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BBA - Proteins and Proteomics (v.1753, #1)

Editorial Board (pp. ii).

Dialysis-related amyloidosis: From molecular mechanism to therapies by Yuji Goto; Vittorio Bellotti; Rino Esposito (pp. 1-3).

Historical background and clinical treatment of dialysis-related amyloidosis by Suguru Yamamoto; Fumitake Gejyo (pp. 4-10).

Dialysis-related amyloidosis (DRA) is a frequent and serious complication in patients on long-term dialysis. The amyloid has a marked affinity for joint tissues, and carpal tunnel syndrome, polyarthralgia, destructive spondyloarthropathy, and bone cysts are the major clinical manifestations of DRA. β₂-Microglobulin (β₂-m) was identified as the major protein constituent of the amyloid fibrils. Risk factors for the development of DRA include age, duration of dialysis treatment, use of low-flux dialysis membrane, use of low purity dialysate, monocyte chemoattractant protein-1 GG genotype, and apolipoprotein E4 allele, although the retention of β₂-m in the plasma appears to be prerequisite. Clinical therapeutic strategies for DRA include dialysis, medical or surgical therapy, and renal transplantation. Preventive measures have attempted to remove β₂-m from the serum by using high-flux membranes and a β₂-m adsorption column in hemodialysis. Renal transplantation is a radical approach to treating the arthralgias attributed to the amyloid deposits while the regression of dialysi-related amyloid deposits is not identified after successful renal transplantation in many studies. It is necessary to elucidate the pathogenesis of DRA and to establish more effective prevention and therapy in the future.

Keywords: Abbreviations; AGE; advanced glycation end products; β; ₂; -m; β; ₂; -microglobulin; CTS; carpal tunnel syndrome; DRA; dialysis-related amyloidosis; DSA; destructive spondyloarthropathy; HLA; human leukocyte antigen; IL; interleukin; MRI; magnetic resonance imaging; SAP; serum amyloid P componentβ; ₂; -microglobulin; Dialysis-related amyloidosis; Hemodialysis; Carpal tunnel syndrome; High-flux membrane; β; ₂; -microglobulin adsorption column

Clinical aspects of systemic amyloid diseases by Laura Obici; Vittorio Perfetti; Giovanni Palladini; Remigio Moratti; Giampaolo Merlini (pp. 11-22).

Amyloidosis is a protein misfolding disorder in which soluble proteins aggregate as insoluble amyloid fibrils. Protein aggregates and amyloid fibrils cause functional and structural organ damage respectively. To date, at least 24 different proteins have been recognized as causative agents of amyloid diseases, localized or systemic. The two most common forms of systemic amyloidosis are light-chain (AL) amyloidosis and reactive AA amyloidosis due to chronic inflammatory diseases. β₂-microglobulin amyloidosis is a common complication associated with long-term hemodialysis. Hereditary systemic amyloidoses are a group of autosomal dominant disorders caused by mutations in the genes of several plasma proteins. Heterogeneity in clinical presentation, pattern of amyloid-related organ toxicity and rate of disease progression is observed among systemic amyloidoses. In particular, β₂-microglobulin presents unique clinical features compared to the other systemic forms. The phenotypic features of hereditary systemic amyloidoses may instead overlap those of the two more common forms of acquired amyloidoses mentioned above and therefore a correct diagnosis can not rely only on clinical grounds. Unequivocal identification of the deposited protein is essential in order to avoid misdiagnosis and inappropriate treatment. Amyloid deposits can be reabsorbed and organ dysfunction reversed if the concentration of the amyloidogenic protein is reduced or zeroed. At present, the most effective approach to treatment of the systemic amyloidoses involves shutting down, or substantially reducing the synthesis of the amyloid precursor, or, as in the case of β₂-microglobulin, promoting its clearance.

Keywords: Immunoglobulin light-chain; Hereditary amyloidosis; β; ₂; -microglobulin; Chronic inflammation; Chemotherapy; Transplantation

Proteomics of β2-microglobulin amyloid fibrils by Monica Stoppini; Palma Mangione; Maria Monti; Sofia Giorgetti; Loredana Marchese; Patrizia Arcidiaco; Laura Verga; Siro Segagni; Piero Pucci; Giampaolo Merlini; Vittorio Bellotti (pp. 23-33).

Knowledge on the chemical structure of β2-microglobulin in natural amyloid fibrils is quite limited because of the difficulty in obtaining tissue samples suitable for biochemical studies. We have reviewed the available information on the chemical modifications and we present new data of β2-microglobulin extracted from non-osteotendinous tissues. β2-microglobulin can accumulate in these compartments after long-term haemodialysis but rarely forms amyloid deposits. We confirm that truncation at the N-terminus is an event specific to β2-microglobulin derived from fibrils but is not observed in the β2-microglobulin from plasma or from the insoluble non-fibrillar material deposited in the heart and spleen. We also confirm the partial deamidation of Asn 17 and Asn 42, as well as the oxidation of Met 99 in fibrillar β2-microglobulin. Other previously reported chemical modifications cannot be excluded, but should involve less than 1–2% of the intact molecule.

Keywords: β2-microglobulin; Amyloid fibril; Fibril extraction; Proteomic analysis; β2-m modification

Kinetic analysis of the polymerization and depolymerization of β₂-microglobulin-related amyloid fibrils in vitro by Suguru Yamamoto; Kazuhiro Hasegawa; Itaru Yamaguchi; Yuji Goto; Fumitake Gejyo; Hironobu Naiki (pp. 34-43).

β₂-Microglobulin-related (Aβ₂M) amyloidosis is a serious complication in patients on long-term dialysis, and partial unfolding of β₂-microglobulin (β₂-m) is believed to be prerequisite to its assembly into Aβ₂M amyloid fibrils. Many kinds of amyloid-associated molecules (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of Aβ₂M amyloidosis. The formation of Aβ₂M amyloid fibrils in vitro was first observed at low pH (2.0–3.0). Very recently, low concentrations of 2,2,2-trifluoroethanol (TFE) and the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, have been reported to cause the extension of Aβ₂M amyloid fibrils at a neutral pH, inducing partial unfolding of β₂-m and stabilization of the fibrils. Moreover, apoE, GAGs and PGs were found to stabilize Aβ₂M amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Some GAGs, especially heparin enhanced the fibril extension in the presence of TFE at a neutral pH. Some PGs, especially biglycan also induced the polymerization of acid-denatured β₂-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of β₂-m and amyloid fibrils will have significant effects on the deposition of Aβ₂M amyloid fibrils.

Keywords: Abbreviations; AA; amyloid protein A; AApoAII; apolipoprotein A-II-related murine senile; Aβ; amyloid β-peptide; Aβ; ₂; M; β; ₂; -microglobulin-related; AIAPP; islet amyloid polypeptide (amylin)-related; AL; immunoglobulin light chain-related; apoE; apolipoprotein E; apoSAA; serum amyloid A; β; ₂; -m; β; ₂; -microglobulin; CD; circular dichroism; CMC; critical micelle concentration; CS; chondroitin sulfate; CSA; chondroitin sulfate A; CSC; chondroitin sulfate C; DS; dermatan sulfate; DTAC; dodecyl trimethyl ammonium chloride; GAGs; glycosaminoglycans; GM1; GM1 ganglioside; HA; hyaluronic acid; HS; heparan sulfate; HSPG; heparan sulfate proteoglycan; KSPG; keratan sulfate proteoglycan; PGs; proteoglycans; SAP; serum amyloid P component; SB12; lauryl sulfobetain; SDS; sodium dodecyl sulfate; SLRPs; small leucine rich PGs; TFE; 2,2,2-trifluoroethanol; ThT; thioflavin T; Tx100; triton X-100β; ₂; -microglobulin; Glycosaminoglycan; Proteoglycan 2,2,2-trifluoroethanol; Sodium dodecyl sulfate; Amyloid fibril

Limited proteolysis in the investigation of β2-microglobulin amyloidogenic and fibrillar states by M. Monti; A. Amoresano; S. Giorgetti; V. Bellotti; P. Pucci (pp. 44-50).

Amyloid fibrils of patients treated with regular haemodialysis essentially consists of β2-microglobulin (β2-m) and its truncated species ΔN6β2-m lacking six residues at the amino terminus. The truncated fragment shows a higher propensity to self-aggregate and constitutes an excellent candidate for the analysis of a protein in the amyloidogenic conformation. The surface topology and the conformational analysis of native β2-m and the truncated ΔN6β2-m species both in the soluble and in the fibrillar forms were investigated by the limited proteolysis/mass spectrometry strategy. The conformation in solution of a further truncated mutant ΔN3β2-m lacking three residues at the N-terminus was also examined. This approach appeared particularly suited to investigate the regions that are solvent-exposed, or flexible enough to be accessible to protein–protein interactions and to describe the conformation of transient intermediates. Moreover, proteolysis experiments can also be tailored to investigate amyloid fibrils by discriminating the protein regions constituting the unaccessible core of the fibrils and those still flexible and exposed to the solvent. Although native β2-m and ΔN3β2-m shared essentially the same conformation, significative structural differences exist between the native and the ΔN6β2-m proteins in solution with major differences located at the end moiety of strand V and subsequent loop with strand VI and at both the N- and C-termini of the proteins. On the contrary, an identical distribution of preferential proteolytic sites was observed in both proteins in the fibrillar state, which was nearly superimposible to that observed for the soluble form of ΔN6β2-m. These data revealed that synthetic fibrils essentially consists of an unaccessible core comprising residues 20–87 of the β2-m protein with exposed and flexible N- and C-terminal ends. Moreover, proteolytic cleavages observed in vitro at Lys 6 and Lys 19 reproduce specific cleavages that have to take place in vivo to generate the truncated forms of β2-m occurring in natural fibrils. On the basis of these results, a molecular mechanism for fibril formation has been proposed.

Keywords: Amyloid fibril; β2-microglobulin; Limited proteolysis; Mass spectrometry

Towards an understanding of the structural molecular mechanism of β₂-microglobulin amyloid formation in vitro by Sheena E. Radford; Walraj S. Gosal; Geoffrey W. Platt (pp. 51-63).

Deriving a complete understanding of protein self-association into amyloid fibrils across multiple distance and time scales is an enormous challenge. At small length scales, a detailed description of the partially folded protein ensemble that participates in self-assembly remains obscure. At larger length scales, amyloid fibrils are often heterogeneous, can form along multiple pathways, and are further complicated by phenomena such as phase-separation. Over the last 5 years, we have used an array of biophysical approaches in order to elucidate the structural and molecular mechanism of amyloid fibril formation, focusing on the all β-sheet protein, β₂-microglubulin (β₂m). This protein forms amyloid deposits in the human disease ‘dialysis-related amyloidosis’ (DRA). We have shown that under acidic conditions β₂m rapidly associates in vitro to form amyloid-like fibrils that have different morphological properties, but which contain an underpinning cross-β structure. In this review, we discuss our current knowledge of the structure of these fibrils, as well as the structural, kinetic and thermodynamic relationship between fibrils with different morphologies. The results provide some of the first insights into the shape of the self-assembly free-energy landscape for this protein and highlight the parallel nature of the assembly process. We include a detailed description of the structure and dynamics of partially folded and acid unfolded species of β₂m using NMR, and highlight regions thought to be important in early self-association events. Finally, we discuss briefly how knowledge of assembly mechanisms in vitro can be used to inform the design of therapeutic strategies for this, and other amyloid disorders, and we speculate on how the increasing power of biophysical approaches may lead to a fuller description of protein self-assembly into amyloid in the future.

Keywords: Beta-2-microglobulin; Amyloid; NMR; Intermediate; AFM

Structural stability of amyloid fibrils of β₂-microglobulin in comparison with its native fold by Eri Chatani; Yuji Goto (pp. 64-75).

Among various amyloidogenic proteins, β₂-microglobulin (β2-m) responsible for dialysis-related amyloidosis is a target of extensive study because of its clinical importance and suitable size for examining the formation of amyloid fibrils in comparison with protein folding to the native state. The structure and stability of amyloid fibrils have been studied with various physicochemical methods, including H/D exchange of amyloid fibrils combined with dissolution of fibrils by dimethylsulfoxide and NMR analysis, thermodynamic analysis of amyloid fibril formation by isothermal calorimetry, and analysis of the effects of pressure on the structure of amyloid fibrils. The results are consistent with the view that amyloid fibrils are a main-chain-dominated structure with larger numbers of hydrogen bonds and pressure-accessible cavities in the interior, in contrast to the side-chain-dominated native structure with the optimal packing of amino acid residues. We consider that a main-chain dominated structure provides the structural basis for various conformational states even with one protein. When this feature is combined with another unique feature, template-dependent growth, propagation and maturation of the amyloid conformation, which cannot be predicted with Anfinsen's dogma, take place.

Keywords: Abbreviations; β2-m; β; ₂; -microglobulin; DMSO; dimethylsulfoxide; NMR; nuclear magnetic resonance; ThT; thioflavin T; TIRFM; total internal reflection fluorescence microscopyAmyloid fibril; β; ₂; -microglobulin; Dialysis-related amyloidosis; High pressure; Seed-dependent growth; Conformational propagation

Solution structure of β₂-microglobulin and insights into fibrillogenesis by Gennaro Esposito; Alessandra Corazza; Paolo Viglino; Giuliana Verdone; Fabio Pettirossi; Federico Fogolari; Ads Makek; Sofia Giorgetti; Palma Mangione; Monica Stoppini; Vittorio Bellotti (pp. 76-84).

The solution structure of human β₂-microglobulin (β₂-m) was determined by¹H NMR spectroscopy and restrained modeling calculations. Compared to the crystal structure of type I major histocompatibility complex (MHC-I), where the protein is associated to the heavy-chain component, several differences are observed, i.e., increased separation between strands A and B, displacements of strand C′ and loop DE, shortening of strands D and E. These modifications can be considered as the prodromes of the amyloid transition. Even minor charge changes in response to pH, as is the case with H31 imidazole protonation, trigger the transition that starts with unpairing of strand A. The same mechanism accounts for the partial unfolding and fiber formation subsequent to Cu²⁺ binding which is shown to occur primarily at H31. Solvation of the protected regions in MHC-I decreases the tertiary packing by breaking the contiguity of the surface hydrophobic patches via surface charge cluster. Mutants or truncated forms of β₂-m can be designed to remove the instability from H31 titration or to enhance the instability through surface charge suppression. By monitoring the conformational evolution of wild-type protein and variants thereof, either in response or absence of external perturbation, valuable insights into intermediate structure and fibrillogenesis mechanisms are gained.

Keywords: β; ₂; -microglobulin conformation; β; ₂; -microglobulin NMR structure; Protein NMR; Amyloidogenic protein NMR; β; ₂; -microglobulin solution structure; β; ₂; -microglobulin mutant

The three-dimensional structure of β2 microglobulin: Results from X-ray crystallography by Camillo Rosano; Simone Zuccotti; Martino Bolognesi (pp. 85-91).

β2-microglobulin, the light chain component of the major histocompatibility complex I, is involved in the development of DRA, an amyloid deposition disease occurring in man. Specifically, the β2-microglobulin component, dissociated form the complex heavy chain, gives rise to amyloidogenic deposits in the joints of patients exposed to long dialysis periods. β2-microglobulin three-dimensional structure is based on an antiparallel β−barrel fold, with immunoglobulin domain topology, displaying structural flexibility in the crystal and NMR structures so fare determined. The structural bases of amyloidogenic potential in β2-microglobulin can be related to local unfolding, to the tendency to aggregate laterally through non-compensated β-strands, and partly also to its trend towards N-terminal proteolytic degradation. Such trends emerge quite clearly from inspection of a limited number of crystal structures of β2-microglobulin as an isolated chain, separated form the major histocompatibility complex I heavy chain.

Keywords: Abbreviations; r.m.s.; root mean square; β2m; β2 microglobulin; MHC-I; human class I Major Histocompatibility Complex; DRA; dialysis related amyloidosis; H31Y-β2m; the His31; →; Tyr β2m mutantβ2 microglobulin; Class I major histocompatibility complex; Dialysis related amyloidosis; Amyloid fibril; Cross-β structure

From chance to frequent encounters: Origins of β2-microglobulin fibrillogenesis by Catherine M. Eakin; Andrew D. Miranker (pp. 92-99).

It is generally accepted that amyloid formation requires partial, but not complete unfolding of a polypeptide chain. Amyloid formation by β-2 microglobulin (β2m), however, readily occurs under strongly native conditions provided that there is exposure to specific transition metal cations. In this review, we discuss transition metal catalyzed conformational changes in several amyloidogenic systems including prion protein, Alzheimer's and Parkinson's diseases. For some systems, including β2m from dialysis related amyloidosis (DRA), catalysis overcomes an entropic barrier to protein aggregation. Recent data suggest that β2m samples conformations that are under thermodynamic control, resulting in local or partial unfolding under native conditions. Furthermore, exposure to transition metal cations stabilizes these partially unfolded states and promotes the formation of small oligomers, whose structures are simultaneously near-native and amyloid-like. By serving as a tether, Cu²⁺ enables the encounter of amyloidogenic conformations to occur on time scales which are significantly more rapid than would occur between freely diffusing monomeric protein. Once amyloid formation occurs, the requirement for Cu²⁺ is lost. We assert that β2m amyloid fiber formation at neutral pH may be facilitated by rearrangements catalyzed by the transient and pair wise tethering of β2m at the blood/dialysate interface present during therapeutic hemodialysis.

Keywords: Amyloid; Hemodialysis; β-2 microglobulin; Protein folding

FT-IR approaches on amyloid fibril structure by Hirotsugu Hiramatsu; Teizo Kitagawa (pp. 100-107).

This review treats recent achievements of Fourier-transform infrared absorption spectroscopy on protein science, especially on amyloid fibril structure. It includes the brief explanation of theoretical background, description of related techniques, and recent applications to analysis of fibril structure. Concerns to theoretical background, successful analysis of Amide I in terms of transition dipole coupling between the CO oscillators in peptide main chain has been described. The theory enables us to estimate a content of secondary structure in a protein. Related experimental techniques such as linear dichroism measurement, application of microscope, and isotope labeling, are introduced. The linear-dichroism measurement brings direct information on molecular orientation, microscope enables to treat a well-prepared particle, and isotope-label technique allows our structural discussion with one-residue resolution. Application of IR absorption spectroscopy and related techniques on amyloid fibril structure is reviewed. The model obtained is compared with protein native structure.

Keywords: FT-IR; Amide I; Isotope label; IR linear dichroism; Microscope; Amyloid fibril structure

Structural studies reveal that the diverse morphology of β₂-microglobulin aggregates is a reflection of different molecular architectures by J�zsef Kardos; Daichi Okuno; Tomoji Kawai; Yoshihisa Hagihara; Noboru Yumoto; Teizo Kitagawa; P�ter Z�vodszky; Hironobu Naiki; Yuji Goto (pp. 108-120).

Amyloid deposition accompanies over 20 degenerative diseases in human, including Alzheimer's, Parkinson's, and prion diseases. Recent studies revealed the importance of other type of protein aggregates, e.g., non-specific aggregates, protofibrils, and small oligomers in the development of such diseases and proved their increased toxicity for living cells in comparison with mature amyloid fibrils. We carried out a comparative structural analysis of different monomeric and aggregated states of β₂-microglobulin, a protein responsible for hemodialysis-related amyloidosis. We investigated the structure of the native and acid-denatured states, as well as that of mature fibrils, immature fibrils, amorphous aggregates, and heat-induced filaments, prepared under various in vitro conditions. Infrared spectroscopy demonstrated that the β-sheet compositions of immature fibrils, heat-induced filaments and amorphous aggregates are characteristic of antiparallel intermolecular β-sheet structure while mature fibrils are different from all others suggesting a unique overall structure and assembly. Filamentous aggregates prepared by heat treatment are of importance in understanding the in vivo disease because of their stability under physiological conditions, where amyloid fibrils and protofibrils formed at acidic pH depolymerize. Atomic force microscopy of heat-induced filaments represented a morphology similar to that of the low pH immature fibrils. At a pH close to the pI of the protein, amorphous aggregates were formed readily with association of the molecules in native-like conformation, followed by formation of intermolecular β-sheet structure in a longer time-scale. Extent of the core buried from the solvent in the various states was investigated by H/D exchange of the amide protons.

Keywords: Abbreviations; β2m; β; ₂; -microglobulin; H/D; hydrogen-deuterium; FTIR; Fourier transform infrared; ThT; thioflavin T; AFM; atomic force microscopy; CD; circular dichroism; DSC; differential scanning calorimetry; pD*; pH-meter reading in D; ₂; O solutionAmyloid formation; Protein aggregation; β; ₂; -microglobulin; Fourier transform infrared spectroscopy; Secondary structure; Hydrogen-deuterium exchange

Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques: β₂-microglobulin amyloidosis by Hadar Benyamini; Kannan Gunasekaran; Haim Wolfson; Ruth Nussinov (pp. 121-130).

Obtaining atomic resolution structural models of amyloid fibrils is currently impossible, yet crucial for our understanding of the amyloid mechanism. Different pathways in the transformation of a native globular domain to an amyloid fibril invariably involve domain destabilization. Hence, locating the unstable segments of a domain is important for understanding its amyloidogenic transformation and possibly control it. Since relative conservation is suggested to relate to local stability [H. Benyamini, K. Gunasekaran, H. Wolfson, R. Nussinov, Conservation and amyloid formation: a study of the gelsolin-like family, Proteins 51 (2003) 266–282. [24]], we performed an extensive, sequence and structure conservation analysis of the β₂-microglobulin (β₂-m) domain. Our dataset include 51 high resolution structures belonging to the “C1 set domain�? family and 132 clustered PSI-BLAST search results. Segments of the β₂-m domain corresponding to strands A (residues 12–18), D (45–55) and G (91–95) were found to be less conserved and stable, while the central strands B (residues 22–28), C (36–41), E (62–70) and F (78–83) were found conserved and stable. Our findings are supported by accumulating observations from various experimental methods, including urea denaturation, limited proteolysis, H/D exchange and structure determination by both NMR and X-ray crystallography. We used our conservation findings together with experimental literature information to suggest a structural model for the polymerized unit of β₂-m. Pairwise protein docking and subsequent monomer stacking in the same manner suggest a fibril model consistent with the cross-β structure.

Keywords: Fibril modelling; Protein; β; ₂; -microglobulin

Interactions of charged ligands with β₂-microglobulin conformers in affinity capillary electrophoresis by Niels H.H. Heegaard; Ersilia De Lorenzi (pp. 131-140).

Alternative conformations of β₂-microglobulin (β₂m) are involved in its transformation from soluble monomeric precursor molecules to the insoluble polymeric material that constitutes β₂m amyloid. Accordingly, non-native conditions such as low pH or high ionic strength promote β₂m amyloid formation in vitro. The early events in these processes are not well known, partly because of the paucity of techniques available for the characterization of transient folding intermediates in proteins. We have used high-resolution separations in capillaries (capillary electrophoresis, CE) to resolve putative conformer fractions in native and structurally modified β₂m and to show the induction of alternatively folded β₂m under different experimental conditions. The conformer fractions are observed as distinct peaks in the separation profiles and thus it is possible to probe for the reactivity of these individual β₂m species with specific ligands that, upon binding, alter analyte mobility in affinity capillary electrophoresis experiments. Interactions were shown in this way for the negatively charged substances heparin, Congo red, and suramin, as well as for Cu²⁺ ions. Marked differences in the binding behavior of the β₂m conformational variants compared with native β₂m could be demonstrated. This approach for conformer separation and binding characterization is a valuable starting point for the assessment of various ligand molecules, or analogues thereof, as agents capable of perturbing the mechanisms of fibril formation.

Keywords: β; ₂; -microglobulin; Amyloid; Protein conformation; Capillary electrophoresis; Affinity

β₂-Microglobulin-selective direct hemoperfusion column for the treatment of dialysis-related amyloidosis by Hidetoshi Kutsuki (pp. 141-145).

Lixelle is a direct hemoperfusion-type adsorption column that was developed to selectively eliminate β2-microglobulin (β2-m) from the circulating blood of patients with dialysis-related amyloidosis (DRA). The adsorbent in Lixelle comprises porous cellulose beads to which hydrophobic hexadecyl alkyl chain is covalently bound. One milliliter of wet Lixelle beads eliminates more than 1 mg of β2-m in vitro. In hemodialysis patients who were treated with Lixelle, Lixelle improved joint pain, nocturnal awakening, pinch strength, motor terminal latency, and their activity of daily living. The adsorbent adsorbs β2-m selectively but not specifically, as well as inflammatory cytokines such as interleukin-1β and IL-6 which are considered to be involved in the development of DRA. Lixelle treatments reduce the circulating levels of β2-m and inflammatory cytokines, thereby improving the symptoms of patients with DRA.

Keywords: β2-microglobulin; Dialysis-related amyloidosis; Direct hemoperfusion; Adsorption column; Lixelle

Beta₂-microglobulin removal by extracorporeal renal replacement therapies by Detlef H. Krieter; Horst-Dieter Lemke; Bernard Canaud; Christoph Wanner (pp. 146-153).

There is increasing evidence that end-stage renal disease patients with lower beta₂-microglobulin plasma levels and patients on convective renal replacement therapy are at lower mortality risk. Therefore, an enhanced beta₂-microglobulin removal by renal replacement procedures has to be regarded as a contribution to a more adequate dialysis therapy. In contrast to high-flux dialysis, low-flux hemodialysis is not qualified to eliminate substantial amounts of beta₂-microglobulin. In hemodialysis using modern high-flux dialysis membranes, a beta₂-microglobulin removal similar to that obtained in hemofiltration or hemodiafiltration can be achieved. Several of these high-flux membranes are protein-leaking, making them suitable only for hemodialysis due to a high albumin loss when used in more convective therapy procedures. On-line hemodiafiltration infusing large substitution fluid volumes represents the most efficient and innovative renal replacement therapy form. To maximize beta₂-microglobulin removal, modifications of this procedure have been proposed. These modifications ensure safer operating conditions, such as mixed hemodiafiltration, or control albumin loss at maximum purification from beta₂-microglobulin, such as mid-dilution hemodiafiltration, push/pull hemodiafiltration or programmed filtration. Whether these innovative hemodiafiltration options will become accepted in clinical routine use needs to be proven in future.

Keywords: Beta; ₂; -microglobulin; Beta; ₂; -microglobulin removal; Clinical haemodialysis; Haemofiltration; Haemodiafiltration

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BBA - Proteins and Proteomics (v.1753, #1)