1 is inhibited by its naturally occurring inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) (13). Moe et al. (13) showed that unmodified ß2m induces MMP-1 without concomitant release of TIMP-1 in synovial fibroblasts. AGE modification of ß2m blocked the effect observed with unmodified ß2m. These data suggest that unmodified ß2m induces an imbalance in favor of the collagen-degrading MMP-1 over its inhibitor TIMP-1 in synovial fibroblasts, which may contribute to excessive tissue destruction and cyst formation. It is interesting that AGE modification of ß2m did not pronounce but rather abrogated this effect of ß2m on synovial cells (13). In summary, there is evidence from cell culture work that ß2m itself without the modification by AGE may be involved in inflammatory activities that contribute to bone destruction.
How Can the Dialysis Procedure Influence the Progression of ß2mA?
In preventing the progression of ß2mA, several aspects can be addressed. First, ß2m is the key molecule present in and around amyloid deposits and modified by AGE or even unmodified may exert effects on synovial cells and macrophages that contribute to the induction of a local inflammation that is important in the development of tissue damage. Therefore, and because retention of ß2m is the prerequisite for amyloid formation, removal of circulating ß2m during hemodialysis should be beneficial. Because the molecular weight of ß2m is 11800 daltons, significant clearance of this middle molecule can be achieved only when high-flux dialyzer membranes are used.
Furthermore, activated monocytes/macrophages play an important role in the induction and prolongation of tissue inflammation at the site of ß2mA deposits. One may speculate that preactivation of circulating monocytes during the hemodialysis procedure could aggravate local inflammation, leading to increased damage. Dialysis-dependent stimuli of circulating monocytes are complement-activating dialyzer membranes and pyrogens derived from contaminated dialysate (Figure 1). Standard low-flux hemodialysis with Cuprophan membranes causes complement activation, and the activated complement component C5a induces transcription of cytokine-specific mRNA (TNF-, IL-1ß) in mononuclear cells (PBMC) (14). Under pyrogen-free conditions, C5a-induced cytokine synthesis in PBMC stops at the level of mRNA transcription; the message is degraded and not translated into the cytokine proteins. However, if PBMC are prestimulated ("primed") with activated complement (e.g., during Cuprophan hemodialysis), then a subsequent second stimulation with endotoxin results in significantly higher production of cytokines as compared to that of PBMC without contact to complement (14,15). Endotoxin as the second stimulus can be replaced by other stimuli such as cytokines themselves or AGE-modified proteins, including AGE-ß2m, either free or in amyloid fibrils (15,16). On the basis of these experimental data, one would expect that the use of biocompatible, non-complement-activating membranes could not only prevent activation of PBMC but also ameliorate the course of ß2mA.
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On the basis of these dialyzer membrane characteristics, the use of synthetic high-flux membranes has three aspects that could be beneficial in the treatment of ß2mA: (1) removal of ß2m, (2) low or even no complement activation, and (3) adsorption of pyrogens derived from contaminated dialysate.
Clinical Data on the Role of Dialyzer Membranes in the Treatment of ß2mA
The first clinical study on the long-term influence of dialyzer membrane on complications of dialysis-related amyloidosis (DRA), such as CTS and development of bone cysts, compared high-flux synthetic polyacrylonitrile (AN69) with low-flux Cuprophan (20). A total of 221 patients were treated for more than 5 yr (follow-up up to 15 yr) either only with AN69 or only with Cuprophan membranes. The data demonstrate that patients who were treated solely with AN69 showed fewer x-ray signs of ß2mA and tended to have CTS less frequently (20). The reason for this beneficial effect is most likely multifactorial. The authors discussed that the improved biocompatibility (less complement activation) of the AN69 membrane could have resulted in lower production of ß2m with the consequence of a slower progression of DRA. This explanation was based on in vitro studies showing that monocytes in culture released more ß2m after exposure to Cuprophan compared with exposure to the synthetic membrane polymethylmethacrylate (21). Subsequent in vivo studies showed no dialyzer membrane-dependent effect on ß2m production in chronic hemodialysis patients when Cuprophan was compared to high-flux AN69 and polysulfone (22). Thus, differences in ß2m generation are unlikely to account for the observed beneficial effect of long-term hemodialysis with high-flux synthetic membranes. However, improved biocompatibility and thereby less complement activation of synthetic membranes also decreases activation ("priming") of mononuclear cells and, in turn, may reduce inflammatory reactions that contribute to tissue damage in ß2mA.
High-flux hemodialysis is associated with significant clearance of ß2m. Several studies demonstrated that a single standard high-flux hemodialysis session reduces predialysis ß2m plasma levels to 50%. In case of increased convective transport in high-volume hemodiafiltration, reduction of ß2m plasma concentrations to 25% of predialysis levels reaching postdialysis concentrations as low as 4 mg/L can be achieved (23,24). In the interdialytic interval, plasma concentrations rise again. Compared with patients who are on long-term Cuprophan dialysis, in which predialysis levels of ß2m stay high (25 to 35 mg/L), high-flux hemodialysis using polysulfone reduces predialysis plasma levels of ß2m by approximately 20% (25). With high-volume online hemodiafiltration, predialysis (steady state) levels of ß2m could be reduced by 30% to a mean of approximately 20 mg/L (26,27). In addition to diffusive and convective clearance, adsorption to the synthetic dialyzer membrane may contribute to increased removal of ß2m during high-flux hemodialysis. Although ß2m levels remain one order of magnitude higher than plasma concentrations in healthy subjects (1 to 2 mg/L), the significant reduction in ß2m levels achievable with synthetic high-flux hemodialysis membranes could be beneficial in the course of ß2mA.
Clinical Data on the Role of Contaminated Dialysate in the Progression of ß2mA
Few studies have investigated whether improved bacteriologic quality of dialysate is associated with reduced incidence or severity of complications associated with ß2mA. Clinical data are rare; however, four retrospective studies described a beneficial role of improved dialysate quality on the incidence of CTS (28–32). Baz et al. (28) compared ESRD patients who were on long-term (mean, 6 yr) hemodialysis with cellulosic dialyzers and ultrapure dialysate with a second group of patients who were treated with cellulosic dialyzers and moderately contaminated standard dialysate. With standard dialysate, 24 of 103 patients developed CTS, whereas only 2 of 84 patients who were treated with ultrapure dialysate (bacterial growth < 1 colony-forming units/ml) showed CTS (P < 0.05). The results of this retrospective study have to be interpreted cautiously because the two groups of patients were treated in two different hemodialysis centers at different times. Similar results were reported by Kleophas et al. (29), who analyzed the incidence of CTS in patients who were treated for up to 13 yr predominantly with Cuprophan dialyzers and an ultrapure dialysate produced by a special dialysis system with individual reverse osmosis and ultraviolet irradiation of dialysate (GENIUS; Fresenius Medical Care, Bad Homburg, Germany). The cumulative incidence of CTS after 10 yr was 7% and after 13 yr was 15%. Unfortunately, this study did not include a control group. Instead, the incidence of CTS was compared to that in patients reported previously by Baz et al. (see above). In these patients, the cumulative incidence of CTS after 13 yr was 30% with ultrapure dialysate and 70% with moderately contaminated standard dialysate (Figure 2) (29). A similar experience was described by Koda et al. (30), who reported a cumulative incidence of CTS of approximately 25% after 13 yr and of 60% after 21 yr of hemodialysis in a population in Niigata, Japan, which since 1988 was treated with polysulfone high-flux dialyzers (Table 1, Figure 3). Although the authors focused on the role of the synthetic high-flux dialyzer, it should be noted that they also switched from nonfiltered acetate-buffered dialysate to ultrafiltered bicarbonate dialysate at the same time (Table 1). In the absence of a control group, Koda et al. compared their data with those of another population reported in the literature. The incidence of CTS in Niigata is lower than that reported from Tassin, France, where nonfiltered acetate dialysate and cellulosic dialyzers are exclusively used for more than 20 yr (Table 1). The incidence of CTS in Tassin was 45% after 13 yr and 100% after 20 yr (Figure 3) (31). Finally, our group in a case-control study collected data compatible with a pathogenic role of the bacterial contamination of dialysate in the course of ß2mA. Forty-three ESRD patients evaluated in 1988 for CTS and x-ray findings typical for ß2mA were compared with 43 patients of the 1996 population, matched for age and time on dialysis. The incidence of CTS and radiologic signs of ß2mA was significantly reduced in the 1996 group (32). Analyzing differences in the treatment modalities of the two cohorts, it seemed that the 1988 group spent significantly shorter time on synthetic low- and high-flux dialyzer membranes and significantly longer time in home dialysis with water pretreated only by water softeners, whereas the 1996 group was mainly dialyzed with water pretreated by reverse osmosis. We know from routine bacteriologic testing that the bacterial counts of water treated by reverse osmosis were way below the limits set by German standard regulation (upper limit of bacterial growth, 100 colony-forming units/ml). Bacteriologic data on the water pretreated by water softeners are missing. However, in view of the differing capability of the two water preparation systems to reject bacteria, one has to conclude that the quality of the softened water was inferior to that of the reverse osmosis water (32). Our data do not permit final conclusions concerning the causes for the striking differences in the manifestation of ß2mA in the two groups of patients despite equal total treatment time. Regarding the longer time of use of synthetic membranes in the 1996 group, our data are in agreement with reports showing a reduction of complications of ß2mA by application of synthetic dialyzer membranes (20,30). No prospective controlled clinical studies have addressed the role of dialysate quality in the progression of ß2mA. Nevertheless, the agreement of our results with the findings of the three retrospective uncontrolled studies by Baz, Kleophas, and Koda is highly suggestive of a beneficial effect of improved bacterial quality of dialysate on the incidence of CTS.
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References
This article has been cited by other articles:
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  T. Ookoshi, K. Hasegawa, Y. Ohhashi, H. Kimura, N. Takahashi, H. Yoshida, R. Miyazaki, Y. Goto, and H. Naiki Lysophospholipids induce the nucleation and extension of {beta}2-microglobulin-related amyloid fibrils at a neutral pH Nephrol. Dial. Transplant., October 1, 2008; 23(10): 3247 - 3255. [Abstract] [Full Text] [PDF]
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S. Okuno, E. Ishimura, K. Kohno, Y. Fujino-Katoh, Y. Maeno, T. Yamakawa, M. Inaba, and Y. Nishizawa Serum {beta}2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients Nephrol. Dial. Transplant., September 17, 2008; (2008) gfn521v1. [Abstract] [Full Text] [PDF]
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 W. H. Horl Hemodialysis Membranes: Interleukins, Biocompatibility, and Middle Molecules J. Am. Soc. Nephrol., January 1, 2002; 13(90001): S62 - 71. [Abstract] [Full Text] [PDF]
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