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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2010  |  Volume : 21  |  Issue : 4  |  Page : 701-706
Beta-2 Microglobulin Levels in Hemodialysis Patients


1 Department of Chemical Pathology, University of Health Sciences, Lahore, Pakistan
2 Department of Nephrology, King Edward Medical University, Lahore, Pakistan
3 Allied Health Sciences, University of Health Sciences, Lahore, Pakistan
4 Department of Statistics, Govt. Diyal Singh College, Lahore, Pakistan

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Date of Web Publication26-Jun-2010
 

   Abstract 

The objective of the study was to determine the level of β2-microglobulin (β2-m) in hemodialysis (HD) patients and the factors affecting it. This cross sectional, hospital based study was conducted between September and December 2008 at the Hemodialysis unit of Shalamar Hospital, Lahore. All patients with end-stage renal disease (ESRD) who were on main­tenance HD for more than three months were included in the study. Patients with acute renal failure and on dialysis for less than three months were excluded. Demographic data were collec­ted and details of dialysis (type of dialyzers, dialysate bath, membrane used) were recorded. Blood samples of the patients were drawn for hematological (hemoglobin, hematocrit), bioche­mical (urea, creatinine, uric acid, albumin) and β2-m level measurement. The total number of patients studied was 50. The major causes of ESRD included diabetes mellitus and hypertension seen in 37 (74%) and 10 patients (20%), respectively. The β2-m levels were significantly elevated in the study patients; 92.6 ± 17.1 mg/L with a range of 54 to 130 mg/L as compared to 2.0 ± 1.29 mg/L in the control group. The patients' age had a statistically significant relationship with the β2-m level. The major reason for increased β2-m level was use of low-flux dialyzers. Synthetic polysulphone membrane, bicarbonate, ultra pure dialysate and duration on HD were not asso­ciated with high β2-m levels. Also, we found an inverse relationship between β2-m levels and serum albumin of the study patients. Our study suggests that the β2-m levels are significantly high in dialysis patients. Use of low-flux dialyzer seems to be the major reason for the high β2-m levels. Age and albumin have statistically significant relationship with β2-m levels.

How to cite this article:
Mumtaz A, Anees M, Bilal M, Ibrahim M. Beta-2 Microglobulin Levels in Hemodialysis Patients. Saudi J Kidney Dis Transpl 2010;21:701-6

How to cite this URL:
Mumtaz A, Anees M, Bilal M, Ibrahim M. Beta-2 Microglobulin Levels in Hemodialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2019 Oct 22];21:701-6. Available from: http://www.sjkdt.org/text.asp?2010/21/4/701/64652

   Introduction Top


B2-microglobulin (β2-m), the non-polymor­phic chain of the major histocompatibility Class­ I complex (MHC-I), is found on the surface of all nucleated cells and plays a central role in cellular immunology. Its synthesis rate normally ranges from 2-4 mg/kg/day with a half life of 2-5 hours. [1] In healthy individuals, the plasma concentration varies from 1 to 3 mg/L which varies inversely with the glomerular filtration rate (GFR). More than 95% of β2-m is elimi­nated by degradation in the proximal tubule. Since this compound cannot be removed from the serum by the kidney or certain dialysis membranes in patients with renal dysfunction on dialysis, β2-m concentration is increased by up to 60-fold in patients with end-stage renal disease (ESRD). [2] Accumulation of β2-m in these patients lead to Dialysis-Related Amy­loidosis (DRA). In general, it becomes appa­rent only after more than 5-7 years of renal re­placement therapy. This type of amyloid may be seen even in patients with long-standing, severe renal failure who are not yet treated by dialysis or related procedures. [3] Age above 40­years at the start of dialysis, [4] duration of dia­lysis, [5] use of cuprophane and low-flux mem­branes and use of low purity dialysate are iden­tifiable risk factors. β2-m-related amyloid has a marked affinity for joint tissues (cartilage, cap­sule, synovium). The main signs and symptoms of DRA are musculoskeletal disorders such as carpal tunnel syndrome, joint arthro-pathy, and bone cysts leading occasionally to pathologic bone fractures. After long-term dialysis the­rapy, extra-articular symptoms such as ische­mic colitis, amyloid tumor, heart failure with pulmonary hypertension, gastrointestinal tract bleeding, can also occur. β2-m is an important predictor of mortality in dialysis patients. Ac­cording to Okuno S et al, [6] Kaplan-Meier ana­lysis revealed that all-cause mortality in the higher β2-m group (≥ 32.2 mg/L) was signifi­cantly higher compared to that in the lower β2­-m group (≤ 32.2 mg/L) (P < 0.001). AK Cheung et al, [7] in the HEMO study, reported that the pre-dialysis serum β2-m level predicted mor­tality. There was 11% increase in mortality for each 10 mg/L increase in β2-m level even after adjustment for years on dialysis and residual kidney function. Clinical therapeutic strategies for DRA include dialysis, medical or surgical therapy and renal transplantation. Renal trans­plantation usually leads to symptomatic im­provement within days, likely related to use of steroids and immunosuppressive therapy. [8] In Pakistan, due to paucity of indigenous research, β2-m levels in hemodialysis (HD) patients is not known. Hence, this cross-sectional study was conducted to check the levels of β2-m among patients on HD as well as factors affecting it.


   Materials and Methods Top


This study was conducted at the HD unit of Shalimar Hospital, Lahore from January to April 2008. All patients with ESRD, who were on regular HD for more than three months were included in the study. The study patients were informed about the study and consent was obtained. Patients with acute renal failure and those with ESRD on HD for less than three months were excluded from the study. Demographic data including age, sex, cause of ESRD, HBsAg and Anti-HCV status as well as details of dialysis (dialysate bath, porosity of dialyzers and dialyzer membrane) were recor­ded. Pre-dialysis blood sample of the patients was drawn to measure hematological (hemo­globin and hematocrit) and biochemical para­meters (urea, creatinine, albumin and uric acid) and β2-m levels. Fifteen normal individuals were included as controls.


   Statistical Analysis Top


The data were analyzed by using standard SPSS software version-16 (SPSS Inc, Chica­go) for statistical analysis. Mean ±SD is given for quantitative variables including blood urea, serum creatnine, serum uric acid, serum albu­min, serum β2-m, blood hemoglobin and he­matocrit. Levene's test was applied for Equa­lity of Variances. A P-value of < 0.05 was considered statistically significant.


   Results Top


The total number of patients who were on maintenance HD for more than three months was 50. The major cause of ESRD was dia­betes mellitus followed by hypertension as shown in [Table 1] and the mean duration on dialysis was 13.82 months with a range of three to sixty months. Majority of the patients were anti-HCV and HbsAg negative. All the study patients were being dialyzed using low­flux synthetic membrane dialyzers and bicar­bonate dialysate bath. Hematological and bio­chemical data of patients and controls are shown in [Table 2]. The mean β2-m level was 92.6 mg/L with a range of 54 to 130 mg/L.


   Discussion Top


Dialysis is the process of separation of solu­ble substances from colloids and their removal through a semi-permeable membrane, down a concentration gradient. Currently, more than one million patients worldwide undergo either HD or PD to maintain life. [9] However, dialysis does not restore all renal functions. [10] Uremic toxins are classified as small molecular weight and middle molecules (substances with a mo­lecular weight between 0.5 and 2 kDa) as well as large peptides, which are normally excreted or metabolized by the healthy kidney. These middle molecules will accumulate in chronic HD patients if they are being dialyzed with low quality membranes [Figure 1].

In this study, the β2-m levels were signi­ficantly elevated (P = 0.001) compared to con­trol subjects. Similar high levels was observed by Mario T et al [11] (42.14 ±14 mg/L), Kuchle et al (51 ±11 mg/L) [12] and T Jeloka et al. [13] AK Cheung [14] also found that the cumulative mean pre-dialysis serum β2-m level was signifi­cantly lower with use of high-flux dialyzers than with low-flux dialyzers (33.6 versus 41.5 mg/L).

The major reason for such a high level of β2­m in this study was that the dialyzer used for HD in our patients was of the low-flux type. As β2-m is a middle molecule of molecular weight of 12000 Da, conventional, low-flux dialyzers do not clear these molecules which lead to accumulation of this silent killer in the body. Financial constrains are the major reason for using low-flux dialyzers in our patients. The cost of dialysis when low-flux dialyzers are used is about US Dollars 400 as against the cost for using high-flux HF dialyzers, which is about 50 US Dollars more. This factor is the major reason for using low-flux dialyzers and accumulation of β2-m in these patients.

The clearance of β2-m with different dialy­zers after three and half hours of dialysis is depicted in [Figure 2]. There was almost no clea­rance with low-flux dialyzers; however, high-flux dialyzers F60, Primus 1350, BioCare130 gave clearance of β2-m of 50%, 60% and 64%, respectively.

Bio-incompatibility of dialyzers plays an im­portant role in accumulation of β2-m in these patients. Depending on the type of dialyzers used, blood-membrane contact results in the ge­neration of the complement activation products C3a and C5a, which elicit important physiolo­gical reactions, such as changes in the expre­ssion of adhesion molecules on peripheral blood mononuclear cells and polymerphonuclear cells. [15],[16],[17] In our dialysis setup, we use dialyzers of synthetic membranes material (polysulfone) which are biocompatible than previously used cellulose-based dialyzers. Thus, dialyzer mem­branes probably had no role to play in causing the high level of β2-m in these patients. Ferreira A et al [18] reported that the serum β2-m level was higher in patients dialyzed with cellulose­based dialyzers (59.8 ±14.1 mg/L) than syn­thetic high-flux dialyzers (32.8 ±8.7 mg/L).

The dialysate bath is another factor that can cause increased β2-m level in these patients. Microbiological purity and/or the use of bicar­bonate buffer appear to be associated with a decreased prevalence of amyloidosis. [19],[20] In our dialysis unit, bicarbonate is used as dialysate bath and ultra pure water for dialysis. We have Fresenius Medical Care, Germany, hemodialysis machines which have inbuilt Diasafe fil­ters which make the water ultra pure. Along with this, the quality of water of our dialysis unit is checked on regular basis and it is free from any contaminants. Thus, in our patients, dialysate bath and water probably did not play any role in β2-m accumulation. Similar obser­vations have been reported by Furuya R et al. [21] According to them, switching from conventio­nal to ultra pure dialysate significantly dec­reased plasma levels of β2-m from 30.1 ±1.4 to 27.1 ±1.4 mg/L (P < 0.05) after one month of use.

Apart from the variables described above, even the type of dialysis delivered like hemo­diafiltration (HDF) and hemofiltration (HF) are better for removal of β2-m than standard dif­fusive HD. Economic constrains is an important factor for not using these modalities for dia­lysis. Also, modalities such as HDF and HF are not available in routine hemodialysis machines. According to Willy Lorny et al, [22] during HDF with online replacement of solution at a rate of 100 mL/min, clearance of β2-m was 116.8 mL/min as against 63.8 mL/min on conven­tional HD (P = 0.0000).

The duration on HD treatment plays an im­portant role in the development of DRA. [23],[24],[25] For the development of clinical effects of β2­m, more than five to seven years are required. However, a recent, large scale post mortem study showed that incipient dialysis related amyloid deposits occur in as many as 21% of cases within two years, and in 33% of cases within four years, which increased to 100% in pa­tients treated for more than 13 years after the start of renal replacement therapy. [23],[24],[25],[26] In our study patients, there were no clinical manifes­tations of DRA due to raised β2-m levels such as carpel tunnel syndrome, joint arthropathy and fractures. But in this study, mean duration on dialysis was one year and three months with range of 3 to 60 months. This short duration on dialysis may be the reason for not affecting the synovial membranes although histopathological confirmation of beta-2m deposition with Congo red stain was not obtained.

Age at the onset of dialysis plays an impor­tant role in the development of DRA. In this study, age had a statistically significant posi­tive correlation with β2-m level. Similar findings were observed by Van Ypersele et al. [4] Accor­ding to them, age at onset of dialysis was found to have a striking correlation with the development of carpal tunnel syndrome and bone amyloidosis.

Albumin is used for routine nutritional as­sessment in dialysis patients. Hypoalbumine­mia is a very important predictor for morbidity and mortality of dialysis patients. [27] In this study, mean serum albumin was 3.24 ±g/L with range of 1.9 to 5.4 g/L. Majority of the patients (74%) had low serum albumin (< 3.8 g/L) and serum albumin level had a significant negative correlation with 132-m levels. This negative correlation supports the direct effect of both of these parameters on the mortality of dialysis patients. According to Cianciolo G et al, [28] Cox analysis for carpal tunnel syndrome confirmed serum albumin (RR 0.59, P < 0.0001) and resi­dual GFR (RR 0.75, P < 0.0001) as protective factors.


   Conclusion Top


Our study suggests that β2-m levels are sig­nificantly high in dialysis patients. Use of low­flux dialyzer seems to be the major reason for the high levels of β2-m. Age has positive cor­relation and albumin has negative correlation with β2-m levels.

Limitations

Our study had a few limitations as follows:

  1. It was a cross-sectional design and the pre­dialysis β2-m levels were not measured in patients with chronic kidney disease.
  2. We have not compared the effect of high­flux dialyzers on the level of β2-m.
  3. For determination of the effect of β2-m level on the tissues, x-rays and histopatho­logical analysis was not done.


 
   References Top

1.Kleinman KS, Coburn J, Amyloid syndromes associated with hemodialysis. Kidney Int 1989;35:567-75.  Back to cited text no. 1      
2.Floege J, Ehlerding G. Beta 2-microglobulin associated amyloidosis. Nephron 1996;72:9-26.  Back to cited text no. 2      
3.Jadoul M, Garbar C, Noel H, et al. Histological prevalence of β2m amylodosis in hemodialysis patients: A prospective postmortem study. Kidney Int 1997;51:1928-32.  Back to cited text no. 3      
4.Van Y, Persele de Strihou C, Jadoul M, Malghern J, Maldague B, Jamart J. Effect of dialysis mem­brane and patient's age on signs of dialysis­related amyloidosis. The Working Party on Dial­ysis Amyloidosis. Kidney Int 1991;39(5):1012-9.  Back to cited text no. 4      
5.Hurst NP, van den Bergh R, Disney A, et al. Dialysis related arthropathy: a survey of 95 patients receiving chronic hemodialysis with special reference to beta 2 m related amyloi-dosis. Ann Rheum Dis 1989;48:409-20.  Back to cited text no. 5      
6.Okuno S, Ishimura E, Kohno K, et al. Serum beta 2-micrglobulin is a significant predictor of mor­tality in maintenance of hemodialysis patients. Nephrol Dial Transplant 2009;24(2):571-7.  Back to cited text no. 6      
7.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. 7      
8.Jadoul M, Dnueket T, Zingraff J, Van Ypersele DE, Strihou C. Does dialysis related arnyloi-dosis regress after renal transplant? Nephrol Dial Transpl 1997;12:655-7.  Back to cited text no. 8      
9.US Renal Data System. USRDS 2004.Annual data report atlas of end stage renal disease in the United State 2004.NIH.National Institute of Diabetes and Digestive and Kidney Disease, Bethesda,MD.  Back to cited text no. 9      
10.Erkan D, Yonca A, Sarper E, Gur A, Ahmad Y. Beat 2 m amyloidosis in hemodialysis and peri­toneal dialysis patients. Therap Apheresis Dial 2008;12(4):306-10.  Back to cited text no. 10      
11.Traut M, Haufe CC, Eismann U, Deppisch RM, Stein G, Wolf G. Increased binding of Beta-2­Microglobulin to blood cells in dialysis patients treated with high-flux dialyzers compared with low-flux membranes contributed to reduced Beta­2-microglobulin concentrations. Blood Purif 2007; 25:432-40.  Back to cited text no. 11      
12.Kuchle C, Fricke H, Held E, Schiff H. High-flux hemocialysis postpones clinical manifestation of dialysis-related amyloidosis. Am J Nephrol 1996; 16(6):484-8.  Back to cited text no. 12      
13.Jeloka T, Mathur G,, Kaur R, Kohli R, Singh NP, Rizvi SN. β2 Microglobulin in chronic renal failure and effect of different dialyzer membrane on its clearance. Indian J Nephrol 2001,11:160-4.  Back to cited text no. 13    Medknow Journal  
14.Cheung AK, Greene T, Leypoldt JK, et al. Asso­ciation between serum 2-microglobulin level and infectious mortality in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:69-77.  Back to cited text no. 14      
15.Grooteman MP, Nube MJ. Haemodialysis-related bioincompatibility: fundamental aspects and clinical relevance. Neth J Med 1998;52: 169-78.  Back to cited text no. 15      
16.Horl WH. Hemodialysis membranes: Interleu­kins, biocompatibility, and middle molecules. J Am Soc Nephrol 2002;13: S62-71.  Back to cited text no. 16      
17.Lonnemann G. Should ultra-pur6e dialysate be mandatory. Nephrol Dial Transplant 2000;15 (Suppl 1):55-9.  Back to cited text no. 17      
18.Ferreira A, Urena P, Ang KS, et al. Relation-ship between serum beta 2-microglobulin, bone histo­logy, and dialysis membranes in uraemic patients. Nephrol Dial Transplant 1995;10(9): 1701-7.  Back to cited text no. 18      
19.Lonnemann G, Koch KM. β2-Microglobulin amy­loidosis: Effects of ultrapure cialysate and type of dialyzer membrane. J Am Soc Nephrol 2002; 13:S72-7.  Back to cited text no. 19      
20.Arizono K, Nomura K, Motoyama T, et al. Use of ultrapure dialysate in reducetion of chronic inflammation during hemodialysis. Blood Purif 2004;22(suppl 2):26-9.  Back to cited text no. 20      
21.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.  Back to cited text no. 21      
22.Lorny W, Because J, Billiouw JM, Sierens L, Van Malderen P. Remarkable removal of beta-2 microglobulin by on line hemodiafiltration. Am J Nephrol 1998;18:105-8.  Back to cited text no. 22      
23.Al-Taee IK, Al-Safar JJ, Al-Falahi YS, Al­Shamma IA. The clinical significance of β2-mic­roglobulin in end-stage renal disease. Saudi J Kidney Dis Transpl 2003;14(4):492-6.  Back to cited text no. 23      
24.McCarthy JT, Williams AW, Johnson WJ. Serum beta 2-microglobulin concentration in dialysis patients: importance of intrinsic renal function. J Lab Clin Ivied 1994;123(4):495-505.  Back to cited text no. 24      
25.Alhomrany MA, Khan MR, Adzaku F, Harding MG. Carpel tunnel syndrome in hemodialysis patients: Early detection by electroneurophysio­logical studies. 2001;6(6): 259-62.  Back to cited text no. 25      
26.Dixit MP, Cabansag MR, Piscitelli J, Greifer I, Silverstein DM. Serum beta2-microglobulin and immunoglobulin levels in young hemodialysis patients. Pediater Nephrol 1999;13(2):139- 42.  Back to cited text no. 26      
27.Collins AJ, Ma JZ, Umen A, Keshaviah P. Urea index and other predictors of long-term outcome in hemodialysis patients survival. Am J Kidney Dis 1994;20:32-8.  Back to cited text no. 27      
28.Cianciolo G, Coli L, La Manna G, et al. Is beta 2­microglobulin-related amyloidosis of hemodia­lysis patients a multifactorial disease? A new pathogenetic approach. Int J Artif Organs 2007; 30(10):864-78.  Back to cited text no. 28      

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