β2 Microglobulin-Derived Amyloid in Dialysis Patients

  • E. Ritz
  • R. Deppisch
  • G. Stein
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 260)


In the recent past, a whole spectrum of osteoarticular problems has been recognized in patients on longterm hemodialysis. After the recognition by Assenat et al. (1) of amyloid-related carpal tunnel syndrome in hemodialysis patients whose primary renal disease had not been amyloidosis, many reports confirmed its high prevalence in dialysis patients (2). In addition, joint pain, joint swelling and recurrent hemarthros were recognized as the consequence of synovial amyloid deposits (3) which had many similarities with articular amyloidosis of the AL type (4). Finally, amyloid containing bone cysts, pathological fractures (5) and destructive arthropathy in the appendicular or axial skeleton (6) were noted with increasing frequency. Todate, this new form of amyloid has not been demonstrated in non-dialysed uremic patients. However, in patients with preterminal renal failure, similar amyloid has been recognized as a structural component of matrix stones either within the kidney or passed into the urine (7,8). While extrarenal amyloid, todate, has only been demonstrated in patients on renal replacement therapy, i. e. hemodialysis, hemofiltration or CAPD (9), it is unknown whether the phenomenon is causally related to these treatment modalities or whether it merely reflects longer patients survival and continued exposure to risk. It came as a major breakthrough when such amyloid could be characterized at the molecular level by Gejyo(10). He documented that these amyloid fibrils are derived from the circulating precursor molecule beta-2-microglobulin (β2 m). The clinical problems of dialysisrelated amyloid have been reviewed extensively elsewhere (9, 11). This communication will mainly discuss problems of pathogenesis and treatment.


Hemodialysis Patient Carpal Tunnel Syndrome Amyloid Fibril Bone Cyst Proteolytic Modification 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Assenat, H., Calemard, E., Charra, B., Laurent, G., Terrat, J.C., Vanel, T.: Hémodialyse, syndrome du canal carpien et substance amyloide. Nouv. Press Méd. 9:1715 (1980).Google Scholar
  2. 2.
    Schwarz, A., Keller, F., Seyfer, S., Poll, W., Molzahn, M., Distler, A.: Carpal tunnel syndrome: a major complication in long-term hemodialysis patients. Clin. Nephrol. 22:133 (1984).PubMedGoogle Scholar
  3. 3.
    Charra, B., Calemard, E., Uzan, M., Terrat, J.C., Vanel, T., Laurent, G.: Carpal tunnel syndrome, shoulder pain and amyloid deposits in longterm haemodialysis patients. Proc. EDTA-ERA 21:291 (1984).Google Scholar
  4. 4.
    Gordon, D.A., Pruzanski, W., Ogrylo, M.A., Little, H.A.: Amyloid arthritis simulating rheumatoid disease in five patients with multiple myeloma. Am. J. Med. 55:142 (1973) .PubMedCrossRefGoogle Scholar
  5. 5.
    Huaux, J. P., Nöel, H. , Bastien, P., Malghem, J., Maldague, B., Devogelaer, J.P., Nagant de Deuxchaisnes, C: Amylose articulaire, facture du col femoral, et hémodialyse périodique chronique. Rev. Rhum. 52:179 (1985).PubMedGoogle Scholar
  6. 6.
    Kuntz, D., Naveau, B., Bardin, T., Drüeke, T., Treves, R., Dryll, A.,: Destructive spondylarthropathy in hemodialyzed patients: a new syndrome. Arthritis Rheum. 27: 369 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    Bommer, J., Ritz, E., Tschöpe, W., Waldherr, R., Gebhardt, M.: Urinary matrix calculi consisting of microfibrillar protein in patients on maintenance hemodialysis. Kidney Int. 16:722 (1979).PubMedCrossRefGoogle Scholar
  8. 8.
    Linke, P.R., Bommer, J., Ritz, E., Waldherr, R., Eulitz, M.: Amyloid kidney stones of uremic patients consist of beta-2-microglobulin fragments. Biochem. Biophvs. Res. Commun. 136:665 (1986).CrossRefGoogle Scholar
  9. 9.
    Ritz, E., Bommer, J., Zeier, M.: β2 Mikroglobulinbedingte Amyloidose. Dtsch. Med. Wschr. 113:190 (1988).PubMedCrossRefGoogle Scholar
  10. 10.
    Gejyo, F., Yamada, T., Odani, S., Nakagawa, Y., Kunimoto, T., Kataoka, H., Suzuki, M., Hirasawa, Y., Shirahama, T., Cohen, A.S., Schmid, K.: A new form of amyloid protein associated with hemodialysis was identified as β2 microglobulin. Biochem. Biophvs. Res. Commun. 129:701 (1985).CrossRefGoogle Scholar
  11. 11.
    Van Ypersele de Strihou, C., Honhon, B., Vandenbroucke, J.M., Huaux, J.P., Nöel, H., Maldagüe, B.: L’amylose du dialyse. Actualités Néphrologiques. Flammarion, Paris, 371 (1987).Google Scholar
  12. 12.
    Becker, J.W., Reeke, G.N.: Three dimensional structure of β2m microglobulin. Proc. Nat. Acad. Sci. (Wash.), 82:4225 (1985).CrossRefGoogle Scholar
  13. 13.
    Bernabeu, C., van de Rijn, M., Lerch, P.G., Terhorst, C.P.: β2 microglobulin from serum associates with MHC class I antigens on the surface of cultured cells. Nature (Lond.), 308:642 (1984).CrossRefGoogle Scholar
  14. 14.
    Evrin, P.E., Nilsson, K.: β2 microglobulin production in vitro by human hematopoetic mesenchymal and epithelial cells. J. Immunol. 112:137 (1974).PubMedGoogle Scholar
  15. 15.
    Rosa, F., Felions, M., Dron, M., Tovey, M., Revel, M.: Presence of abnormal β2 microglobulin in RBA in Daudi cells. Induction by interferon. Immunoqenetics 17:125 (1983).CrossRefGoogle Scholar
  16. 16.
    Collins, T., Lapierre, L.A., Fiers, W., Strominger, J.L., Pober, J.S.: Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A, B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc. Nat. Acad. Sci. (Wash.) 83:446 (1986).CrossRefGoogle Scholar
  17. 17.
    Ramadori, G. , Mitsch, A., Rieder, H., Meyer zum Büschenfelde, K.-H.: Alpha- and gamma-interferon (IFN, IFN) but not interleukin-1 (IL-1) modulate synthesis and secretion of β2-microglobulin by hepatocytes. Eur. J. Clin. Invest. 18:343 (1988).PubMedCrossRefGoogle Scholar
  18. 18.
    Karlsson, F.A., Groth, T., Sege, K., Wibell, L., Peterson, P.A.: Turnover in humans of β2 microglobulin: the constant chain of HLA antigens. Eur. J. Clin. Invest. 10:293 (1980).PubMedCrossRefGoogle Scholar
  19. 19.
    Vincent, C., Revillard, J.P., Gallard, M. , Traeger, J.: Serum β2 microglobulin in hemodialysed patients. Nephron 21:260 (1978).PubMedCrossRefGoogle Scholar
  20. 20.
    Nguyen-Simonet, H. , Vincent, C., Gauthier, C., Revillard, J.P., Pellet, M.V.: Turnover studies of human β2 microglobulin in the rat. Evidence for a β2 microglobulin binding plasma protein. Clin. Sci. 62:403 (1982).Google Scholar
  21. 21.
    Bommer, J., Seelig, P., Seelig, R., Geerlings, W., Bommer, G., Ritz, E.: Determinants of plasma β2 m microglobulin concentration. Possible relation to membrane biocompatibility. Nephrol. Dial. Transplant. 2:22 (1987) .PubMedGoogle Scholar
  22. 22.
    Ogawa, H., Saito, A., Oda, O., Nakajima, M., Chung, T.G.: Detection of novel β2-microglobulin in the serum of hemodialysis patients and its amyloidogenic predisposition. Clin. Nephrol. 30:158 (1988).PubMedGoogle Scholar
  23. 23.
    Vincent, C., Revillard, J.P.: Autoantibodies specific for β2 microglobulin in normal human serum. Molec. Immunol. 20:877 (1983).CrossRefGoogle Scholar
  24. 24.
    Göhl, H., Raff, M., Harttig, H., Deppisch, R.: PC-PE-hollow fiber membrane; structure, performance, characteristics and manufacturing. Blood Purif. 4:23 (1986).PubMedCrossRefGoogle Scholar
  25. 25.
    Flöge, J., Granolleras, C., Göhl, H., Smeby, L. , Koch, K.M., Shaldon, S.: Hydrophilic high flux polyamide membranes for beta-2-microglobulin removal. Proc. ASAIO, 10 (1987).Google Scholar
  26. 26.
    Olbricht, C.J., Häbel, U., Frei, U., Koch, K.M.: Effects of runing time on functional characteristics of hemofilters in CAVH. Blood Purif. 5:301 (a) (1987).Google Scholar
  27. 27.
    Flöge, J., Granolleras, C., Koch, K.M., Shaldon, S.: β2 microglobulin kinetics during hemodialysis and hemofiltration. Nephrol. Dial. Transpl. 1:223 (1987).Google Scholar
  28. 28.
    Goldman, M., Dhaene, M., Vanherweghem, J.L.: Removal of β2 microglobulin by adsorption on dialysis membranes. Nephrol. Dial. Transpl. 2:576 (1987).Google Scholar
  29. 29.
    Jorstad, S., Smeby, L.C., Balstad, T., Wideroe, T.E.: Removal, generations and adsorption of β2 microglobulin during hemofiltrations with five different membranes. Blood Purif. 6:96 (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    Kaiser, J., Hagemann, J., v. Herrath, D., Schaefer, K.: Different handling of β2 microglobulin during hemodialysis and hemofiltration. Nephron 48:132 (1988).PubMedCrossRefGoogle Scholar
  31. 31.
    Bergström, J., Wehle, B.: No change in corrected β2 microglobulin concentration after cuprophane haemodialysis. Lancet I:628 (1987).CrossRefGoogle Scholar
  32. 32.
    Bommer, J., Ritz, E., Seres, T., Bommer, G.: Evidence against shedding of β2 microglobulin during hemodialysis with cuprammonium membranes. Arauivos de Medicina 1:316 (1988).Google Scholar
  33. 33.
    Bardin, T., Zingraff, J., Kuntz, D., Drüeke, T.: Dialysis-related amyloidosis. Nephrol. Dial. Transpl. 1:151 (1986).Google Scholar
  34. 34.
    Connors, L.H., Shirahama, T., Skinner, M., Fenves, A., Cohen, A.S.: In vitro formation of amyloid fibrils from intact β2 microglobulin. Biochem. Biophys. Res. Commun. 31:1063 (1985).CrossRefGoogle Scholar
  35. 35.
    Ritz, E., Bommer, J., Hänsch, M., Rauterberg, E.W.: Beta-2-microglobulin derived amyloid — unsolved problems and unvertainties about dialytic strategies. VIII é Symposium Gambro: Arthropathies des Dialyses et Amylose B-2 M, Paris (1987).Google Scholar
  36. 36.
    Linke, R., Hampl, H., Lobeck, H., Ritz, E., Waldherr, R., Eulitz, M.: Lysine-specific cleavage of β2 microglobulin in amyloid associated with hemodialysis. Kidney Int. (in press) (1988).Google Scholar
  37. 37.
    Sethi, D., Gower, P.E.: Synovial fluid β2 microglobulin levels in dialysis arthropathy. New Engl. J. Med. 315: 1419 (1986).PubMedCrossRefGoogle Scholar
  38. 38.
    McKeating, J., Griffith, P.D., Grandy, J.: Cytomegalovirus in urine specimens has host β2 microglobulin bound to viral envelope: a mechanism of evading the host immune response? J. Gen. Virol. 68:785 (1987).PubMedCrossRefGoogle Scholar
  39. 39.
    Sethi, D., Woodrow, D.F., Brown, E.A.: Beta-2-microglobulin derived amyloid and iron in dialysis arthropathies. Nephrol. Dial. Transpl. 2:449 (1987).Google Scholar
  40. 40.
    Sethi, D., Müller, B.R., Brown, E.A., Maini, R.N., Gower, P.E.: C-reactive protein in hemodialysis patients with dialysis arthropathy. Nephrol. Dial. Transpl. 3:269 (1988).Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • E. Ritz
    • 1
    • 2
  • R. Deppisch
    • 1
    • 2
  • G. Stein
    • 1
    • 2
  1. 1.Department Internal MedicineRuperto-Carola-UniversityHeidelbergGermany
  2. 2.Klinik für Innere MedizinFriedrich Schiller-Universität JenaGermany

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