Dialysis-Associated Amyloidosis

  • Paweena Susantitaphong
  • Laura M. Dember
  • Bertrand L. JaberEmail author
Part of the Current Clinical Pathology book series (CCPATH)


Dialysis-associated amyloidosis resulting from the accumulation of beta-2 microglobulin (β2m) is an important long-term complication in patients with chronic kidney failure on long-term dialysis. Bone and peri-articular tissue are the most common sites of β2m deposition. Typical clinical manifestations include the carpal tunnel syndrome, chronic arthropathy, spondyloarthropathies, subchondral bone cysts, and fractures. Although the pathogenesis of dialysis-associated amyloidosis has not been fully elucidated, there are several relevant molecular pathways that have been identified. Histopathological examination is the gold standard for diagnosing β2m-related amyloidosis. The diagnosis is made on the basis of positive Congo red staining with typical green-yellow birefringence under polarized light, coupled with positive anti-β2m antibody immuno-staining or amyloid protein identification by proteomic methods. The β2m amyloid deposition starts early in the course of the disease, long before the development of symptoms. Therefore, early detection especially in high-risk patients may be important to prevent or delay disease progression before the development of debilitating complications. Novel dialysis modalities to enhance β2m removal and ultrapure dialysate to reduce β2m synthesis from chronic inflammation are treatment strategies for dialysis-related amyloidosis. However, successful kidney transplantation remains the only potential curative treatment of choice.


Dialysis Hemodialysis amyloidosis Beta-2 microglobulin Arthropathy Bone cysts 


  1. 1.
    Sergio R, Acchiardo M. Chapter 79—dialysis amyloidosis, section 25- dialysis amyloidosis. Handbook of Dialysis Therapy 4th ed. In: Allen R, Nissenson M, Richard N, Fine MD, editors. Saunders: Elsevier; 2007. p 1041–7.Google Scholar
  2. 2.
    Dember LM, Jaber BL. Dialysis-related amyloidosis: late finding or hidden epidemic? Semin Dial. 2006;19(2):105–9. Epub 2006/03/23.CrossRefPubMedGoogle Scholar
  3. 3.
    Harris HW, Gill 3rd TJ. Expression of class I transplantation antigens. Transplantation. 1986;42(2):109–17.CrossRefPubMedGoogle Scholar
  4. 4.
    Bernier GM, Conrad ME. Catabolsm of human beta-2-microglobulin by the rat kidney. Am J Physiol. 1969;217(5):1359–62. Epub 1969/11/01.PubMedGoogle Scholar
  5. 5.
    Miyata T, Jadoul M, Kurokawa K, Van Ypersele de Strihou C. Beta-2 microglobulin in renal disease. J Am Soc Nephrol. 1998;9(9):1723–35. Epub 1998/09/04.PubMedGoogle Scholar
  6. 6.
    Drueke TB, Massy ZA. Beta2-microglobulin. Semin Dial. 2009;22(4):378–80. Epub 2009/08/28.CrossRefPubMedGoogle Scholar
  7. 7.
    Yamamoto S, Kazama JJ, Narita I, Naiki H, Gejyo F. Recent progress in understanding dialysis-related amyloidosis. Bone. 2009;45 Suppl 1:S39–42. Epub 2009/03/24.CrossRefPubMedGoogle Scholar
  8. 8.
    Valleix S, Gillmore JD, Bridoux F, Mangione PP, Dogan A, Nedelec B, et al. Hereditary systemic amyloidosis due to Asp76Asn variant beta2-microglobulin. N Engl J Med. 2012;366(24):2276–83. Epub 2012/06/15.CrossRefPubMedGoogle Scholar
  9. 9.
    Schwalbe S, Holzhauer M, Schaeffer J, Galanski M, Koch KM, Floege J. Beta 2-microglobulin associated amyloidosis: a vanishing complication of long-term hemodialysis? Kidney Int. 1997;52(4):1077–83. Epub 1997/11/05.CrossRefPubMedGoogle Scholar
  10. 10.
    Jadoul M, Garbar C, Noel H, Sennesael J, Vanholder R, Bernaert P, et al. Histological prevalence of beta 2-microglobulin amyloidosis in hemodialysis: a prospective post-mortem study. Kidney Int. 1997;51(6):1928–32. Epub 1997/06/01.CrossRefPubMedGoogle Scholar
  11. 11.
    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 hemodialysis patients. Kidney Int. 1998;54(3):956–9. Epub 1998/09/12.CrossRefPubMedGoogle Scholar
  12. 12.
    Naiki H, Yamamoto S, Hasegawa K, Yamaguchi I, Goto Y, Gejyo F. Molecular interactions in the formation and deposition of beta2-microglobulin-related amyloid fibrils. Amyloid. 2005;12(1):15–25. Epub 2005/08/04.CrossRefPubMedGoogle Scholar
  13. 13.
    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-microglobulin-related amyloid fibrils at a neutral pH. Biochemistry. 2004;43(34):11075–82. Epub 2004/08/25.CrossRefPubMedGoogle Scholar
  14. 14.
    Moe SM, Chen NX. The role of the synovium and cartilage in the pathogenesis of beta(2)-microglobulin amyloidosis. Semin Dial. 2001;14(2):127–30. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  15. 15.
    Heegaard NH. beta(2)-microglobulin: from physiology to amyloidosis. Amyloid. 2009;16(3):151–73. Epub 2009/08/07.CrossRefPubMedGoogle Scholar
  16. 16.
    Niwa T. Dialysis-related amyloidosis: pathogenesis focusing on AGE modification. Semin Dial. 2001;14(2):123–6. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  17. 17.
    Tran M, Rutecki GW, Sprague SM. The pathogenesis of beta(2)-microglobulin-induced bone lesions in dialysis-related amyloidosis. Semin Dial. 2001;14(2):131–3. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  18. 18.
    Naganuma T, Sugimura K, Uchida J, Tashiro K, Yoshimura R, Takemoto Y, et al. Increased levels of serum matrix metalloproteinase-3 in haemodialysis patients with dialysis-related amyloidosis. Nephrology (Carlton). 2008;13(2):104–8. Epub 2008/02/16.CrossRefGoogle Scholar
  19. 19.
    Kazama JJ, Maruyama H, Gejyo F. Osteoclastogenesis and osteoclast activation in dialysis-related amyloid osteopathy. Am J Kidney Dis. 2001;38(4 Suppl 1):S156–60. Epub 2001/09/29.CrossRefPubMedGoogle Scholar
  20. 20.
    Stoppini M, Mangione P, Monti M, Giorgetti S, Marchese L, Arcidiaco P, et al. Proteomics of beta2-microglobulin amyloid fibrils. Biochim Biophys Acta. 2005;1753(1):23–33. Epub 2005/09/13.CrossRefPubMedGoogle Scholar
  21. 21.
    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 J Med. 1986;314(9):585–6. Epub 1986/02/27.CrossRefPubMedGoogle Scholar
  22. 22.
    Yamamoto S, Kazama JJ, Maruyama H, Nishi S, Narita I, Gejyo F. Patients undergoing dialysis therapy for 30 years or more survive with serious osteoarticular disorders. Clin Nephrol. 2008;70(6):496–502. Epub 2008/12/04.CrossRefPubMedGoogle Scholar
  23. 23.
    Schiffl H. Impact of advanced dialysis technology on the prevalence of dialysis-related amyloidosis in long-term maintenance dialysis patients. Hemodial Int. 2014;18(1):136–41. Epub 2013/05/31.CrossRefPubMedGoogle Scholar
  24. 24.
    Celik G, Capraz I, Yontem M, Bilge M, Unaldi M, Mehmetoglu I. The relationship between the antioxidant system, oxidative stress and dialysis-related amyloidosis in hemodialysis patients. Saudi J Kidney Dis Transpl. 2013;24(6):1157–64. Epub 2013/11/16.CrossRefPubMedGoogle Scholar
  25. 25.
    Jaradat MI, Moe SM. Effect of hemodialysis membranes on beta 2-microglobulin amyloidosis. Semin Dial. 2001;14(2):107–12. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  26. 26.
    Schiffl H, Lang SM, Stratakis D, Fischer R. Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters. Nephrol Dial Transplant. 2001;16(9):1863–9. Epub 2001/08/28.CrossRefPubMedGoogle Scholar
  27. 27.
    Gejyo F, Narita I. Current clinical and pathogenetic understanding of beta2-m amyloidosis in long-term haemodialysis patients. Nephrology (Carlton). 2003;8(Suppl):S45–9. Epub 2004/03/12.CrossRefGoogle Scholar
  28. 28.
    Danesh F, Ho LT. Dialysis-related amyloidosis: history and clinical manifestations. Semin Dial. 2001;14(2):80–5. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  29. 29.
    Bataille S, Fernandez C, Zink JV, Brunet P, Berland Y, Burtey S. The Case | A hip fracture in a hemodialysis patient. Pathologic right-hip fracture from beta2-microglobulin amyloidosis. Kidney Int. 2013;83(6):1211–2. Epub 2013/06/04.CrossRefPubMedGoogle Scholar
  30. 30.
    Gal R, Korzets A, Schwartz A, Rath-Wolfson L, Gafter U. Systemic distribution of beta 2-microglobulin-derived amyloidosis in patients who undergo long-term hemodialysis. Report of seven cases and review of the literature. Arch Pathol Lab Med. 1994;118(7):718–21. Epub 1994/07/01.PubMedGoogle Scholar
  31. 31.
    Choi HS, Heller D, Picken MM, Sidhu GS, Kahn T. Infarction of intestine with massive amyloid deposition in two patients on long-term hemodialysis. Gastroenterology. 1989;96(1):230–4. Epub 1989/01/01.PubMedGoogle Scholar
  32. 32.
    Zhou H, Pfeifer U, Linke R. Generalized amyloidosis from beta 2-microglobulin, with caecal perforation after long-term haemodialysis. Virchows Arch A Pathol Anat Histopathol. 1991;419(4):349–53. Epub 1991/01/01.CrossRefPubMedGoogle Scholar
  33. 33.
    Esslimani M, Serre I, Granier M, Robert M, Baldet P, Costes V. Urogenital amyloidosis: clinico-pathological study of 8 cases. Ann Pathol. 1999;19(6):487–91. Epub 2000/01/05. Amylose urogenitale: etude anatomo-clinique a propos de 8 cas.PubMedGoogle Scholar
  34. 34.
    Saito A, Gejyo F. Current clinical aspects of dialysis-related amyloidosis in chronic dialysis patients. Ther Apher Dial. 2006;10(4):316–20. Epub 2006/08/17.CrossRefPubMedGoogle Scholar
  35. 35.
    Kiss E, Keusch G, Zanetti M, Jung T, Schwarz A, Schocke M, et al. Dialysis-related amyloidosis revisited. AJR Am J Roentgenol. 2005;185(6):1460–7. Epub 2005/11/24.CrossRefPubMedGoogle Scholar
  36. 36.
    Ketteler M, Koch KM, Floege J. Imaging techniques in the diagnosis of dialysis-related amyloidosis. Semin Dial. 2001;14(2):90–3. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  37. 37.
    Kay J, Benson CB, Lester S, Corson JM, Pinkus GS, Lazarus JM, et al. Utility of high-resolution ultrasound for the diagnosis of dialysis-related amyloidosis. Arthritis Rheum. 1992;35(8):926–32. Epub 1992/08/11.CrossRefPubMedGoogle Scholar
  38. 38.
    Jadoul M, Garbar C, van Ypersele de Strihou C. Pathological aspects of beta(2)-microglobulin amyloidosis. Semin Dial. 2001;14(2):86–9. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  39. 39.
    Mendoza PD, Fenves AZ, Punar M, Stone MJ. Subcutaneous beta2-microglobulin amyloid shoulder nodulesin a long-term hemodialysis patient. Proc (Bayl Univ Med Cent). 2010;23(2):139–41. Epub 2010/04/17.Google Scholar
  40. 40.
    Lornoy W, Becaus I, Billiouw JM, Sierens L, Van Malderen P, D’Haenens P. On-line haemodiafiltration. Remarkable removal of beta2-microglobulin. Long-term clinical observations. Nephrol Dial Transplant. 2000;15 Suppl 1:49–54. Epub 2000/03/29.CrossRefPubMedGoogle Scholar
  41. 41.
    Rabindranath KS, Strippoli GF, Daly C, Roderick PJ, Wallace S, MacLeod AM. Haemodiafiltration, haemofiltration and haemodialysis for end-stage kidney disease. Cochrane Database Syst Rev. 2006;4:CD006258. Epub 2006/10/21.PubMedGoogle Scholar
  42. 42.
    Jaber BL, Zimmerman DL, Teehan GS, Swedko P, Burns K, Meyer KB, et al. Daily hemofiltration for end-stage renal disease: a feasibility and efficacy trial. Blood Purif. 2004;22(6):481–9. Epub 2004/11/04.CrossRefPubMedGoogle Scholar
  43. 43.
    Raj DS, Ouwendyk M, Francoeur R, Pierratos A. beta(2)-microglobulin kinetics in nocturnal haemodialysis. Nephrol Dial Transplant. 2000;15(1):58–64. Epub 1999/12/23.CrossRefPubMedGoogle Scholar
  44. 44.
    Leypoldt JK, Cheung AK, Deeter RB, Goldfarb-Rumyantzev A, Greene T, Depner TA, et al. Kinetics of urea and beta-microglobulin during and after short hemodialysis treatments. Kidney Int. 2004;66(4):1669–76. Epub 2004/10/02.CrossRefPubMedGoogle Scholar
  45. 45.
    Kutsuki H. beta(2)-Microglobulin-selective direct hemoperfusion column for the treatment of dialysis-related amyloidosis. Biochim Biophys Acta. 2005;1753(1):141–5. Epub 2005/09/20.CrossRefPubMedGoogle Scholar
  46. 46.
    Yamamoto Y, Hirawa N, Yamaguchi S, Ogawa N, Takeda H, Shibuya K, et al. Long-term efficacy and safety of the small-sized beta2-microglobulin adsorption column for dialysis-related amyloidosis. Ther Apher Dial. 2011;15(5):466–74. Epub 2011/10/07.CrossRefPubMedGoogle Scholar
  47. 47.
    Lin CL, Yang CW, Chiang CC, Chang CT, Huang CC. Long-term on-line hemodiafiltration reduces predialysis beta-2-microglobulin levels in chronic hemodialysis patients. Blood Purif. 2001;19(3):301–7. Epub 2001/03/13.CrossRefPubMedGoogle Scholar
  48. 48.
    Thomas G, Jaber BL. Convective therapies for removal of middle molecular weight uremic toxins in end-stage renal disease: a review of the evidence. Semin Dial. 2009;22(6):610–4. Epub 2009/12/19.CrossRefPubMedGoogle Scholar
  49. 49.
    Gejyo F, Amano I, Ando T, Ishida M, Obayashi S, Ogawa H, et al. Survey of the effects of a column for adsorption of beta2-microglobulin in patients with dialysis-related amyloidosis in Japan. Ther Apher Dial. 2013;17(1):40–7. Epub 2013/02/06.CrossRefPubMedGoogle Scholar
  50. 50.
    Montagna G, Cazzulani B, Obici L, Uggetti C, Giorgetti S, Porcari R, et al. Benefit of doxycycline treatment on articular disability caused by dialysis related amyloidosis. Amyloid. 2013;20(3):173–8. Epub 2013/06/06.CrossRefPubMedGoogle Scholar
  51. 51.
    Campistol JM. Dialysis-related amyloidosis after renal transplantation. Semin Dial. 2001;14(2):99–102. Epub 2001/03/27.CrossRefPubMedGoogle Scholar
  52. 52.
    Leypoldt JK. Kinetics of beta-microglobulin and phosphate during hemodialysis: effects of treatment frequency and duration. Semin Dial. 2005;18(5):401–8.CrossRefPubMedGoogle Scholar
  53. 53.
    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. J Am Soc Nephrol. 2006;17(2):546–55. Epub 2005/12/31.CrossRefPubMedGoogle Scholar
  54. 54.
    Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M, Wizemann V, et al. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol. 2009;20(3):645–54. Epub 2008/12/19.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Haase M, Bellomo R, Baldwin I, Haase-Fielitz A, Fealy N, Morgera S, et al. Beta2-microglobulin removal and plasma albumin levels with high cut-off hemodialysis. Int J Artif Organs. 2007;30(5):385–92. Epub 2007/06/07.PubMedGoogle Scholar
  56. 56.
    Lee D, Haase M, Haase-Fielitz A, Paizis K, Goehl H, Bellomo R. A pilot, randomized, double-blind, cross-over study of high cut-off versus high-flux dialysis membranes. Blood Purif. 2009;28(4):365–72. Epub 2009/09/05.CrossRefPubMedGoogle Scholar
  57. 57.
    Susantitaphong P, Siribamrungwong M, Jaber BL. Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2013;28(11):2859–74. Epub 2013/10/02.CrossRefPubMedGoogle Scholar
  58. 58.
    Susantitaphong P, Riella C, Jaber BL. Effect of ultrapure dialysate on markers of inflammation, oxidative stress, nutrition and anemia parameters: a meta-analysis. Nephrol Dial Transplant. 2013;28(2):438–46. Epub 2013/01/08.CrossRefPubMedGoogle Scholar
  59. 59.
    Regazzoni L, Colombo R, Bertoletti L, Vistoli G, Aldini G, Serra M, et al. Screening of fibrillogenesis inhibitors of beta2-microglobulin: integrated strategies by mass spectrometry capillary electrophoresis and in silico simulations. Anal Chim Acta. 2011;685(2):153–61. Epub 2010/12/21.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Paweena Susantitaphong
    • 1
    • 2
  • Laura M. Dember
    • 3
  • Bertrand L. Jaber
    • 1
    Email author
  1. 1.Division of Nephrology, Department of MedicineSt. Elizabeth’s Medical Center, Tufts University School of MedicineBostonUSA
  2. 2.Extracorporeal Multiorgan Support Dialysis Center, Division of Nephrology, Department of MedicineKing Chulalongkorn Memorial Hospital, Chulalongkorn UniversityBangkokThailand
  3. 3.Renal-Electrolyte and Hypertension DivisionPerelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA

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