**Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment**

Suguru Yamamoto, Junichiro James Kazama, Hiroki Maruyama and Ichiei Narita

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53390

## **1. Introduction**

[175] Stangou AJ, Hawkins PN. Liver transplantation in transthyretin-related familial

[176] Ruygrok PN, Gane EJ, McCall JL, Chen XZ, Haydock DA, Munn SR. Combined heart and liver transplantation for familial amyloidosis. Intern Med J. Jan-Feb 2001;31(1):

[177] Barreiros AP, Post F, Hoppe-Lotichius M, et al. Liver transplantation and combined liver-heart transplantation in patients with familial amyloid polyneuropathy: a sin‐

[178] Miller SR, Sekijima Y, Kelly JW. Native state stabilization by NSAIDs inhibits trans‐ thyretin amyloidogenesis from the most common familial disease variants. Lab In‐

[179] Lachmann HJ, Hawkins PN. Novel pharmacological strategies in amyloidosis. Neph‐

[180] Jones D. Modifying protein misfolding. Nat Rev Drug Discov. Nov 2010;9(11):

[181] Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clini‐ cal outcome in AA amyloidosis in relation to circulating concentration of serum amy‐

[182] Gottenberg JE, Merle-Vincent F, Bentaberry F, et al. Anti-tumor necrosis factor alpha therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthriti‐ des: a followup report of tolerability and efficacy. Arthritis Rheum. Jul 2003;48(7):

[183] Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. Apr

[184] Lachmann HJ, Gilbertson JA, Gillmore JD, Hawkins PN, Pepys MB. Unicentric Cas‐ tleman's disease complicated by systemic AA amyloidosis: a curable disease. QJM.

[185] Dember LM, Hawkins PN, Hazenberg BP, et al. Eprodisate for the treatment of renal

[186] Manenti L, Tansinda P, Vaglio A. Eprodisate in amyloid A amyloidosis: a novel ther‐ apeutic approach? Expert Opin Pharmacother. Aug 2008;9(12):2175-2180.

disease in AA amyloidosis. N Engl J Med. Jun 7 2007;356(23):2349-2360.

amyloid polyneuropathy. Curr Opin Neurol. Oct 2004;17(5):615-620.

gle-center experience. Liver Transpl. Mar 2010;16(3):314-323.

66-67.

66 Amyloidosis

825-827.

2019-2024.

17 1986;314(16):1001-1005.

Apr 2002;95(4):211-218.

vest. May 2004;84(5):545-552.

ron Clin Pract. 2003;94(4):c85-88.

loid A protein. Lancet. Jul 7 2001;358(9275):24-29.

Amyloidosis is defined as an insoluble protein fibril that is deposited, mainly, in the extracel‐ lular spaces of organs and tissues as a result of a sequence of changes in protein folding. Precursor proteins change their conformation that forms amyloid fibrils, then deposited amyloid induce organ damage with disease specific conditions.

To date, there are 27 types of amyloidosis known extracellular fibril proteins in human, and each amyloidosis is characterized amyloid protein precursor, systemic (S) or localized organ (L), and syndrome or involved tissues [1]. In the nomenclature, dialysis-related amyloidosis (DRA) is defined as β2-microglobulin-related (Aβ2M) amyloid which precursor protein is β2 microglobulin (β2-m). It is associated to dialysis, a kidney replacement therapy, and deposits in systemic (S), mainly joint tissues [1].

Long-term dialysis treatment for end-stage kidney disease often induces the Aβ2-m amyloid deposition in mainly osteoarticular tissues that induces various disorders, such as carpal tunnel syndrome (CTS), destructive spondyloarthropathy (DSA), and cystic bone lesions as well as in systemic organs such as heart and gastrointestinal tract when disease advances. Several biomolecules including β2-m as well as clinical risk factors are thought to relate with Aβ2M amyloidogenesis (Figure 1). Recent progress of dialysis therapy has improved survival of dialysis patients, however, older age and long-term dialysis treatment may increase the onset and acceleration of DRA. In this article, we described about DRA focused on pathogen‐ esis, clinical manifestations and treatment, and showed DRA is still one of serious complica‐ tions for patients undergoing long-term dialysis treatment.

© 2013 Yamamoto et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

disulphide bond (Cys25-Cys80). β2-m changes the conformation under various *in vivo* or *in vitro* conditions, such as acidic pH [2], 2,2,2-trifluoroethanol (TFE) [3], sodium dodecyl sulfate (SDS) [4], lysophospholipids [5], non-esterified fatty acids [6], heating [7] and agitation [8]. Proper dose of those molecules induce conformational intermediate that is required for Aβ2M

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

69

β2-m is a component of MHC class I molecules, which are present on all nucleated cells. Most β2-m is normally eliminated by the kidney via glomerular filtration and subsequent tubular catabolism with Megalin [9]. Thus, severe kidney damage induces the retention of β2-m in

Some clinical studies have attempted to identify the conformational intermediate form of circulating β2-m. Capillary electrophoresis reveals that patients undergoing hemodialysis due to end-stage kidney disease, but not healthy control subjects, have the conformational intermediate form of β2-m in serum [10]. The level of predialysis serum β2-m intermediate was 2.7±1.4 mg/L and native β2-m was 29.4±6.8 mg/L in 31 hemodialysis patients. Hemodialysis using a polymethylmethacrylate and online hemodiafiltration with a polysulfone membrane decreased the level of the native form, while any change in the intermediate form was variable [10]. These results suggest that intermediate β2-m is increased in hemodialysis patients and is difficult to remove with dialysis treatment. It may suggest that the intermediate form is immobilized in the extracellular space where Aβ2-m amyloid has a marked affinity for joint tissues (cartilage, capsule, and synovium). In addition, immunoaffinity–liquid chromatogra‐ phy–mass spectrometry analysis and immunoassay revealed the generation of lysine-58– cleaved and truncated β2-m (ΔK58-β2-m), which was found in serum from 20–40% HD patients but not in serum from control subjects [11]. However, this truncated form has not been demonstrated in the tissue containing Aβ2-m amyloid [12]. It is not certain whether the conformational intermediate or the truncated form of β2-m has a critical role of onset/progress of DRA, and future studies will be needed to understand the pathogenesis for Aβ2-m amyloid

A nucleation-dependent polymerization model explains the general mechanisms of amyloid fibril formation in vitro, in various types of amyloidosis [13-18]. This model consists of two phases, i.e., nucleation and extension phases. Nucleus formation requires a series of association steps of monomers, which are thermodynamically unfavorable, representing the rate-limiting step in amyloid fibril formation in vitro. Once the nucleus (n-mer) has been formed, further addition of monomers to the nucleus becomes thermodynamically favorable, resulting in rapid extension of amyloid fibrils according to a first-order kinetic model, i.e., via the consecutive

In the mechanism of amyloidogenesis from β2-m, natively folded proteins, partial unfolding of protein is prerequisite to its assembly into amyloid fibrils [3, 13, 19, 20]. The extension of

association of precursor proteins onto the ends of existing fibrils [14, 17, 18].

amyloid fibril formation/extension (see below section).

**2.2. Retention of conformational intermediate-β2-m**

serum due to impaired excretion from the kidney.

fibrils formation/extension.

**2.3. Aβ2-m amyloid fibril formation and extension**

## **2. Pathogenesis of dialysis-related amyloidosis**

#### **2.1. β2-microglobulin**

β2-m is a polypeptide of 99 residues that has a molecular weight of 11.8 kDa. It forms the beta chain of the human leukocyte antigen (HLA) class I molecule and has a well-known βsandwich structure that involves a 7-strand β-pleated structure stabilized with a single disulphide bond (Cys25-Cys80). β2-m changes the conformation under various *in vivo* or *in vitro* conditions, such as acidic pH [2], 2,2,2-trifluoroethanol (TFE) [3], sodium dodecyl sulfate (SDS) [4], lysophospholipids [5], non-esterified fatty acids [6], heating [7] and agitation [8]. Proper dose of those molecules induce conformational intermediate that is required for Aβ2M amyloid fibril formation/extension (see below section).

## **2.2. Retention of conformational intermediate-β2-m**

β2-m is a component of MHC class I molecules, which are present on all nucleated cells. Most β2-m is normally eliminated by the kidney via glomerular filtration and subsequent tubular catabolism with Megalin [9]. Thus, severe kidney damage induces the retention of β2-m in serum due to impaired excretion from the kidney.

Some clinical studies have attempted to identify the conformational intermediate form of circulating β2-m. Capillary electrophoresis reveals that patients undergoing hemodialysis due to end-stage kidney disease, but not healthy control subjects, have the conformational intermediate form of β2-m in serum [10]. The level of predialysis serum β2-m intermediate was 2.7±1.4 mg/L and native β2-m was 29.4±6.8 mg/L in 31 hemodialysis patients. Hemodialysis using a polymethylmethacrylate and online hemodiafiltration with a polysulfone membrane decreased the level of the native form, while any change in the intermediate form was variable [10]. These results suggest that intermediate β2-m is increased in hemodialysis patients and is difficult to remove with dialysis treatment. It may suggest that the intermediate form is immobilized in the extracellular space where Aβ2-m amyloid has a marked affinity for joint tissues (cartilage, capsule, and synovium). In addition, immunoaffinity–liquid chromatogra‐ phy–mass spectrometry analysis and immunoassay revealed the generation of lysine-58– cleaved and truncated β2-m (ΔK58-β2-m), which was found in serum from 20–40% HD patients but not in serum from control subjects [11]. However, this truncated form has not been demonstrated in the tissue containing Aβ2-m amyloid [12]. It is not certain whether the conformational intermediate or the truncated form of β2-m has a critical role of onset/progress of DRA, and future studies will be needed to understand the pathogenesis for Aβ2-m amyloid fibrils formation/extension.

### **2.3. Aβ2-m amyloid fibril formation and extension**

**Figure 1.** Pathogenesis of dialysis-related amyloidosis (DRA). DRA is induced not only accumulation of β2-microglobu‐

β2-m is a polypeptide of 99 residues that has a molecular weight of 11.8 kDa. It forms the beta chain of the human leukocyte antigen (HLA) class I molecule and has a well-known βsandwich structure that involves a 7-strand β-pleated structure stabilized with a single

lin but also several biomolecules and clinical risk factors.

**2.1. β2-microglobulin**

68 Amyloidosis

**2. Pathogenesis of dialysis-related amyloidosis**

A nucleation-dependent polymerization model explains the general mechanisms of amyloid fibril formation in vitro, in various types of amyloidosis [13-18]. This model consists of two phases, i.e., nucleation and extension phases. Nucleus formation requires a series of association steps of monomers, which are thermodynamically unfavorable, representing the rate-limiting step in amyloid fibril formation in vitro. Once the nucleus (n-mer) has been formed, further addition of monomers to the nucleus becomes thermodynamically favorable, resulting in rapid extension of amyloid fibrils according to a first-order kinetic model, i.e., via the consecutive association of precursor proteins onto the ends of existing fibrils [14, 17, 18].

In the mechanism of amyloidogenesis from β2-m, natively folded proteins, partial unfolding of protein is prerequisite to its assembly into amyloid fibrils [3, 13, 19, 20]. The extension of

amyloid fibril formation and extension at a neutral pH [5]. The mechanism of amyloidogenesis is due to make β2-m monomer into partially unfolding the compact structure as well as stabilizing the extended fibrils in vitro. Clinically, plasma LPA concentration is higher in patients undergoing hemodialysis treatment as compare to healthy subjects [5]. It's unclear the local concentration of lysophospholipids in the lesion that Aβ2M amyloid deposits, it may be reasonable to consider the reaction between β2-m and lysophospholipids that are increased in chronic kidney disease (CKD) undergoing dialysis treatment. Joint tissues that Aβ2M amyloid deposits at early stage in dialysis patients, contains many kinds of glycosaminogly‐ cans and proteoglycans. Depolymerization of Aβ2M amyloid fibrils at a neutral pH in vitro was inhibited dose-dependently by the presence of some glycosaminoglycans (heparin, dermatan sulfate or heparin sulfate) or proteoglycans (biglycan, decorin or keratan sulfate proteoglycan) [21]. In addition, some glycosaminoglycans, especially heparin, enhanced the Aβ2M amyloid fibril extension induced by low concentration of TFE at a neutral pH [3]. These results suggest that some glycosaminoglycans and proteoglycans stabilize extended Aβ2M amyloid fibrils possibly by binding directly to the surface of the fibrils in vivo. Heparin is widely used for the hemodialysis treatment as an anticoagulant. Although no significant difference in the prevalence of Aβ2M amyloidosis was found between continuous ambulatory peritoneal dialysis patients and hemodialysis patients carefully matched for time on dialysis and age at the onset of dialysis [23], our study may suggest that heparin could exert a subtle

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

71

effect for the development of Aβ2M amyloidosis under some clinical conditions.

ship between those biomolecules and Aβ2M amyloid in the lesion.

**2.4. Progress of bone disease after deposition of amyloid fibrils**

**3.1. Serum β2-m levels in patients undergoing dialysis treatment**

expression in inflammatory cells.

**3. Clinical manifestations**

Those molecules are picked up from the results of in vitro amyloid fibril formation, extension, and depolymerization, and further studies will be needed to analyze the histological relation‐

It is not clearly understood the progress of bone disease after deposition of amyloid fibrils. Deposited amyloidosis induces compression that induced CTS and joint arthropathy. Also amyloid deposition induces local osteolysis that induced bone cysts and DSA. The progress through synovial inflammation and subsequent osteoclastogenesis and/or osteoclast activa‐ tion through three possible pathways: (i) indirect action of inflammatory cytokines through the expression in osteoblasts of receptor activator of nuclear factor-κB ligand/osteoprotegerin ligand (RANKL/OPGL), (ii) direct action of inflammatory cytokines, and (iii) RANKL/OPGL

Advanced CKD induces the serum level of β2-m to elevate due to the impaired metabolism and excretion in the kidney. The average serum concentration levels of β2-m in patients undergoing dialysis is significantly higher compared to those in normal subjects (25–45 vs. 1– 2 mg/L) [10, 24-27]. It is clearly understood that the impairment of metabolism in the kidney

**Figure 2.** β2-microglobulin-related (Aβ2M) amyloid fibril extension in vitro. Sub-micellar concentration of sodium do‐ decyl sulfate (SDS) induces Aβ2M amyloid fibrils extension at a neutral pH while micellar concentration induces amy‐ loid fibril depolimerization in vitro. The amount of extended fibrils is measured by Thioflavin T (A), and observed by electron microscopy (B). Bar shows 250 nm.

Aβ2M amyloid fibrils, as well as the formation of the fibrils from β2-m are greatly dependent on the pH of the reaction mixture, with the optimum pH around 2.0-3.0 [13, 14]. At pH 2.5, where the extension of Aβ2M amyloid fibrils is optimum, β2-m loses much of the secondary and tertiary structures observed at pH 7.5 [13, 19]. Aβ2M amyloid fibrils readily depolymerize into monomeric β2-m at a neutral pH [19], however, low concentration of TFE [3] and submicellar concentration of SDS [4] induced Aβ2M amyloid fibrils extension with changing conformation of β2-m monomer and inhibiting depolymerization of amyloid fibrils at a neutral pH in vitro (Figure 2). While TFE and SDS are organic compounds, several biomolecules could induce Aβ2M amyloidogenesis in vivo, such as apolipoprotein E, proteoglycans, glicosami‐ noglycans, type1 collagen, non-esterified fatty acid, and lysophospholipids. [4-6, 21, 22]. For example, some lysophospholipids, especially lysophosphatidic acid (LPA) induces both amyloid fibril formation and extension at a neutral pH [5]. The mechanism of amyloidogenesis is due to make β2-m monomer into partially unfolding the compact structure as well as stabilizing the extended fibrils in vitro. Clinically, plasma LPA concentration is higher in patients undergoing hemodialysis treatment as compare to healthy subjects [5]. It's unclear the local concentration of lysophospholipids in the lesion that Aβ2M amyloid deposits, it may be reasonable to consider the reaction between β2-m and lysophospholipids that are increased in chronic kidney disease (CKD) undergoing dialysis treatment. Joint tissues that Aβ2M amyloid deposits at early stage in dialysis patients, contains many kinds of glycosaminogly‐ cans and proteoglycans. Depolymerization of Aβ2M amyloid fibrils at a neutral pH in vitro was inhibited dose-dependently by the presence of some glycosaminoglycans (heparin, dermatan sulfate or heparin sulfate) or proteoglycans (biglycan, decorin or keratan sulfate proteoglycan) [21]. In addition, some glycosaminoglycans, especially heparin, enhanced the Aβ2M amyloid fibril extension induced by low concentration of TFE at a neutral pH [3]. These results suggest that some glycosaminoglycans and proteoglycans stabilize extended Aβ2M amyloid fibrils possibly by binding directly to the surface of the fibrils in vivo. Heparin is widely used for the hemodialysis treatment as an anticoagulant. Although no significant difference in the prevalence of Aβ2M amyloidosis was found between continuous ambulatory peritoneal dialysis patients and hemodialysis patients carefully matched for time on dialysis and age at the onset of dialysis [23], our study may suggest that heparin could exert a subtle effect for the development of Aβ2M amyloidosis under some clinical conditions.

Those molecules are picked up from the results of in vitro amyloid fibril formation, extension, and depolymerization, and further studies will be needed to analyze the histological relation‐ ship between those biomolecules and Aβ2M amyloid in the lesion.

#### **2.4. Progress of bone disease after deposition of amyloid fibrils**

It is not clearly understood the progress of bone disease after deposition of amyloid fibrils. Deposited amyloidosis induces compression that induced CTS and joint arthropathy. Also amyloid deposition induces local osteolysis that induced bone cysts and DSA. The progress through synovial inflammation and subsequent osteoclastogenesis and/or osteoclast activa‐ tion through three possible pathways: (i) indirect action of inflammatory cytokines through the expression in osteoblasts of receptor activator of nuclear factor-κB ligand/osteoprotegerin ligand (RANKL/OPGL), (ii) direct action of inflammatory cytokines, and (iii) RANKL/OPGL expression in inflammatory cells.

## **3. Clinical manifestations**

Aβ2M amyloid fibrils, as well as the formation of the fibrils from β2-m are greatly dependent on the pH of the reaction mixture, with the optimum pH around 2.0-3.0 [13, 14]. At pH 2.5, where the extension of Aβ2M amyloid fibrils is optimum, β2-m loses much of the secondary and tertiary structures observed at pH 7.5 [13, 19]. Aβ2M amyloid fibrils readily depolymerize into monomeric β2-m at a neutral pH [19], however, low concentration of TFE [3] and submicellar concentration of SDS [4] induced Aβ2M amyloid fibrils extension with changing conformation of β2-m monomer and inhibiting depolymerization of amyloid fibrils at a neutral pH in vitro (Figure 2). While TFE and SDS are organic compounds, several biomolecules could induce Aβ2M amyloidogenesis in vivo, such as apolipoprotein E, proteoglycans, glicosami‐ noglycans, type1 collagen, non-esterified fatty acid, and lysophospholipids. [4-6, 21, 22]. For example, some lysophospholipids, especially lysophosphatidic acid (LPA) induces both

**Figure 2.** β2-microglobulin-related (Aβ2M) amyloid fibril extension in vitro. Sub-micellar concentration of sodium do‐ decyl sulfate (SDS) induces Aβ2M amyloid fibrils extension at a neutral pH while micellar concentration induces amy‐ loid fibril depolimerization in vitro. The amount of extended fibrils is measured by Thioflavin T (A), and observed by

electron microscopy (B). Bar shows 250 nm.

70 Amyloidosis

## **3.1. Serum β2-m levels in patients undergoing dialysis treatment**

Advanced CKD induces the serum level of β2-m to elevate due to the impaired metabolism and excretion in the kidney. The average serum concentration levels of β2-m in patients undergoing dialysis is significantly higher compared to those in normal subjects (25–45 vs. 1– 2 mg/L) [10, 24-27]. It is clearly understood that the impairment of metabolism in the kidney is the main cause of fluid retention in HD patients; however, it is not clear whether the production of β2-m is increased with CKD and/or dialysis treatment. However, a study shows that the amount of β2-m on the surface of granulocytes, lymphocytes and monocytes in hemodialysis patients is higher than that in control subjects while mRNA expression of β2-m in blood cells is no significant difference between them [28]. This result shows the possibility that increased binding of β2-m to blood cells is one of major cause of retention of β2-m in dialysis patients. Thus continuous higher serum levels of β2-m could induced DRA after long-term dialysis treatment [24, 29].

rate increased along with the increasing duration of dialysis therapy. The incidence rate of histories of surgeries for osteoarticular disorders, related to DRA was 25.0, 66.0, and 77.8 % in 20-24 years, 25-29 years, and 30 years or more after the initiation of dialysis therapy, respec‐ tively (Figure 3). In the patients undergoing dialysis therapy for 30 years or more, the incidence rate of histories of surgeries for CTS, DSA, and joint arthropathy was 72.2%, 50.0%, and 22.2%, respectively that indicated they had analogous histories of surgeries for various osteoarticular disorders (Figure 4). These results indicate that the frequency and severity of osteoarticular disorders which may be caused by DRA accelerated with the increasing duration of dialysis

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

73

therapy especially for the patients undergoing dialysis therapy for 30 years or more.

**Figure 3.** The incidence rate of histories of surgeries for osteo-articular disorders, related to dialysis-related amyloido‐ sis (DRA). The rate is 25.0, 66.0, and 77.8 % in 20-24 years, 25-29 years, and 30 years or more after the initiation of dialysis therapy, respectively. In the patients undergoing dialysis therapy for 30 years or more, the rate for carpal tun‐ nel syndrome (CTS), destructive spondyloarthropathy (DSA), and joint arthropathy was 72.2%, 50.0%, and 22.2%, re‐

spectively.

#### **3.2. Risk factors of DRA**

Risk factors of DRA are (i) long-term dialysis treatment, (ii) initiation dialysis treatment in young age, (iii) hemodialysis treatment with low purity dialysate, (iv) use of low-flux dialysis membrane [30], while the pathogenesis of DRA with those risk factors is still incompletely understood. Recently it has trend to use high-flux dialysis membrane and high purity dialysate in hemodialysis treatment. However, progress of dialysis treatment as well as treatment for other diseases makes better survival of dialysis patients and older initiation of dialysis treatment. Thus long-term and old age dialysis patients increase, and DRA is still one of serious complications for patients undergoing dialysis treatment.

Serum level of β2-m, precursor protein of DRA, increase in dialysis patients and is believed most important for onset and progress of DRA. While cross sectional study shows no relation between onset of DRA and serum level of β2-m [24], DRA may be onset after accumulation of β2-m with long duration of dialysis treatment [29].

#### **3.3. Clinical manifestations**

Long-term dialysis treatment for end-stage kidney disease often induces the Aβ2-m amyloid deposition in mainly osteoarticular tissues that induces various disorders, such as CTS, DSA, and cystic bone lesions as well as in rarely systemic organs such as heart [31] and gastrointes‐ tinal tract [32] when disease is advanced. CTS is induced by the deposition of Aβ2-m amyloid around synovium in carpal tunnel and the compression of median nerve. DSA is induced by the deposition of Aβ2-m amyloid and the defect of bone in spine. It is radiographically characterized by severe narrowing of the intervertebral disk space and erosions as well as cysts of the adjacent vertebral plates. DSA lesions are mostly detected in the highly mobile areas, such as C5–C7 and L3–L5 [33]. Cystic lesions occur in bones, such as carpal and femur that Aβ2-m amyloid deposition is found around them. Cystic lesions as well as mineral bone disorder associated with CKD increase the risk of bone fracture.

DRA, induce various osteo-articular disorders, is one of serious complications in patients undergoing long-term dialysis treatment even improvement of dialysis treatment such as dialysis membrane and dialysate [34, 35]. For example, we researched over a four year period 359 end-stage kidney disease patients undergoing dialysis treatment were admitted in our center for the treatment of their dialysis-related complications [34]. DSA was a major cause of hospital admission in the patients undergoing dialysis therapy for 20 years or more, and the rate increased along with the increasing duration of dialysis therapy. The incidence rate of histories of surgeries for osteoarticular disorders, related to DRA was 25.0, 66.0, and 77.8 % in 20-24 years, 25-29 years, and 30 years or more after the initiation of dialysis therapy, respec‐ tively (Figure 3). In the patients undergoing dialysis therapy for 30 years or more, the incidence rate of histories of surgeries for CTS, DSA, and joint arthropathy was 72.2%, 50.0%, and 22.2%, respectively that indicated they had analogous histories of surgeries for various osteoarticular disorders (Figure 4). These results indicate that the frequency and severity of osteoarticular disorders which may be caused by DRA accelerated with the increasing duration of dialysis therapy especially for the patients undergoing dialysis therapy for 30 years or more.

is the main cause of fluid retention in HD patients; however, it is not clear whether the production of β2-m is increased with CKD and/or dialysis treatment. However, a study shows that the amount of β2-m on the surface of granulocytes, lymphocytes and monocytes in hemodialysis patients is higher than that in control subjects while mRNA expression of β2-m in blood cells is no significant difference between them [28]. This result shows the possibility that increased binding of β2-m to blood cells is one of major cause of retention of β2-m in dialysis patients. Thus continuous higher serum levels of β2-m could induced DRA after long-term

Risk factors of DRA are (i) long-term dialysis treatment, (ii) initiation dialysis treatment in young age, (iii) hemodialysis treatment with low purity dialysate, (iv) use of low-flux dialysis membrane [30], while the pathogenesis of DRA with those risk factors is still incompletely understood. Recently it has trend to use high-flux dialysis membrane and high purity dialysate in hemodialysis treatment. However, progress of dialysis treatment as well as treatment for other diseases makes better survival of dialysis patients and older initiation of dialysis treatment. Thus long-term and old age dialysis patients increase, and DRA is still one of serious

Serum level of β2-m, precursor protein of DRA, increase in dialysis patients and is believed most important for onset and progress of DRA. While cross sectional study shows no relation between onset of DRA and serum level of β2-m [24], DRA may be onset after accumulation of

Long-term dialysis treatment for end-stage kidney disease often induces the Aβ2-m amyloid deposition in mainly osteoarticular tissues that induces various disorders, such as CTS, DSA, and cystic bone lesions as well as in rarely systemic organs such as heart [31] and gastrointes‐ tinal tract [32] when disease is advanced. CTS is induced by the deposition of Aβ2-m amyloid around synovium in carpal tunnel and the compression of median nerve. DSA is induced by the deposition of Aβ2-m amyloid and the defect of bone in spine. It is radiographically characterized by severe narrowing of the intervertebral disk space and erosions as well as cysts of the adjacent vertebral plates. DSA lesions are mostly detected in the highly mobile areas, such as C5–C7 and L3–L5 [33]. Cystic lesions occur in bones, such as carpal and femur that Aβ2-m amyloid deposition is found around them. Cystic lesions as well as mineral bone

DRA, induce various osteo-articular disorders, is one of serious complications in patients undergoing long-term dialysis treatment even improvement of dialysis treatment such as dialysis membrane and dialysate [34, 35]. For example, we researched over a four year period 359 end-stage kidney disease patients undergoing dialysis treatment were admitted in our center for the treatment of their dialysis-related complications [34]. DSA was a major cause of hospital admission in the patients undergoing dialysis therapy for 20 years or more, and the

dialysis treatment [24, 29].

72 Amyloidosis

**3.2. Risk factors of DRA**

**3.3. Clinical manifestations**

complications for patients undergoing dialysis treatment.

disorder associated with CKD increase the risk of bone fracture.

β2-m with long duration of dialysis treatment [29].

**Figure 3.** The incidence rate of histories of surgeries for osteo-articular disorders, related to dialysis-related amyloido‐ sis (DRA). The rate is 25.0, 66.0, and 77.8 % in 20-24 years, 25-29 years, and 30 years or more after the initiation of dialysis therapy, respectively. In the patients undergoing dialysis therapy for 30 years or more, the rate for carpal tun‐ nel syndrome (CTS), destructive spondyloarthropathy (DSA), and joint arthropathy was 72.2%, 50.0%, and 22.2%, re‐ spectively.

dialysis therapy. All of those patients received the surgeries more than 2 times, furthermore, some of them received more than 4 times for 30 years or more. The surgery for DSA was done for 17 patients (16%) in 27.1 ± 4.7 years after initiation of dialysis treatment. There is dissociation in the incidence of history of surgery for DSA between in our center [34] and in our related hospitals while that for CTS was similar. The main reason may be that our center is a university teaching hospital and severe patients are referred to our hospital. This is a major limitation, however, it should be remembered that one of the main causes for admission was DSA in the patients undergoing long-term dialysis therapy. Our results may suggest that DRA is one of most serious complications in the patients undergoing dialysis therapy for 30 years or more. Further study will be needed about the detail of DRA in the in long-term dialysis patients. In our studies, the main factor associated with osteoarticular disorders which may be caused by DRA was the duration of dialysis therapy despite the younger age at initiation of dialysis therapy [34]. Other risk factors, such as dialyzer and dialysate could not be considered because of the consistent improvements in the technologies from year to year. For example, long-term dialysis patients had used the low-flux dialyzer for several years since initiating therapy, but now use a high-flux dialyzer. Short-term patients however, have used the high-flux dialyzer

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

75

In summary of our clinical research, the frequency and seriousness of osteoarticular disorders which may be caused by DRA were accelerated with the duration of dialysis therapy, especially

Main purpose of treatment for DRA is a) to prevent the deposition of Aβ2-m amyloid fibrils in the lesions, and b) to relieve symptoms induced by Aβ2-m amyloid deposition. Remove β2-m with dialysis treatment and suppression of systemic/local inflammation are beneficial to prevent the deposition of Aβ2-m amyloid fibrils. Practically, it should be used biocompatible high-flux dialysis membrane and high purity dialysate in hemodialysis treatment. In addition, hemofiltration, hemodiafiltration, and use of β2-m adsorption column have much effect to reduce β2-m and to improve symptoms [36]. Non-steroidal anti-inflammatory drugs or low dose of steroid sometimes show relief of symptoms induced by Aβ2-m amyloid deposition while use of steroid for long duration has risk to induce adverse effect, such as infection and osteoporosis. Surgical treatments are needed when Aβ2-m amyloid deposition induces severe

The use of high-flux dialyzer membrane leads to a reduction in the serum level of β2-m as compared to using low-flux dialyzer membrane. In the HEMO Study [26], the predialysis serum β2-m level was lower in the high-flux membrane group than in the low-flux membrane group. In another study, switching of dialyzer from conventional to high-flux membrane reduced the predialysis serum β2-m level [37]. Clinically, Küchle et al [38]examined the effect

since the initiation of dialysis therapy.

in cases treated for 30 years or more.

**4. Treatment for DRA**

osteoarticular symptoms.

**4.1. Hemodialysis/hemodiafiltration**

**Figure 4.** A case of long-term dialysis patients complicated with various osteo-articular disorders related to dialysisrelated amyloidosis (DRA). A man had end-stage kidney disease due to chronic glomerulo nephritis and received he‐ modialysis treatment for 30 years. He had various DRA-related osteo-articlular disorders, such as carpal tunnel syndrome (CTS), joint artholopathy, and destructive spondyloartholopahty (DSA) that needed surgical treatment.

Next, we researched 102 patients undergoing dialysis treatment for 30 years or more in our related hospitals, and their complication of osteoarticular disorders. The age at initiation of dialysis therapy was 27.3 ± 7.7 years, and the duration of dialysis therapy was 32.3 ± 1.8 years. The surgery for CTS was done for 80 patients (76%) in 21.6 ± 5.5 years after the initiation of dialysis therapy. All of those patients received the surgeries more than 2 times, furthermore, some of them received more than 4 times for 30 years or more. The surgery for DSA was done for 17 patients (16%) in 27.1 ± 4.7 years after initiation of dialysis treatment. There is dissociation in the incidence of history of surgery for DSA between in our center [34] and in our related hospitals while that for CTS was similar. The main reason may be that our center is a university teaching hospital and severe patients are referred to our hospital. This is a major limitation, however, it should be remembered that one of the main causes for admission was DSA in the patients undergoing long-term dialysis therapy. Our results may suggest that DRA is one of most serious complications in the patients undergoing dialysis therapy for 30 years or more. Further study will be needed about the detail of DRA in the in long-term dialysis patients. In our studies, the main factor associated with osteoarticular disorders which may be caused by DRA was the duration of dialysis therapy despite the younger age at initiation of dialysis therapy [34]. Other risk factors, such as dialyzer and dialysate could not be considered because of the consistent improvements in the technologies from year to year. For example, long-term dialysis patients had used the low-flux dialyzer for several years since initiating therapy, but now use a high-flux dialyzer. Short-term patients however, have used the high-flux dialyzer since the initiation of dialysis therapy.

In summary of our clinical research, the frequency and seriousness of osteoarticular disorders which may be caused by DRA were accelerated with the duration of dialysis therapy, especially in cases treated for 30 years or more.

## **4. Treatment for DRA**

Main purpose of treatment for DRA is a) to prevent the deposition of Aβ2-m amyloid fibrils in the lesions, and b) to relieve symptoms induced by Aβ2-m amyloid deposition. Remove β2-m with dialysis treatment and suppression of systemic/local inflammation are beneficial to prevent the deposition of Aβ2-m amyloid fibrils. Practically, it should be used biocompatible high-flux dialysis membrane and high purity dialysate in hemodialysis treatment. In addition, hemofiltration, hemodiafiltration, and use of β2-m adsorption column have much effect to reduce β2-m and to improve symptoms [36]. Non-steroidal anti-inflammatory drugs or low dose of steroid sometimes show relief of symptoms induced by Aβ2-m amyloid deposition while use of steroid for long duration has risk to induce adverse effect, such as infection and osteoporosis. Surgical treatments are needed when Aβ2-m amyloid deposition induces severe osteoarticular symptoms.

#### **4.1. Hemodialysis/hemodiafiltration**

**Figure 4.** A case of long-term dialysis patients complicated with various osteo-articular disorders related to dialysisrelated amyloidosis (DRA). A man had end-stage kidney disease due to chronic glomerulo nephritis and received he‐ modialysis treatment for 30 years. He had various DRA-related osteo-articlular disorders, such as carpal tunnel syndrome (CTS), joint artholopathy, and destructive spondyloartholopahty (DSA) that needed surgical treatment.

74 Amyloidosis

Next, we researched 102 patients undergoing dialysis treatment for 30 years or more in our related hospitals, and their complication of osteoarticular disorders. The age at initiation of dialysis therapy was 27.3 ± 7.7 years, and the duration of dialysis therapy was 32.3 ± 1.8 years. The surgery for CTS was done for 80 patients (76%) in 21.6 ± 5.5 years after the initiation of

The use of high-flux dialyzer membrane leads to a reduction in the serum level of β2-m as compared to using low-flux dialyzer membrane. In the HEMO Study [26], the predialysis serum β2-m level was lower in the high-flux membrane group than in the low-flux membrane group. In another study, switching of dialyzer from conventional to high-flux membrane reduced the predialysis serum β2-m level [37]. Clinically, Küchle et al [38]examined the effect of polysulfone high-flux dialysis membrane in hemodialysis treatment, and showed less onset of CTS, arthropathy and bone cysts as well as lower concentration of serum β2-m as compare to use of low-flux dialysis membrane. The reason why high-flux membrane produces a lower level of serum β2-m is not only that it promotes better clearance, but that it also increases the binding of β2-m to blood cells, such as granulocytes, lymphocytes and monocytes [28]. High purity dialysate with low endotoxin reduced serum β2-m, pentosidine, C-reactive protein, and interleukin-6 [39] that probably accelerates Aβ2-m amyloid deposition.

According to a prospective multicenter study, a β2-m adsorption column that was placed in series with a polysulfone dialyzer increased serum β2-m reduction in patients undergoing hemodialysis as compare to hemodialysis treatment without β2-m adsorption column [42]. This study also showed improvements of DRA-related symptoms, such as joint pain and activity of daily living, and it may suggest that the column absorbs not only β2-m, but also other molecules related to inflammation. Furthermore, a clinical study showed shrink the size

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

77

A significant inverse relationship is observed between residual renal function and serum β2 m level [44]. This suggests that peritoneal dialysis may keep lower serum levels of β2-m because of better maintenance of intrinsic renal function, but not peritoneal function, than hemodial‐ ysis. However the prevalence of histological DRA in peritoneal dialysis patients is not significantly different from that observed in a group of hemodialysis patients matched for age and dialysis duration [23]. End-stage kidney disease patients can do peritoneal dialysis only for 5-10 years, and it is difficult to discuss which treatment shows benefit to prevent DRA. A radical approach for DRA is kidney transplantation that reduces serum β2-m, improves symptoms related to DRA and inhibits the progression [45]. The effects of kidney transplan‐ tation on DRA probably due to not only recover of kidney function but also effect of immu‐

Use of steroid shows beneficial effect for the pain induced by DRA while surgical treatment will be needed for advanced CTS and DSA. However, DSA induces serious neurological symptoms and it is sometimes hard to relief them with surgery. For example, 95 of 865 patients undergoing dialysis treatment had surgeries for DSA, while rate of post-operative complica‐ tions, such as infection and cardiac events, was much higher than those without DSA [46].

**5. DRA, a part of chronic kidney disease-mineral and bone disorder**

preventing osteoarticular complications in dialysis patients (Figure 6).

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder, which consists from abnormal levels of mineral-related bicochemistries, bone abnormalities, and soft tissue calcification [47]. Various types of bone abnormalities are observed in CKD patients, such as high-turnover bone disease and osteomalacia. DRA causes bone abnormalities in patients undergoing dialysis treatment. Bone cyst, joint arthropathy, and DSA are frequency and specifically found in patients especially undergoing long-term hemodialysis therapy [48]. It remains controversial whether DRA and related osteopathy should be included in CKD-MBD. However, DRA is at least closely involved with CKD-MBD, from the view point of

of bone cysts when they are checked by X-ray [43].

**4.3. Other kidney replacement therapies**

nosuppression therapy.

**4.4. Medical and surgical treatment**

Hemodiafiltration has better clearance of middle size molecules than HD and is known to reduce the risk of progression of DRA. A recent multicenter prospective randomized study revealed that on line HDF showed greater efficiency than HD with low-flux membrane in reducing the basal level of β2-m [40].

## **4.2. HD with β2-m adsorption column**

A β2-m adsorption column has been developed as a way to directly eliminate serum β2-m. This adsorption column system is designed for direct hemoperfusion (Figure 5). Adsorption of β2 m by this column is a result both of hydrophobic and molecular size-dependent interactions between the ligand in the column and β2-m molecule. The effects of this column show the reduction rate; 60.0-78.9 %, the amount of adsorption; 157-300 mg, serum β2-m after treatment; 6.8-13.5 mg/L with single treatment [41-43].

**Figure 5.** A schematic representation of hemodialysis treatment with β2-microglobulin (β2-m) adsorption column. The β2-m adsorption column is placed in series with the dialyzer, with blood flowing through the column first.

According to a prospective multicenter study, a β2-m adsorption column that was placed in series with a polysulfone dialyzer increased serum β2-m reduction in patients undergoing hemodialysis as compare to hemodialysis treatment without β2-m adsorption column [42]. This study also showed improvements of DRA-related symptoms, such as joint pain and activity of daily living, and it may suggest that the column absorbs not only β2-m, but also other molecules related to inflammation. Furthermore, a clinical study showed shrink the size of bone cysts when they are checked by X-ray [43].

#### **4.3. Other kidney replacement therapies**

of polysulfone high-flux dialysis membrane in hemodialysis treatment, and showed less onset of CTS, arthropathy and bone cysts as well as lower concentration of serum β2-m as compare to use of low-flux dialysis membrane. The reason why high-flux membrane produces a lower level of serum β2-m is not only that it promotes better clearance, but that it also increases the binding of β2-m to blood cells, such as granulocytes, lymphocytes and monocytes [28]. High purity dialysate with low endotoxin reduced serum β2-m, pentosidine, C-reactive protein, and

Hemodiafiltration has better clearance of middle size molecules than HD and is known to reduce the risk of progression of DRA. A recent multicenter prospective randomized study revealed that on line HDF showed greater efficiency than HD with low-flux membrane in

A β2-m adsorption column has been developed as a way to directly eliminate serum β2-m. This adsorption column system is designed for direct hemoperfusion (Figure 5). Adsorption of β2 m by this column is a result both of hydrophobic and molecular size-dependent interactions between the ligand in the column and β2-m molecule. The effects of this column show the reduction rate; 60.0-78.9 %, the amount of adsorption; 157-300 mg, serum β2-m after treatment;

**Figure 5.** A schematic representation of hemodialysis treatment with β2-microglobulin (β2-m) adsorption column. The

β2-m adsorption column is placed in series with the dialyzer, with blood flowing through the column first.

interleukin-6 [39] that probably accelerates Aβ2-m amyloid deposition.

reducing the basal level of β2-m [40].

76 Amyloidosis

**4.2. HD with β2-m adsorption column**

6.8-13.5 mg/L with single treatment [41-43].

A significant inverse relationship is observed between residual renal function and serum β2 m level [44]. This suggests that peritoneal dialysis may keep lower serum levels of β2-m because of better maintenance of intrinsic renal function, but not peritoneal function, than hemodial‐ ysis. However the prevalence of histological DRA in peritoneal dialysis patients is not significantly different from that observed in a group of hemodialysis patients matched for age and dialysis duration [23]. End-stage kidney disease patients can do peritoneal dialysis only for 5-10 years, and it is difficult to discuss which treatment shows benefit to prevent DRA. A radical approach for DRA is kidney transplantation that reduces serum β2-m, improves symptoms related to DRA and inhibits the progression [45]. The effects of kidney transplan‐ tation on DRA probably due to not only recover of kidney function but also effect of immu‐ nosuppression therapy.

#### **4.4. Medical and surgical treatment**

Use of steroid shows beneficial effect for the pain induced by DRA while surgical treatment will be needed for advanced CTS and DSA. However, DSA induces serious neurological symptoms and it is sometimes hard to relief them with surgery. For example, 95 of 865 patients undergoing dialysis treatment had surgeries for DSA, while rate of post-operative complica‐ tions, such as infection and cardiac events, was much higher than those without DSA [46].

## **5. DRA, a part of chronic kidney disease-mineral and bone disorder**

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder, which consists from abnormal levels of mineral-related bicochemistries, bone abnormalities, and soft tissue calcification [47]. Various types of bone abnormalities are observed in CKD patients, such as high-turnover bone disease and osteomalacia. DRA causes bone abnormalities in patients undergoing dialysis treatment. Bone cyst, joint arthropathy, and DSA are frequency and specifically found in patients especially undergoing long-term hemodialysis therapy [48]. It remains controversial whether DRA and related osteopathy should be included in CKD-MBD. However, DRA is at least closely involved with CKD-MBD, from the view point of preventing osteoarticular complications in dialysis patients (Figure 6).

involvement in amyloid deposition in vivo. These findings will develop more beneficial

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

79

Department of Clinical Nephroscience, Niigata University Graduate School of Medical and

Blood Purification Center, Niigata University Medical and Dental Hospital, Niigata, Japan

Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of

[1] Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, Saraiva MJ, et al. Amyloid fi‐ bril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid : the international journal of ex‐ perimental and clinical investigation : the official journal of the International Society

[2] Yamaguchi I, Hasegawa K, Naiki H, Mitsu T, Matuo Y, Gejyo F. Extension of A be‐ ta2M amyloid fibrils with recombinant human beta2-microglobulin. Amyloid : the international journal of experimental and clinical investigation : the official journal of

[3] Yamamoto S, Yamaguchi I, Hasegawa K, Tsutsumi S, Goto Y, Gejyo F, et al. Glycosa‐ minoglycans enhance the trifluoroethanol-induced extension of beta 2-microglobu‐ lin-related amyloid fibrils at a neutral pH. J Am Soc Nephrol. 2004;15(1):126-33.

[4] Yamamoto S, Hasegawa K, Yamaguchi I, Tsutsumi S, Kardos J, Goto Y, et al. Low concentrations of sodium dodecyl sulfate induce the extension of beta 2-microglobu‐

[5] Ookoshi T, Hasegawa K, Ohhashi Y, Kimura H, Takahashi N, Yoshida H, et al. Lyso‐ phospholipids induce the nucleation and extension of beta2-microglobulin-related

[6] Hasegawa K, Tsutsumi-Yasuhara S, Ookoshi T, Ohhashi Y, Kimura H, Takahashi N, et al. Growth of beta(2)-microglobulin-related amyloid fibrils by non-esterified fatty

lin-related amyloid fibrils at a neutral pH. Biochemistry. 2004;43(34):11075-82.

amyloid fibrils at a neutral pH. Nephrol Dial Transplant. 2008;23(10):3247-55.

prevention and treatment for DRA as well as improvement of dialysis treatment.

Suguru Yamamoto, Junichiro James Kazama, Hiroki Maruyama and Ichiei Narita

**Author details**

**References**

Dental Sciences, Niigata, Japan

Medical and Dental Science, Niigata, Japan

of Amyloidosis. 2010;17(3-4):101-4.

the International Society of Amyloidosis. 2001;8(1):30-40.

acids at a neutral pH. Biochem J. 2008;416(2):307-15.

**Figure 6.** Dialysis-related amyloidosis (DRA) in chronic kidney disease-mineral bone disorder (CKD-MBD). CKD-MBD as well as DRA contains various types of bone abnormalities. Furthermore, β2-microglobulin/DRA may be involved with cardiovascular disease, bone fracture, and mortality which are clinical outcomes of CKD-MBD. In the view point of bone abnormalities, DRA may be related strongly with CKD-MBD.

CKD- MBD contains various types of bone abnormalities, such as high-turnover bone disease, osteomalacia, and adyanmic bone disease. DRA, such as bone cyst, joint arthropathy and DSA, also causes bone abnormalities and is included in renal osteodystorphy. Recently, some groups reported the relation between serum levels of β2-m and atherosclerosis [49] or mortality [26], thus β2-m/DRA may be involved with cardiovascular disease, bone fracture, and mortality which are clinical outcomes of CKD-MBD. In the view point of bone abnormalities, DRA related osteopathy may enhance the serious bone disorder, such as bone fractures and DSA, in the presence of other bone abnormalities, such as high-turnover bone disease and osteo‐ malacia. DRA is a serious complication in patients who are receiving long-term dialysis therapy and obviously seems more harmful than other osteodystrophy in terms of mainte‐ nance of their ADL and quality of life. Further studies will be needed for this assumption.

## **6. Conclusion**

DRA is still one of major and serious complications in end-stage kidney disease patients undergoing long-term dialysis treatment. Several biomolecules that may relate to Aβ2M amyloidogenesis are raised from in vitro studies, and that will be needed to investigate the involvement in amyloid deposition in vivo. These findings will develop more beneficial prevention and treatment for DRA as well as improvement of dialysis treatment.

## **Author details**

Suguru Yamamoto, Junichiro James Kazama, Hiroki Maruyama and Ichiei Narita

Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Blood Purification Center, Niigata University Medical and Dental Hospital, Niigata, Japan

Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan

## **References**

**Figure 6.** Dialysis-related amyloidosis (DRA) in chronic kidney disease-mineral bone disorder (CKD-MBD). CKD-MBD as well as DRA contains various types of bone abnormalities. Furthermore, β2-microglobulin/DRA may be involved with cardiovascular disease, bone fracture, and mortality which are clinical outcomes of CKD-MBD. In the view point of

CKD- MBD contains various types of bone abnormalities, such as high-turnover bone disease, osteomalacia, and adyanmic bone disease. DRA, such as bone cyst, joint arthropathy and DSA, also causes bone abnormalities and is included in renal osteodystorphy. Recently, some groups reported the relation between serum levels of β2-m and atherosclerosis [49] or mortality [26], thus β2-m/DRA may be involved with cardiovascular disease, bone fracture, and mortality which are clinical outcomes of CKD-MBD. In the view point of bone abnormalities, DRA related osteopathy may enhance the serious bone disorder, such as bone fractures and DSA, in the presence of other bone abnormalities, such as high-turnover bone disease and osteo‐ malacia. DRA is a serious complication in patients who are receiving long-term dialysis therapy and obviously seems more harmful than other osteodystrophy in terms of mainte‐ nance of their ADL and quality of life. Further studies will be needed for this assumption.

DRA is still one of major and serious complications in end-stage kidney disease patients undergoing long-term dialysis treatment. Several biomolecules that may relate to Aβ2M amyloidogenesis are raised from in vitro studies, and that will be needed to investigate the

bone abnormalities, DRA may be related strongly with CKD-MBD.

**6. Conclusion**

78 Amyloidosis


[7] Sasahara K, Naiki H, Goto Y. Exothermic effects observed upon heating of beta2-mi‐ croglobulin monomers in the presence of amyloid seeds. Biochemistry. 2006;45(29): 8760-9.

[20] Kelly JW. Alternative conformations of amyloidogenic proteins govern their behav‐

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

81

[21] Yamaguchi I, Suda H, Tsuzuike N, Seto K, Seki M, Yamaguchi Y, et al. Glycosamino‐ glycan and proteoglycan inhibit the depolymerization of beta2-microglobulin amy‐

[22] Relini A, De Stefano S, Torrassa S, Cavalleri O, Rolandi R, Gliozzi A, et al. Heparin strongly enhances the formation of beta2-microglobulin amyloid fibrils in the pres‐

[23] Jadoul M, Garbar C, Vanholder R, Sennesael J, Michel C, Robert A, et al. Prevalence of histological beta2-microglobulin amyloidosis in CAPD patients compared with he‐

[24] Gejyo F, Homma N, Suzuki Y, Arakawa M. Serum levels of beta 2-microglobulin as a new form of amyloid protein in patients undergoing long-term hemodialysis. N Engl

[25] Ikee R, Honda K, Oka M, Maesato K, Mano T, Moriya H, et al. Association of heart valve calcification with malnutrition-inflammation complex syndrome, beta-micro‐ globulin, and carotid intima media thickness in patients on hemodialysis. Ther

[26] Cheung AK, Rocco MV, Yan G, Leypoldt JK, Levin NW, Greene T, et al. Serum beta-2 microglobulin levels predict mortality in dialysis patients: results of the HEMO study. Journal of the American Society of Nephrology : JASN. 2006;17(2):546-55. [27] Okuno S, Ishimura E, Kohno K, Fujino-Katoh Y, Maeno Y, Yamakawa T, et al. Serum beta2-microglobulin level is a significant predictor of mortality in maintenance hae‐

[28] Traut M, Haufe CC, Eismann U, Deppisch RM, Stein G, Wolf G. Increased binding of beta-2-microglobulin to blood cells in dialysis patients treated with high-flux dia‐ lyzers compared with low-flux membranes contributed to reduced beta-2-microglo‐ bulin concentrations. Results of a cross-over study. Blood purification. 2007;25(5-6):

[29] Dember LM, Jaber BL. Dialysis-related amyloidosis: late finding or hidden epidemic?

[30] Davison AM. beta 2-microglobulin and amyloidosis: who is at risk? Nephrol Dial

[31] Takayama F, Miyazaki S, Morita T, Hirasawa Y, Niwa T. Dialysis-related amyloido‐ sis of the heart in long-term hemodialysis patients. Kidney international Supplement.

modialysis patients. Nephrol Dial Transplant. 2009;24(2):571-7.

ior. Current opinion in structural biology. 1996;6(1):11-7.

ence of type I collagen. J Biol Chem. 2008;283(8):4912-20.

loid fibrils in vitro. Kidney Int. 2003;64(3):1080-8.

modialysis patients. Kidney Int. 1998;54(3):956-9.

J Med. 1986;314(9):585-6.

Apher Dial. 2008;12(6):464-8.

Seminars in dialysis. 2006;19(2):105-9.

Transplant. 1995;10 Suppl 10:48-51.

432-40.

2001;78:S172-6.


[20] Kelly JW. Alternative conformations of amyloidogenic proteins govern their behav‐ ior. Current opinion in structural biology. 1996;6(1):11-7.

[7] Sasahara K, Naiki H, Goto Y. Exothermic effects observed upon heating of beta2-mi‐ croglobulin monomers in the presence of amyloid seeds. Biochemistry. 2006;45(29):

[8] Sasahara K, Yagi H, Sakai M, Naiki H, Goto Y. Amyloid nucleation triggered by agi‐ tation of beta2-microglobulin under acidic and neutral pH conditions. Biochemistry.

[9] Orlando RA, Rader K, Authier F, Yamazaki H, Posner BI, Bergeron JJ, et al. Megalin

[10] Uji Y, Motomiya Y, Ando Y. A circulating beta 2-microglobulin intermediate in he‐

[11] Corlin DB, Johnsen CK, Nissen MH, Heegaard NH. A beta2-microglobulin cleavage variant fibrillates at near-physiological pH. Biochem Biophys Res Commun.

[12] Giorgetti S, Stoppini M, Tennent GA, Relini A, Marchese L, Raimondi S, et al. Lysine 58-cleaved beta2-microglobulin is not detectable by 2D electrophoresis in ex vivo amyloid fibrils of two patients affected by dialysis-related amyloidosis. Protein Sci.

[13] Kad NM, Thomson NH, Smith DP, Smith DA, Radford SE. Beta(2)-microglobulin and its deamidated variant, N17D form amyloid fibrils with a range of morphologies

[14] Naiki H, Hashimoto N, Suzuki S, Kimura H, Nakakuki K, Gejyo F. Establishment of a kinetic model of dialysis-related amyloid fibril extension in vitro. Amyloid : the in‐ ternational journal of experimental and clinical investigation : the official journal of

[15] Naiki H, Gejyo F, Nakakuki K. Concentration-dependent inhibitory effects of apoli‐ poprotein E on Alzheimer's beta-amyloid fibril formation in vitro. Biochemistry.

[16] Jarrett JT, Lansbury PT, Jr. Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell. 1993;73(6):1055-8.

[17] Naiki H, Higuchi K, Nakakuki K, Takeda T. Kinetic analysis of amyloid fibril poly‐

[18] Naiki H, Nakakuki K. First-order kinetic model of Alzheimer's beta-amyloid fibril ex‐

[19] Yamaguchi I, Hasegawa K, Takahashi N, Gejyo F, Naiki H. Apolipoprotein E inhibits the depolymerization of beta 2-microglobulin-related amyloid fibrils at a neutral pH.

is an endocytic receptor for insulin. J Am Soc Nephrol. 1998;9(10):1759-66.

modialysis patients. Nephron Clin Pract. 2009;111(3):c173-81.

8760-9.

80 Amyloidosis

2008;47(8):2650-60.

2009;381(2):187-91.

2007;16(2):343-9.

1997;36(20):6243-50.

in vitro. J Mol Biol. 2001;313(3):559-71.

the International Society of Amyloidosis. 1997;4:223-32.

merization in vitro. Lab Invest. 1991;65(1):104-10.

tension in vitro. Lab Invest. 1996;74(2):374-83.

Biochemistry. 2001;40(29):8499-507.


[32] Araki H, Muramoto H, Oda K, Koni I, Mabuchi H, Mizukami Y, et al. Severe gastro‐ intestinal complications of dialysis-related amyloidosis in two patients on long-term hemodialysis. American journal of nephrology. 1996;16(2):149-53.

[44] Yamamoto S, Kasai A, Shimada H. High peritoneal clearance of small molecules did not provide low serum beta2-microglobulin concentrations in peritoneal dialysis pa‐

Dialysis-Related Amyloidosis: Pathogenesis and Clinical Features in Patients Undergoing Dialysis Treatment

http://dx.doi.org/10.5772/53390

83

[45] Mourad G, Argiles A. Renal transplantation relieves the symptoms but does not re‐ verse beta 2-microglobulin amyloidosis. J Am Soc Nephrol. 1996;7(5):798-804.

[46] Chikuda H, Yasunaga H, Horiguchi H, Takeshita K, Kawaguchi H, Matsuda S, et al. Mortality and morbidity in dialysis-dependent patients undergoing spinal surgery: analysis of a national administrative database in Japan. The Journal of bone and joint

[47] Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, et al. Defini‐ tion, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69(11):

[49] Zumrutdal A, Sezer S, Demircan S, Seydaoglu G, Ozdemir FN, Haberal M. Cardiac troponin I and beta 2 microglobulin as risk factors for early-onset atherosclerosis in

[48] Koch KM. Dialysis-related amyloidosis. Kidney Int. 1992;41(5):1416-29.

patients on haemodialysis. Nephrology (Carlton). 2005;10(5):453-8.

tients. Perit Dial Int. 2003;23 Suppl 2:S34-6.

surgery American volume. 2012;94(5):433-8.

1945-53.


[44] Yamamoto S, Kasai A, Shimada H. High peritoneal clearance of small molecules did not provide low serum beta2-microglobulin concentrations in peritoneal dialysis pa‐ tients. Perit Dial Int. 2003;23 Suppl 2:S34-6.

[32] Araki H, Muramoto H, Oda K, Koni I, Mabuchi H, Mizukami Y, et al. Severe gastro‐ intestinal complications of dialysis-related amyloidosis in two patients on long-term

[33] Maruyama H, Gejyo F, Arakawa M. Clinical studies of destructive spondyloarthrop‐

[34] Yamamoto S, Kazama JJ, Maruyama H, Nishi S, Narita I, Gejyo F. Patients undergo‐ ing dialysis therapy for 30 years or more survive with serious osteoarticular disor‐

[35] Otsubo S, Kimata N, Okutsu I, Oshikawa K, Ueda S, Sugimoto H, et al. Characteris‐ tics of dialysis-related amyloidosis in patients on haemodialysis therapy for more

[36] Nakai S, Iseki K, Tabei K, Kubo K, Masakane I, Fushimi K, et al. Outcomes of hemo‐ diafiltration based on Japanese dialysis patient registry. Am J Kidney Dis. 2001;38(4

[37] Koda Y, Nishi S, Miyazaki S, Haginoshita S, Sakurabayashi T, Suzuki M, et al. Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syn‐ drome and mortality of hemodialysis patients. Kidney Int. 1997;52(4):1096-101. [38] Kuchle C, Fricke H, Held E, Schiffl H. High-flux hemodialysis postpones clinical manifestation of dialysis-related amyloidosis. Am J Nephrol. 1996;16(6):484-8.

[39] Furuya R, Kumagai H, Takahashi M, Sano K, Hishida A. Ultrapure dialysate reduces plasma levels of beta2-microglobulin and pentosidine in hemodialysis patients.

[40] Pedrini LA, De Cristofaro V, Comelli M, Casino FG, Prencipe M, Baroni A, et al. Long-term effects of high-efficiency on-line haemodiafiltration on uraemic toxicity. A multicentre prospective randomized study. Nephrol Dial Transplant.26(8):2617-24.

[41] Gejyo F, Homma N, Hasegawa S, Arakawa M. A new therapeutic approach to dialy‐ sis amyloidosis: intensive removal of beta 2-microglobulin with adsorbent column.

[42] Gejyo F, Kawaguchi Y, Hara S, Nakazawa R, Azuma N, Ogawa H, et al. Arresting dialysis-related amyloidosis: a prospective multicenter controlled trial of direct he‐ moperfusion with a beta2-microglobulin adsorption column. Artif Organs.

[43] Homma N, Gejyo F, Hasegawa S, Teramura T, Ei I, Maruyama H, et al. Effects of a new adsorbent column for removing beta-2-microglobulin from circulating blood of

hemodialysis. American journal of nephrology. 1996;16(2):149-53.

athy in long-term hemodialysis patients. Nephron. 1992;61(1):37-44.

than 30 years. Nephrol Dial Transplant. 2009;24(5):1593-8.

ders. Clin Nephrol. 2008;70(6):496-502.

Suppl 1):S212-6.

82 Amyloidosis

Blood Purif. 2005;23(4):311-6.

Artif Organs. 1993;17(4):240-3.

dialysis patients. Contrib Nephrol. 1995;112:164-71.

2004;28(4):371-80.


**Chapter 5**

**Ocular Presentations of Amyloidosis**

Elias Khalilipour and Hamid Riazi Esfehani

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53910

**1. Introduction**

different tissue.[1-3]

**2.** Metachromasia in crystal violet staining.

change under polarized light).

These amyloid proteins can be classified into:

**c.** Transthyretine in familial amyloidosis.

**3.** Ultraviolet fluorescence in Thioflavin-T staining

**b.** Amyloid A protein (AA) in secondary amyloidosis.

Hesam Hashemian, Mahmoud Jabbarvand, Mehdi Khodaparast,

Amyloidosis is a term used for some clinical disorders that result from deposition of in‐ soluble amyloid fibrils in extra- and intracellular spaces leading to many tissue dysfunc‐ tions and disrupt tissue architectures in human body. These set of disorders with similar pathophysiology, and involvement of metabolic pathways result in protein deposition in

Amyloid deposits in various groups of amyloidosis have these common findings:

**a.** Immunoglobulin light chains (AL) in primary systemic amyloidosis.

**1.** Homogeneous granular, filamentous eosinophilia in hematoxylin and eosin staining.

**4.** Orange-red staining with Congo red, which exhibits two additional properties – Bire‐ fringence (ability to rotate polarized light by 90°) and Dichroism (red to green color

**d.** A protein known as Amyloid P component (AP ). These conditions may be primary or secondary, localized or systemic, and familial or nonfamilial. Primary systemic amyloi‐ dosis includes so many clinical disorders like heart failure, gastrointestinal tract in‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Hashemian et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,
