Saudi Journal of Kidney Diseases and Transplantation

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


Alain G Assounga 
 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

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

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;32:1214-1220


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 25 ];32:1214-1220
Available from: https://www.sjkdt.org/text.asp?2021/32/5/1214/344740


Full Text



 Introduction



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



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



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}

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



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}

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



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.

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