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Saudi Journal of Kidney Diseases and Transplantation
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REVIEW ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 5  |  Page : 1214-1220
Beta 2 microglobulin in kidney failure: A review and an algorithm for renal replacement therapy


Department of Nephrology, Division of Medicine, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal; Deparment of Nephrology, Inkosi Albert Luthuli Central Hospital, Durban, South Africa

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Date of Web Publication4-May-2022
 

   Abstract 


For decades, beta 2 microglobulin (B2M) has been a subject of great interest in nephrology and other fields such as multiple myeloma. B2M, a 99 amino acid protein, is associated with amyloid deposits in patients undergoing renal replacement therapy (RRT). The source of information is published articles on B2M in chronic renal failure since 1960. We have reviewed literature published since 1960 to date, highlighting the milestones of the role of B2M in chronic kidney disease (CKD) and B2M serum values in patients treated by various RRTs. B2M deposits associated with the disease include carpal tunnel syndrome, spondyloarthropathy, and arthritis of large joints such as the shoulders. The role of RRT in the removal of B2M in CKD is discussed. Recent reports include factors affecting the process of fibrillation and deposition of B2M in tissues. A comparative report of various modalities of treatment on the serum levels of B2M is provided. The presence of significant residual urine output in continuous ambulatory peritoneal dialysis patients may explain why peritoneal dialysis is a modality that is associated with the lowest level of serum B2M. Patients treated with hemodiafiltration or hemodialysis (HD) using high flux dialyzers have lower levels of B2M than those treated by HD with low flux dialyzers. Finally, based on the literature review, an algorithm for RRT using B2M level monitoring and other variables is proposed and needs evaluation in a controlled trial.

How to cite this article:
Assounga AG. Beta 2 microglobulin in kidney failure: A review and an algorithm for renal replacement therapy. Saudi J Kidney Dis Transpl 2021;32:1214-20

How to cite this URL:
Assounga AG. Beta 2 microglobulin in kidney failure: A review and an algorithm for renal replacement therapy. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 May 21];32:1214-20. Available from: https://www.sjkdt.org/text.asp?2021/32/5/1214/344740



   Introduction Top


Despite numerous studies highlighting the vital role of beta 2 microglobulin (B2M) in chronic kidney diseases (CKDs), its use has remained limited to clinical research.[1],[2] Unlike in conditions such that multiple myeloma, where B2M level is used in international staging, the test for serum B2M in renal disease has not yet graduated to be part of the routine clinical use.[1] We have reviewed literature published since 1960 to date, highlighting the milestones of the role of B2M in CKD. In this review, we present the extent of the role of B2M in CKD and propose an algorithm for its use in clinical practice.


   Genetics and Structure of Beta 2 Microglobulin Top


The B2M gene is located in the long arm of chromosome 15 at the locus 15q21.1. It is comprised of 4 exons. B2M protein is a 99 amino acid polypeptide with seven stranded Beta sheet characteristics of the immunoglobulin domain.[3],[4],[5] It is noncovalently bound to major histocompatibility complex (MHC) class I protein on the cell surface of all nucleated cells.[5],[6]

B2M molecule confers stability to the MHC Class 1 protein-B2M complex that presents antigen (nonamer peptide) to the T cell receptor on CD8 T Cell. Some mutations in the B2M gene have resulted in the absence of MHC class I protein on the cell surface and a severe immunodeficient state. Hence, B2M plays a significant role in the immune system by assisting the antigen presentation.[7]


   Beta 2 Microglobulin in Kidney Disease Top


B2M, a 11800-dalton protein, was isolated in 1964 and purified in 1968 by Berggard and Bearn, from urines of patients intoxicated with cadmium.[7]

In 1973 elevated serum levels of B2M were detected in patients with chronic kidney failure.[8] Twelve years later, in 1985, B2M was associated with renal disease by Gejyo et al, who identified that amyloid deposits of patients on dialysis for several years contain B2M.[9] Since then, B2M has attracted considerable interest in nephrology.[1],[2],[5],[10]

The association of serum B2M with kidney disease is overwhelming. In end-stage kidney disease (ESKD), high levels of B2M is associated with mortality[10] as well as morbidity, including vascular calcification.[6] B2M is also positively associated with malnutrition and inflammation[11] and inversely associated with glomerular filtration rate (GFR).[12] In the case of kidney transplantation, serum B2M level at discharge posttransplantation is associated with chronic allograph nephropathy in the future.[13]

In type 2 diabetes mellitus, B2M was associated with nephropathy at a very early stage, in the subclinical phase, as reported by Kim et al.[14]

The HEMO study also has established that B2M is associated with a deterioration of kidney function.[10] A comparative study by Shahjahan et al showed that GFR is associated better with B2M than with creatinine in CKD stage 1–4.[15] As shown in [Table 1], we and others have shown that serum B2M levels are high in ESKD patients undergoing any renal replacement therapy (RRT) type. Kidney residual function is the most significant factor associated with low levels of B2M.[2] Hence, patients on continuous ambulatory peritoneal dialysis having the best kidney residual function also have the lowest serum B2M levels.[2],[10] Those on hemodiafiltration follow them. Patients on hemodialysis (HD) have the highest B2M levels of all ESKD patients on [Table 1].[2]
Table 1: Beta 2 microglobulin in end-stage renal disease on renal replacement treatment.

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Although high levels of B2M deposits occur in tissues such that the skin, B2M-related pathology occurs mainly via amyloid deposits.[16]

Carpal tunnel syndrome (CTS) is one of the most known complications of B2M in ESKD patients and is relatively common, especially after five years of RRT.[4],[17],[18] In CTS, B2M deposits accumulate in the carpal tunnel leading to the compression of the median nerve to provoke pain and weakness in the median nerve territory at the wrist and below. Other common areas of deposits include the spine and joints involving large bones such as the shoulders.[4],[19]

The process of B2M amyloid deposits comprises a fibrillation process, which includes the modification of B2M to link with advanced glycation end-products forming B2M-AGE complexes.[20],[21] It is reported that human fibroblasts through B2M-AGE receptor and the inflammatory cytokines are involved in the B2M amyloid deposits process.[20],[21],[22]

A better understanding of the B2M amyloid formation and deposits may assist in designing an appropriate treatment to prevent or delay B2M deposits.


   Beta 2 Microglobulin and Prescription of Renal Replacement Therapy Top


Since the early days, some progress has occurred in B2M amyloid disease. The frequency of CTS has reduced, as shown by several reports.[27],[28] However, serum B2M levels are still high. A study of intensive a weekly hemofiltration regime performed on ESKD patients failed to bring the level of B2M to the normal range.[29] A weekly accumulation of 700 mg of B2M was observed since the weekly generation of B2M was 1300 mg, while the total weekly removal via hemofiltration was only 600 mg.[30],[31] This resistance in B2M removal may be due to a delay in body intercompartment transfer, as reported by Ward et al.[32] With the advent of hemodiafiltration and high-flux HD, B2M clearance has increased. However, so did the cost of dialysis. Patients with a high level of toxins are those who should benefit the most from hemodiafiltration or high-flux HD. Also, given the indiscriminate removal of middle molecules, it may not be wise to systematically remove all of them as this may lead to the removal of useful vitamins or other vital compounds, for instance. Hence, the following algorithm is proposed [Figure 1].
Figure 1: Algorithm for renal replacement therapy in CKD stage 5 patients using Beta 2 microglobulin serum level.
PD: Peritoneal dialysis, PET: Peritoneal equilibration test, APD: Automated peritoneal dialysis, CAPD: Continuous peritoneal dialysis, CKD: Chronic kidney disease.


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From the standpoint of serum B2M minimization in CKD stage 5 patients, PD is the preferred dialysis modality in this algorithm. This is probably owing to the fact that it is the best to preserve residual renal clearance. Serum B2M of 40 mg/L is proposed as a cutoff value to decide between HD with low-flux dialyzer and with high-flux dialyzer or hemodiafiltration. A choice of a cut-off value between 35 and 40 mg/L should be adequate as it is informed by data from the most widely used test and publications with the most significant number of participants.[2],[10] It appears that radioimmunoassay is the most reported serum B2M test.[2],[10] ELISA test is the second test type used in B2M measurement, with higher results than those obtained by the radioimmunoassay test [Table 1].

B2M assessment test should be done before starting RRT and be repeated at a frequency to be determined (for example, 3–6 months could be tested). Patients may be transferred according to the appropriate dialysis modality according to the algorithm in [Figure 1].


   Conclusion Top


In this review, we have analyzed a significant body of work on B2M with an emphasis on clinical application. We discuss current knowledge to guide the management of CKD patients on dialysis to prevent or reduce B2M and amyloid deposits. We have proposed an algorithm which needs to be evaluated in a controlled trial to determine whether the B2M monitoring leads to a cost-effective and efficient management of CKD stage 5 patients.

Conflicts of interest: None declared.



 
   References Top

1.
Argyropoulos CP, Chen SS, Ng YH, et al. Rediscovering beta-2 microglobulin as a biomarker across the spectrum of kidney diseases. Front Med (Lausanne) 2017;4:73.  Back to cited text no. 1
    
2.
Assounga A, Canaud B, Flavier JL, et al. What does circulating beta 2 microglobulin signify in uremic patients on maintenance dialysis? Nephrologie 1987;8:301-6.  Back to cited text no. 2
    
3.
Güssow D, Rein R, Ginjaar I, et al. The human beta 2-microglobulin gene. Primary structure and definition of the transcriptional unit. J Immunol 1987;139:3132-8.  Back to cited text no. 3
    
4.
Charra B, Calemard E, Uzan M, Terrat JC, Vanel T, Laurent G. Carpal tunnel syndrome, shoulder pain and amyloid deposits in long-term haemodialysis patients. Proc Eur Dial Transplant Assoc Eur Ren Assoc 1985;21:291-5.  Back to cited text no. 4
    
5.
Mumtaz A, Anees M, Bilal M, Ibrahim M. Beta-2 microglobulin levels in hemodialysis patients. Saudi J Kidney Dis Transpl 2010;21: 701-6.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Liabeuf S, Lenglet A, Desjardins L, et al. Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients. Kidney Int 2012;82:1297-303.  Back to cited text no. 6
    
7.
Berggard I, Bearn AG. Isolation and properties of a low molecular weight B2 microglobulin occurring in human biological fluids. J Biol Chem 1968;213:4095-103.  Back to cited text no. 7
    
8.
Hall PW, Vasiljevic M. Beta-2-microglobulin excretion as an index of renal tubular disorders with special reference to endemic Balkan nephropathy. J Lab Clin Med 1973;81:897-904.  Back to cited text no. 8
    
9.
Gejyo F, Yamada T, Odani S, et al. A new form of amyloid protein associated with chronic hemodialysis was identified as beta 2-microglobulin. Biochem Biophys Res Commun 1985;129:701-6.  Back to cited text no. 9
    
10.
Cheung AK, Rocco MV, Yan G, et al. Serum beta-2 microglobulin levels predict mortality in dialysis patients: Results of the HEMO study. J Am Soc Nephrol 2006;17:546-55.  Back to cited text no. 10
    
11.
Wu HC, Lee LC, Wang WJ. Associations among serum beta 2 microglobulin, malnutrition, inflammation, and advanced cardiovascular event in patients with chronic kidney disease. J Clin Lab Anal 2017;31:e22056.  Back to cited text no. 11
    
12.
Sedighi O, Abediankenari S, Omranifar B. Association between plasma Beta-2 microglobulin level and cardiac performance in patients with chronic kidney disease. Nephrourol Mon 2015;7:e23563.  Back to cited text no. 12
    
13.
Astor BC, Muth B, Kaufman DB, Pirsch JD, Michael Hofmann R, Djamali A. Serum β2-microglobulin at discharge predicts mortality and graft loss following kidney transplantation. Kidney Int 2013;84:810-7.  Back to cited text no. 13
    
14.
Kim MK, Yun KJ, Chun HJ, et al. Clinical utility of serum beta-2-microglobulin as a predictor of diabetic complications in patients with type 2 diabetes without renal impairment. Diabetes Metab 2014;40:459-65.  Back to cited text no. 14
    
15.
Shahjahan, Yasmin R, Mahsud MA, Khan M, Subzwari J, Hussain J. Correlation of Beta 2 microglobulin with serum creatinine and creatinine clearance in patients with different levels of renal functions. Gomal J Med Sci 2011;9:178-82.  Back to cited text no. 15
    
16.
Assounga AG, Bascoul S, Canaud B, et al. A study of beta 2-microglobulin skin deposits in dialyzed patients and healthy controls. Am J Kidney Dis 1990;15:556-61.  Back to cited text no. 16
    
17.
Gagnon RF, Lough JO, Bourgouin PA. Carpal tunnel syndrome and amyloidosis associated with continuous ambulatory peritoneal dialysis. CMAJ 1988;139:753-5.  Back to cited text no. 17
    
18.
Benz RL, Siegfried JW, Teehan BP. Carpal tunnel syndromein dialysis patients: Comparison between continuous ambulatory peritoneal dialysis and hemodialysis populations. Am J Kidney Dis 1988;11:473-6.  Back to cited text no. 18
    
19.
Kuntz D, Naveau B, Bardin T, Drueke T, Treves R, Dryll A. Destructive spondylarthropathy in hemodialyzed patients. A new syndrome. Arthritis Rheum 1984;27:369-75.  Back to cited text no. 19
    
20.
Owen WF Jr., Hou FF, Stuart RO, Kay J, Boyce J, Chertow GM, et al. β2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblast. Kidney Int 1998;53:1365-73.  Back to cited text no. 20
    
21.
Bertoletti L, Regazzoni L, Altomare A, Colombo R, Colzani M, Vistoli G, et al. Advanced glycation end products of beta2-microglobulin in uremic patients as determined by high resolution mass spectrometry. J Pharm Biomed Anal 2014;91:193-201.  Back to cited text no. 21
    
22.
Ehlerding G, Schaeffer J, Drommer W, Miyata T, Koch KM, Floege J. Alterations of synovial tissue and their potential role in the deposition of β2-microglobulin-associated amyloid. Nephrol Dial Transplant 1998;13:1465-75.  Back to cited text no. 22
    
23.
Raj DS, Ouwendyk M, Francoeur R, Pierratos A. Beta(2)-microglobulin kinetics in nocturnal haemodialysis. Nephrol Dial Transplant 2000;15:58-64.  Back to cited text no. 23
    
24.
Estakhri MA, Kavakeb P, Fathi D, Karimi G, Mohammadpour A, Rahbar M. An investigation of the relationship between Beta-2 microglobulin (β2M) and inflammatory factors (serum levels of CRP and albumin) and high-density lipoproteins (HDL) in hemodialysis. Mod Med Lab 2017;1:17-22.  Back to cited text no. 24
    
25.
Dung NH, Kien NT, Hai NT, et al. Measuring serum beta2-microglobulin to predict long-term mortality in hemodialysis patients using low-flux dialyzer reuse. Ther Clin Risk Manag 2019;15:839-46.  Back to cited text no. 25
    
26.
Okuno S, Ishimura E, Kohno K, et al. Serum β2-microglobulin level is a significant predictor of mortality in maintenance haemo-dialysis patients. Nephrol Dial Transplant 2009;24:571-7.  Back to cited text no. 26
    
27.
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;52:1077-83.  Back to cited text no. 27
    
28.
Hoshino J, Yamagata K, Nishi S, et al. Significance of the decreased risk of dialysis-related amyloidosis now proven by results from Japanese nationwide surveys in 1998 and 2010. Nephrol Dial Transplant 2016;31:595-602.  Back to cited text no. 28
    
29.
Tsai TT, Kaliya-Perumal AK, Jenq CC, et al. The unresolved problem of beta-2 micro-globulin amyloid deposits in the intervertebral discs of long-term dialysis patients. J Orthop Surg Res 2017;12:194.  Back to cited text no. 29
    
30.
Canaud B, Assounga A, Kerr P, Aznar R, Mion C. Failure of a daily haemofiltration programme using a highly permeable membrane to return beta 2-microglobulin concentrations to normal in haemodialysis patients. Nephrol Dial Transplant 1992;7:924-30.  Back to cited text no. 30
    
31.
Canaud B, Morena M, Cristol JP, Krieter D. Beta2-microglobulin, a uremic toxin with a double meaning. Kidney Int 2006;69:1297-9.  Back to cited text no. 31
    
32.
Ward RA, Greene T, Hartmann B, Samtleben W. Resistance to intercompartmental mass transfer limits beta2-microglobulin removal by post-dilution hemodiafiltration. Kidney Int 2006;69:1431-7.  Back to cited text no. 32
    

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Correspondence Address:
Alain G Assounga
Department of Nephrology, Division of Medicine, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, and Inkosi Albert Luthuli Central Hospital, Durban

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.344740

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