Medscape is available in 5 Language Editions – Choose your Edition here.


Dialysis-Related Beta-2m Amyloidosis

  • Author: Anita Basu, MD, FACP; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
Updated: May 01, 2014


Beta-2 ̶ microglobulin (beta-2m) amyloidosis is a disabling condition that affects patients undergoing long-term hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).[1, 2] Case reports involving patients with near ̶ end-stage renal disease also exist. The condition does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant. Beta-2m amyloidosis evolves predictably over time and is rare in the first few years of HD. (See Etiology.)

Beta-2m is a major constituent of amyloid fibrils.[3] It has been shown that, through accumulation, it invades synovial membranes and osteoarticular sites. As a result, it causes destructive osteoarthropathies, such as carpal tunnel syndrome, flexor tenosynovitis, subchondral bone cysts, and erosions, as well as pathologic fractures. (See Etiology, Prognosis, and Presentation.)

Visceral involvement has been found in different organs, such as the gastrointestinal (GI) tract, heart, and tongue, but overt manifestations are rare. (See Presentation and Workup.)


The most severe complication involves beta-2m amyloid deposits destroying paravertebral ligaments and intervertebral discs, which can result in paraplegia. Cardiac involvement, with subsequent fatal arrhythmias, and massive GI bleeding have been described. (See Prognosis, Presentation, Treatment, and Medication.)



Beta-2m is a glycosylated polypeptide with a molecular weight of 11,800 dalton. It makes up the beta chain of the human leukocyte antigen (HLA) class I molecule and has the prominent beta-pleated structure that is characteristic of amyloid fibrils.

Beta-2m is present on the surface of most nucleated cells and in most biologic fluids, including urine and synovial fluid. It circulates as an unbound monomer distributed in the extracellular space and polymerizes to form amyloid deposits in a variety of tissues. Two or 3 conformational isomers of beta-2m are recognized in human serum by capillary electrophoresis.[4]

In the normally functioning kidney, beta-2m is cleared by glomerular filtration and is catabolized in the proximal tubules. Reference range serum levels are 1.5-3 mg/L. In renal failure, impaired renal catabolism causes an increase in synthesis and release of beta-2m, and levels can rise 10- to 60-fold. Retention and accumulation of this type of amyloid protein is presumed to be the main pathogenic process underlying beta-2m amyloidosis.

There is also some suggestion that the dialysis process itself may stimulate beta-2m synthesis, by activation of complements and cytokine production. However, it is unlikely that this is a significant mechanism of dialysis-related amyloidosis (DRA), since the disease is also seen in patients on CAPD and people who have never been on dialysis.

Role of dialysis in amyloidogenesis

Retention of amyloidogenic protein remains a key factor in patients on dialysis. Several factors affecting retention have been implicated, including the following:

  • Type of dialysis membrane
  • Prolonged uremic state and/or decreased diuresis
  • Elevated levels of cytokines
  • Advanced glycation end products
  • Dialysate

Type of dialysis membrane

The healthy kidney can eliminate endogenous end products of metabolism, as well as exogenous toxins that are both large ̶ and small ̶ molecular weight substances. Cuprophan and cellulose acetate membranes previously used in conventional HD have small pores and cannot clear substances with molecular weights higher than 200 dalton. This makes them impermeable to beta-2m, elevating the protein’s serum levels. The newer cellulose triacetate dialyzers and the high-flux synthetic dialyzers remove molecules with a higher molecular weight and do a better job of removing beta-2m.

High cut-off, high-flux dialysis and online hemodiafiltration have been shown to be superior to previously used HD membranes in the removal of beta-2m, possibly decreasing beta-2 amyloidosis.

Beta-2m amyloidosis has also been described in patients receiving long-term CAPD, despite the permeability characteristics of the peritoneal membrane. Clearance of middle molecules is better, however, making CAPD a more biocompatible mode of treatment.

Nonetheless, data are conflicting. Some report the prevalence of beta-2m amyloidosis in patients on long-term CAPD as comparable to the prevalence in patients on HD. Other data show that plasma levels of beta-2m are lower in patients on CAPD, suggesting that accumulation of amyloid may occur more slowly. Some of this may also be related to residual renal function. Results of long-term studies are needed.

Prolonged uremic state and/or decreased diuresis

Membranes with poor biocompatibility cannot completely explain increases in beta-2m, because several reports note individuals who were treated exclusively by CAPD. Cases have also been described in patients with chronic renal failure who have not yet started dialysis. Inadequate diuresis and prolonged uremia are suggested contributing factors.

Elevated levels of cytokines

Dialysis is an inflammatory stimulus, inducing cytokine production and complement activation. The released cytokines, including interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6), are thought to stimulate the synthesis and release of beta-2m by macrophages and/or augment the expression of HLA class I antigens, increasing beta-2m expression.

Advanced glycation end products

Following the identification of advanced glycation end products (AGEs) in beta-2m amyloid deposits, the role of AGE has been the focus of much research.[5]

AGEs make up a heterogeneous group of compounds formed by nonenzymatic glycation and oxidative reactions between reducing sugars, lipids, and protein amino groups.

HD and peritoneal dialysis are ineffective in removing these low–molecular weight compounds from circulation.

As AGE-modified beta-2m accumulates, chemotaxis is enhanced, stimulating macrophages to release proinflammatory cytokines, as well as interfering with collagen synthesis. It has been suggested that the interaction of AGE-modified beta-2m with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of DRA, is mediated by the receptor for AGEs, or RAGE.

RAGEs are central binding sites for AGEs formed in vivo.[6] AGE beta-2m/MP/RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of patients on long-term HD. This inflammatory response may ultimately lead to bone and joint destruction.

Oxidation of beta-2m may enhance amyloid deposition. Studies suggest that increased oxidative stress during HD and exposure of beta-2m to hydroxyl radicals stimulate the autoxidation of unstable molecules, leading to augmented AGE production.


Acetate and/or bacterial lipopolysaccharide (endotoxin) may enter the blood via the dialyzer and stimulate the release of cytokines, inducing beta-2m production.



The incidence of DRA in the United States is not known; however, past studies have suggested an incidence of greater than 95% in patients who have been on dialysis for more than 15 years.

Some European studies have suggested that DRA can be seen in as many as 20% of patients after 2-4 years of HD and in 100% after 13 years of HD. Again, however, the overall incidence and prevalence of beta-2m amyloidosis are not clear. Moreover, most studies have focused on HD-associated amyloidosis and were performed before high-flux dialyzer use became commonplace.

There is some mention in the literature that the incidence and prevalence of beta-2m amyloidosis are less in CAPD than in HD (because of residual renal function). Other studies, however, suggest that there is no significant difference in incidence or prevalence.



The prognosis of beta-2m amyloidosis depends on the duration of dialysis, the age of the patient, the age of the patient at the start of dialysis, and the type of dialysis membrane that is being used. Ultimately, residual renal function is probably the best determinant of beta-2m levels in HD patients and may supersede enhanced convective clearance by hemodiafiltration.[7]

Morbidity and mortality

Patients receiving long-term dialysis can experience disabling musculoskeletal complications.[8] For individuals who are able to undergo renal transplantation, progression of the disease can be halted, but regression is unlikely. Rarely, submucosal bowel deposits have resulted in massive GI bleeding.

Case reports also exist of severe pulmonary hypertension and heart failure due to beta-2m amyloid deposits in the interstitium and/or vasculature of the cardiovascular system.

Studies in Japan have suggested that most patients with carpal tunnel syndrome associated with beta-2m amyloid deposits have undergone HD for 10 years or more. In one study, up to 50% of patients developed this complication after 20 years, and the percentage was even higher after 25 years.

Contributor Information and Disclosures

Anita Basu, MD, FACP Assistant Professor of Medicine, University of Mississippi School of Medicine; Staff Nephrologist, GV (Sonny) Montgomery Veterans Affairs Medical Center

Anita Basu, MD, FACP is a member of the following medical societies: American College of Physicians, National Kidney Foundation

Disclosure: Nothing to disclose.


Carol A Bogdan, MD Consultant in Hematology-Oncology, Myrtle Beach, SC

Disclosure: Nothing to disclose.

Reynaldo Matute, MD Clinical Assistant Professor, Department of Internal Medicine, Division of Nephrology, New York Medical College

Reynaldo Matute, MD is a member of the following medical societies: American Society of Nephrology, National Kidney Foundation

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.


George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

Donald A Feinfeld, MD, FACP, FASN Consulting Staff, Division of Nephrology & Hypertension, Beth Israel Medical Center

Donald A Feinfeld, MD, FACP, FASN is a member of the following medical societies: American Academy of Clinical Toxicology, American Society of Hypertension, American Society of Nephrology, and National Kidney Foundation

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

  1. Drueke TB. Beta2-microglobulin and amyloidosis. Nephrol Dial Transplant. 2000. 15 Suppl 1:17-24. [Medline].

  2. Tan SY, Baillod R, Brown E, Farrington K, Soper C, Percy M, et al. Clinical, radiological and serum amyloid P component scintigraphic features of beta2-microglobulin amyloidosis associated with continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 1999 Jun. 14(6):1467-71. [Medline].

  3. Bely M, Kapp P, Szabo TS, Lakatos T, Apáthy A. Electron microscopic characteristics of beta2-microglobulin amyloid deposits in long-term haemodialysis. Ultrastruct Pathol. 2005 Nov-Dec. 29(6):483-91. [Medline].

  4. Uji Y, Motomiya Y, Ando Y. A Circulating beta(2)-Microglobulin Intermediate in Hemodialysis Patients. Nephron Clin Pract. 2009 Feb 5. 111(3):c173-c181. [Medline].

  5. Thornalley PJ. Glycation free adduct accumulation in renal disease: the new AGE. Pediatr Nephrol. 2005 Nov. 20(11):1515-22. [Medline].

  6. Miyata T, Hori O, Zhang J, Yan SD, Ferran L, Iida Y, et al. The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta2microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway. Implications for the pathogenesis of dialysis-related amyloidosis. J Clin Invest. 1996 Sep 1. 98(5):1088-94. [Medline].

  7. Fry AC, Singh DK, Chandna SM, Farrington K. Relative importance of residual renal function and convection in determining beta-2-microglobulin levels in high-flux haemodialysis and on-line haemodiafiltration. Blood Purif. 2007. 25(3):295-302. [Medline].

  8. Danesh F, Ho LT. Dialysis-related amyloidosis: history and clinical manifestations. Semin Dial. 2001 Mar-Apr;14(2):80-5. [Medline].

  9. Kelly A, Apostle K, Sanders D, Bailey H. Musculoskeletal pain in dialysis-related amyloidosis. Can J Surg. 2007 Aug. 50(4):305-6. [Medline].

  10. 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 Dec. 70(6):496-502. [Medline].

  11. Saito A, Gejyo F. Current clinical aspects of dialysis-related amyloidosis in chronic dialysis patients. Ther Apher Dial. 2006 Aug. 10(4):316-20. [Medline].

  12. Matsuo K, Nakamoto M, Yasunaga C, Goya T, Sugimachi K. Dialysis-related amyloidosis of the tongue in long-term hemodialysis patients. Kidney Int. 1997 Sep. 52(3):832-8. [Medline].

  13. Kiss E, Keusch G, Zanetti M, Jung T, Schwarz A, Schocke M, et al. Dialysis-related amyloidosis revisited. AJR Am J Roentgenol. 2005 Dec. 185(6):1460-7. [Medline].

  14. 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. [Medline].

  15. Furuya R, Kumagai H, Takahashi M, Sano K, Hishida A. Ultrapure dialysate reduces plasma levels of beta2-microglobulin and pentosidine in hemodialysis patients. Blood Purif. 2005. 23(4):311-6. [Medline].

  16. Davankov V, Pavlova L, Tsyurupa M, Brady J, Balsamo M, Yousha E. Polymeric adsorbent for removing toxic proteins from blood of patients with kidney failure. J Chromatogr B Biomed Sci Appl. 2000 Feb 28. 739(1):73-80. [Medline].

  17. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003 Oct. 42(4 Suppl 3):S1-201. [Medline].

  18. Kutsuki H. beta(2)-Microglobulin-selective direct hemoperfusion column for the treatment of dialysis-related amyloidosis. Biochim Biophys Acta. 2005 Nov 10. 1753(1):141-5. [Medline].

  19. Ozawa D, Yagi H, Ban T, Kameda A, Kawakami T, Naiki H, et al. Destruction of amyloid fibrils of a beta2-microglobulin fragment by laser beam irradiation. J Biol Chem. 2009 Jan 9. 284(2):1009-17. [Medline].

  20. Balint E, Marshall CF, Sprague SM. Role of interleukin-6 in beta2-microglobulin-induced bone mineral dissolution. Kidney Int. 2000 Apr. 57(4):1599-607. [Medline].

  21. Dember LM, Jaber BL. Dialysis-related amyloidosis: late finding or hidden epidemic?. Semin Dial. 2006 Mar-Apr. 19(2):105-9. [Medline].

  22. Floege J, Ehlerding G. Beta-2-microglobulin-associated amyloidosis. Nephron. 1996. 72(1):9-26. [Medline].

  23. Gallo G, Kaakour M, Kuman A. Immunohistologic classification of systemic amyloidosis by fat aspiration biopsy. Amyloid, International Journal of Experimental and Clinical Investigation. 1994. 1:94-9.

  24. Garcia-Garcia M, Argiles, Gouin-Charnet A, Durfort M, Garcia-Valero J, Mourad G. Impaired lysosomal processing of beta2-microglobulin by infiltrating macrophages in dialysis amyloidosis. Kidney Int. 1999 Mar. 55(3):899-906. [Medline].

  25. Gejyo F. Beta 2-microglobulin amyloid. Amyloid. 2000 Mar. 7(1):17-8. [Medline].

  26. Gejyo F, Arakawa M. Beta 2-microglobulin-related amyloidosis: where do we stand?. Nephrol Dial Transplant. 1995. 10(2):155-7. [Medline].

  27. 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 May. 30(5):385-92. [Medline].

  28. 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 Jun. 51(6):1928-32. [Medline].

  29. 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 Sep. 54(3):956-9. [Medline].

  30. Kaplan B, Martin BM, Livoff A, Yeremenko D, Livneh A, Cohen HI. Gastrointestinal beta2microglobulin amyloidosis in hemodialysis patients: biochemical analysis of amyloid proteins in small formalin-fixed paraffin-embedded tissue specimens. Mod Pathol. 2005 Dec. 18(12):1610-7. [Medline].

  31. Kay J. Beta 2-microglobulin amyloidosis in renal failure: understanding this recently recognized condition. Cleve Clin J Med. 1999 Mar. 66(3):145-7. [Medline].

  32. Kay J. Review: Beta2-microglobulin amyloidosis. Int J Exp Clin Invest. 1997. 4:187-211.

  33. Kazama JJ, Maruyama H, Gejyo F. Reduction of circulating beta2-microglobulin level for the treatment of dialysis-related amyloidosis. Nephrol Dial Transplant. 2001. 16 Suppl 4:31-5. Review:[Medline].

  34. Miyata T, Ueda Y, Saito A, Kurokawa K. Carbonyl stress' and dialysis-related amyloidosis. Nephrol Dial Transplant. 2000. 15 Suppl 1:25-8. [Medline].

  35. Nangaku M, Miyata T, Kurokawa K. Pathogenesis and management of dialysis-related amyloid bone disease. Am J Med Sci. 1999 Jun. 317(6):410-5. [Medline].

  36. Ritz E, Deppisch R, Stein G. Beta 2 microglobulin-derived amyloid in dialysis patients. Adv Exp Med Biol. 1989. 260:11-8. [Medline].

  37. Varga J, Idelson BA, Felson D, Skinner M, Cohen AS. Lack of amyloid in abdominal fat aspirates from patients undergoing long-term hemodialysis. Arch Intern Med. 1987 Aug. 147(8):1455-7. [Medline].

All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.