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NDT Advance Access published online on September 17, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn521
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Serum β2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients

Senji Okuno1, Eiji Ishimura2, Kaori Kohno1, Yoko Fujino-Katoh1, Yoshifumi Maeno1, Tomoyuki Yamakawa1, Masaaki Inaba2 and Yoshiki Nishizawa2

1 Kidney Center, Shirasagi Hospital 2 Osaka City University Graduate School of Medicine, Osaka, Japan

Correspondence and offprint requests to: Eiji Ishimura, Department of Nephrology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Tel: +81-6-6645-3806; Fax: +81-6-6645-3808; E-mail: ish{at}med.osaka-cu.ac.jp



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. β2-Microglobulin (β2-M) is recognized as a surrogate marker of middle-molecule uraemic toxins and is a key component in the genesis of dialysis-associated amyloidosis. Few studies have evaluated the association of β2-M levels with clinical outcome in dialyzed patients.

Methods. The prognostic implication of serum β2-M levels for the survival of haemodialysis patients was examined in 490 prevalent haemodialysis patients (60.1 ± 11.8 years, haemodialysis duration of 87.4 ± 75.7 months, 288 males and 202 females; 24% diabetics). The patients were divided into two groups according to their serum β2-M levels: lower β2-M group (n = 245) with serum β2-M <32.2 mg/L (the median serum β2-M) and higher β2-M group (n = 245) with that ≥32.2 mg/L.

Results. During the follow-up period of 40 ± 15 months, there were 91 all-cause deaths, and out of them, 36 were from cardiovascular diseases. Kaplan–Meier analysis revealed that all-cause mortality in the higher β2-M group was significantly higher compared to that in the lower β2-M group (P < 0.001). Multivariate Cox proportional hazards analyses showed that serum β2-M level was a significant predictor for all-cause mortality (hazard ratio, 1.05; 95% CI, 1.01–1.08; P = 0.005), and for non-cardiovascular mortality (hazard ratio, 1.06; 95% CI, 1.02–1.10; P = 0.006), after adjustment for age, gender, haemodialysis duration, the presence of diabetes, serum albumin and serum C-reactive protein.

Conclusion. These results demonstrate that the serum β2-M level is a significant predictor of mortality in haemodialysis patients, independent of haemodialysis duration, diabetes, malnutrition and chronic inflammation, suggesting the clinical importance of lowering serum β2-M in these patients.

Keywords: haemodialysis; mortality; non-cardiovascular mortality; β2-microglobulin



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
β2-Microglobulin (β2-M) is a low-molecular-weight protein (11 800 Da), which is produced by all cells expressing the major histocompatibility class I. Under physiological conditions, β2-M is generated at a constant rate, except in patients with systemic inflammation and haematopoietic neoplasia, and is eliminated from circulation through the renal pathway. β2-M is filtered by the glomerulus and is degenerated in the proximal tubules through a megalin-dependent pathway [1]. In patients with a reduced glomerular filtration rate, circulating β2-M levels are elevated. In dialysis patients, in whom the glomerular filtration rate is almost completely abolished, β2-M accumulates in the circulation far above its levels in normal subjects. Although it remains unknown whether β2-M molecule itself is a uraemic toxin, β2-M has been considered to be a surrogate marker of putative middle-molecule uraemic toxins, which are difficult to dialyze by use of low-flux membrane [2]. Furthermore, elevated concentration of circulating β2-M has been demonstrated to be a potential risk for the onset and/or development of dialysis-related amyloidosis [3]. Therefore, removal of circulating β2-M during haemodialysis has been considered to be beneficial. Several methods to reduce plasma β2-M levels have been attempted in dialyzed patients, such as the use of high-flux membrane [2], haemodiafiltration [4–6], ultrapure dialysate [2] and the absorptive affinity column for β2-M [3]. However, few studies have evaluated the association of β2-M levels with clinical outcome in dialyzed patients [7]. In this study, we examined the relationship between serum β2-M and survival of haemodialysis patients in a single dialysis centre, where high-flux membranes are used exclusively as a standard approach and the reuse of membranes is not done at all.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Subjects
There were 541 patients on prevalent haemodialysis (haemodialysis duration >3 months) at Shirasagi Hospital Kidney Center, Osaka, Japan, as of October 1999. Of these, patients with acute illness, significant infection or malignancy were excluded. Of the remaining patients, 490 prevalent haemodialysis patients provided informed consent prior to participation in the present study. The enrolled patients were treated with stable, regular haemodialysis, using bicarbonate dialysate. Our dialysis programme used high-flux membrane as a standard, defined as a β2-M clearance >20 mL/min [8], such as cellulose triacetate, polysulfone, and ethylenevinyl alcohol. Low-flux membrane was not used in our hospital for at least 2 years before 1999. In most patients, the membranes with a surface area of 1.5–2.0 m2 were used. Kt/V was calculated according to the formula of Daugirdas [9]. Dialysate flow was fixed at 500 mL/min, being supplied by a central provider. Blood flow was between 160 and 220 mL/min and each dialysis session was between 3.5 and 4.5 h, in order to achieve the target total Kt/V of around 1.2 per session for three times weekly treatment, as a routine practice in most dialysis facilities in Japan. Dialyzer membrane surface was adjusted to further maintain the target total Kt/V of around 1.2. No reuse of dialyzer was performed in any patient. The clinical diagnoses of primary renal disease were chronic glomerulonephritis (n = 244), diabetic nephropathy (n = 120), hypertensive nephrosclerosis (n = 32), polycystic kidney disease (n = 19), toxaemia of pregnancy (n = 6), gout (n = 5) and others/unknown (n = 64). This ratio of chronic glomerulonephritis, diabetic nephropathy and other diseases as primary renal disease was close to the data of the Japanese Dialysis Registry [10], in which 51.1% of primary renal disease in dialysis patients in 1999 was chronic glomerulonephritis in Japan.

In October 1999, data of the enrolled patients were collected and the observation study was conducted until 31 December 2003. The relationship between the baseline data and outcomes was analysed statistically. This study was approved by the ethics review committee of the hospital.

Biochemical assays and other measurements
Blood was drawn just before the start of a dialysis session in a non-fasting state, to measure serum albumin, creatinine, blood urea nitrogen, C-reactive protein (CRP) and haematocrit, using routine laboratory methods, twice a month as a routine clinical care as performed in most dialysis facilities in Japan. These values were a mean of eight measurements within 4 months. Serum β2-M concentration was measured by latex immunoassay [11] (Mitsubishi-Kagaku Medicine, Tokyo, Japan) at the time of enrolment.

Statistical methods
Data were summarized as the mean ± SD. Differences in the means between two groups were evaluated by unpaired Student's t-test. Data that showed skewed distributions were compared with the Mann–Whitney U-test. Categorical data were compared between groups by the chi-square test. Survival curves were assessed using the Kaplan–Meier analysis and evaluated by the log-rank test. Prognostic variables for survival were initially examined using the univariate Cox proportional hazards method. Multivariate Cox proportional hazards analyses were performed to identify independent factors associated with mortality. In multivariate analyses, age, gender, haemodialysis duration, diabetes and the factors that showed P-values <0.05 on univariate analysis were entered as possible factors associated with mortality. P-values <0.05 were considered statistically significant. All calculations were performed using statistical analysis software StatView 5 (SAS Institute Inc., Cary, NC, USA) on a Windows personal computer.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Serum β2-M concentration and haemodialysis duration
Serum β2-M concentrations of a total of 490 patients were normally distributed (Figure 1), with a mean (±SD) of 32.5 (±7.2) mg/L. Serum β2-M concentrations according to haemodialysis duration are shown in Figure 2. In patients whose dialysis duration was <5 years, serum β2-M concentrations correlated significantly with the duration of dialysis, tending to be higher in patients treated for 5 years compared to shorter durations. Compared to serum β2-M concentrations in patients with a haemodialysis duration of <1 year (n = 41), those in patients with durations of 2– 3 years (n = 47), 5–6 years (n = 43), 6–8 years (n = 49), 8–10 years (n = 45) and 10–14 years (n = 43) were significantly higher (P < 0.05). In patients treated for >5 years, this relationship was reversed, with patients treated for >18 years (n = 45) having significantly lower β2-M levels compared to those of patients treated for 1– 2 years (n = 63), 2–3 years, 3–4 years (n = 48), 4–5 years (n = 39), 5–6 years, 6–8 years, 8–10 years, 10–14 years and 14–18 years (n = 34) (P < 0.01).


Figure 1
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  		Fig. 1 Distribution of serum β2-microglobulin concentrations. Serum β2-microglobulin concentrations were distributed normally.

 

Figure 2
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  		Fig. 2 Serum β2-microglobulin concentration according to haemodialysis duration. Serum β2-microglobulin concentrations increased until 5 years, reached a plateau level, and then decreased after 18 years. *Denotes P <0.05 versus β2-microglobulin concentrations with haemodialysis duration of less than 1 year. #Denotes P < 0.01 versus β2-microglobulin concentrations with haemodialysis duration of 1–2, 2–3, 3–4, 4–5, 5–6, 6–8, 8–10, 10–14 and 14–18 years.

 
Clinical characteristics according to the low- and high-β2-M groups
Patients were divided into two groups according to the median value of the baseline serum β2-M concentration (32.2 mg/L), as follows: a lower β2-M group (serum β2-M < 32.2 mg/L, n = 245) and a higher β2-M group (serum β2-M ≥ 32.2 mg/L, n = 245). Table 1 shows the baseline clinical characteristics of the haemodialysis patients in each of the two groups.


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  		Table 1 Baseline characteristics of the haemodialysis patients according to serum β2-microglobulin (β2-M) concentrations

 
There were no significant differences in age and gender between the two groups. The duration of haemodialysis was significantly longer in the lower β2-M group than that in the higher β2-M group (96.3 ± 85.3 versus 80.4 ± 64.8 months, P = 0.020). The prevalence of diabetes was lower and body mass index was higher in the former than that in the latter group, although the differences did not reach a statistical significance. There was no significant difference in Kt/V between the two groups (P = 0.919).

Serum albumin levels were significantly higher in the lower β2-M group than those in the higher β2-M group (4.1 ± 0.3 versus 4.0 ±0.4 g/dL, P < 0.001), whereas CRP levels were significantly lower in the former group (0.10 versus 0.16 mg/dL, P = 0.002). There was no significant difference in the values of haematocrit, blood urea nitrogen or creatinine between the two groups.

Kaplan–Meier analysis
During the follow-up period of 40 ± 15 months, a total of 91 patients died. The death rate was near to the average of haemodialysis patients in Japan, according to the Japanese Dialysis Registry [10]. Kaplan–Meier analysis was performed to examine the univariate association between the two groups based on the β2-M concentrations and the outcomes of the cohort (Figure 3). Patients with higher β2-M concentrations exhibited a significantly higher death rate than those with lower β2-M concentrations (log-rank test, P < 0.001).


Figure 3
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  		Fig. 3 Kaplan–Meier analysis of all-cause mortality of 490 haemodialysis patients, classified according to lower (<32.2 mg/L, n = 245) and higher (≥32.2 mg/L, n = 245) β2-microglobulin (β2-M) concentrations. Patients with higher β2-M concentrations (thick line) exhibited a significantly higher death rate compared to those with lower β2-M concentrations (thin line) (log-rank test, P < 0.001).

 
Univariate analysis with Cox proportional hazards models
Table 2 presents the univariate associations between mortality and other covariates. In addition to higher β2-M concentrations, increased age, the presence of diabetes, lower body mass index, lower serum albumin, lower serum creatinine and higher serum CRP concentrations were significant univariate predictors of increased all-cause mortality.


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  		Table 2 Univariate Cox proportional hazards analysis of independent predictors of all-cause mortality in haemodialysis patients

 
Multivariate analysis with Cox proportional hazards models
Multivariate Cox proportional hazards analyses were performed to identify the independent predictors of mortality. As shown in Table 3, β2-M concentration was a significant, independent predictor of mortality [hazard ratio (per 1 mg/L increase) 1.05 (95% CI 1.01–1.08), P = 0.005] in addition to age, gender, serum creatinine and serum CRP.


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  		Table 3 Multivariate Cox proportional hazards analysis of independent predictors of all-cause mortality in haemodialysis patients

 
Multivariate analysis of cardiovascular and non-cardiovascular mortality with Cox proportional hazards models
Of the 91 patients who died, 36 patients died from fatal cardiovascular events, as defined previously [12,13]. Cardiovascular deaths included death from ischaemic heart disease (n = 8), congestive heart failure (n = 14), cerebrovascular disease (n = 6) and sudden death (n = 8). Non-cardiovascular deaths consisted of infectious disease (n = 22), cancer (n = 8), hepatic cirrhosis (n = 3) and others (n = 22). As shown in Table 4, higher serum β2-M concentration was a significant, independent predictor of increased mortality from non-cardiovascular disease [hazard ratio (per 1 mg/L increase) 1.06 (95% CI 1.02–1.10), P = 0.006] after adjustment for other confounders, but not from cardiovascular disease.


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  		Table 4 Multivariate Cox proportional hazards analysis of independent predictors of cardiovascular and non-cardiovascular mortality in haemodialysis patients

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In the present observational study, we examined the serum β2-M concentration in maintenance haemodialysis patients, and evaluated the prognostic significance of the baseline β2-M concentrations. We found that serum β2-M concentrations were a significant predictor for all-cause mortality, particularly for non-cardiovascular mortality, after adjustment for age, gender, haemodialysis duration, presence of diabetes, serum albumin and serum CRP. Our study examining prevalent haemodialysis patients demonstrated that lower serum β2-M concentrations were significantly preferable for better survival of haemodialysis patients.

Lowering serum β2-M concentrations has been emphasized in dialysis practice. One of the reasons is that the levels of serum β2-M serve as a surrogate marker of uraemic toxins of other middle molecules that have similar systemic or extracorporeal kinetics in dialysis patients [2,14]. Another reason is that β2-M is a precursor of amyloidosis in haemodialysis patients [2,3,15]. Reduction of serum β2-M has been demonstrated to be effective for the treatment of dialysis-related amyloidosis, through the use of haemodiafiltration, ultrapure dialysate, high-flux membrane and adsorptive affinity column for β2-M [2–7]. Reduction of serum β2-M has been demonstrated through the use of long dialysis and daily dialysis [16,17].

Some studies have reported the influence of middle-molecule clearance on dialysis patients’ survival [18]. As for the relationship between mortality and serum β2-M concentration, however, there have been no reports on this matter, except for the results of the HEMO study [7]. In the HEMO study, serum β2-M concentration correlated significantly with mortality, after adjustment for other confounders. However, serum β2-M levels predicted mortality in the subgroup of patients who had been on dialysis for <3.7 years (mean duration of dialysis in the HEMO study), but not in patients who had been on dialysis for a duration longer than 3.7 years. The HEMO study showed that the predictive value of serum β2-M was stronger in the subgroup of patients with detectable residual kidney function, although the predictive value was marginal in patients with anuria at baseline. They considered that the residual renal function with a shorter duration of haemodialysis, which significantly lowered the β2-M concentration, might be an important determinant of the predictive effect of β2-M concentration on all-cause mortality. However, in the present study in which patients with longer haemodialysis durations of 87.4 ± 75.7 months (7.3 ± 6.3 years) were examined, Cox proportional hazards analysis demonstrated that serum β2-M concentration was a significant predictor for all-cause mortality after adjustment for several confounders. Furthermore, a Cox proportional hazards analysis in patients with longer haemodialysis durations of >5 years (n = 259), in whom residual kidney function was negligible, serum β2-M concentration was also a significant predictor for all-cause mortality (hazard ratio 1.071, 95% CI 1.009–1.137, P = 0.0234), after adjustment for several confounders. The result suggests that serum β2-M is a predictor for all-cause mortality even in longer term haemodialysis patients, without the effect of residual renal function. The reason for the difference seen between the HEMO study and the present study remains unknown. One explanation may be the fact that, in the present study, the haemodialysis duration (87.4 ± 75.7 months) was longer than that of the HEMO study, with mean haemodialysis duration of 3.7 years. Patients with lower serum β2-M concentration and longer duration of haemodialysis may live longer among our study patients, as suggested by the fact that serum β2-M concentration was significantly lower in patients with haemodialysis durations longer than 18 years. Another reason for the difference between the results of the HEMO study and the present study may be the fact that the low-flux membrane was not used in any of the patients in the present study during the study period, and that the high-flux membrane was never reused in our study, whereas in the HEMO study ~40% of the patients used a low-flux membrane with β2-M clearance <10 mL/min and reuse of dialyzers was widespread in the HEMO study [19]. They demonstrated that the high-flux membrane, which significantly lowered β2-M concentration, was associated with lower risk of all-cause mortalities in a subgroup that had been on dialysis for >3.7 years [8]. The effect of sole use of high-flux membranes without reuse in the present study may reduce the middle-molecule uraemic toxins, leading to improved survival of patients with lower serum β2-M and longer haemodialysis duration in the present study. The high-flux membrane used in the present study may have some effect other than lowering serum β2-M, such as better biocompatibility [20] and adsorption of pyrogen [2], leading to lower mortality in patients with lower serum β2-M caused by use of a high-flux membrane.

Concerning the relationship between the serum β2-M concentration and haemodialysis duration, serum β2-M concentrations have been reported to be increased during the early phase of haemodialysis. Fly et al. reported that serum β2-M concentrations increased as the haemodialysis duration increased [6]. In their study, residual renal function was of importance as a determinant of serum β2-M concentrations during the early years of haemodialysis. In their analysis of the HEMO study, Cheung et al. also reported that the mean predialysis β2-M levels continued to increase during follow-up in both the low-flux and high-flux groups [7]. In the present study analysing a total of 490 patients whose mean haemodialysis durations were relatively long (87.4 ± 75.6 months), compared to the previous reports [6,7], we also found that serum β2-M levels continued to be higher up to 5 years of haemodialysis duration (Figure 2). This elevation may be due to the gradual decrease in residual urine as demonstrated by Fly et al. [6]. After 5 years, β2-M levels were at a plateau level. This result is consistent with that reported by Canaud et al., who reported that serum β2-M levels reached a plateau levels after 10 years of dialysis treatment [21]. However, after 18 years, serum β2-M levels were lower (Figure 2). No previous studies have demonstrated lower levels of serum β2-M in patients with extremely long-term haemodialysis, except for an earlier report by Charra et al., who reported lower serum β2-M levels at 20 years of haemodialysis treatment with use of a low-flux membrane, cuprophane [22]. The reason why serum β2-M levels are lower in long-term haemodialysis patients remains unknown. However, based on the findings of Kaplan–Meier analysis and Cox proportional hazards analysis in the present study, it may be considered that patients with higher levels of serum β2-M do not live longer, whereas patients with lower serum β2-M levels do. This may be the reason why serum β2-M levels were lower in patients with extremely longer duration of haemodialysis.

Our present study suggests that lowering serum β2-M levels is preferable for improving survival of haemodialysis patients. Compared to low-flux haemodialysis, which does not remove circulating β2-M, high-flux haemodialysis is associated with a significant clearance of circulating β2-M [2,16]. Although primary data analysis of the HEMO study did not prove a benefit of high-flux compared to low-flux membranes [19], several studies have demonstrated better outcomes in dialysis patients treated with high-flux membranes [23–26]. It was reported that the reduction ratio of β2-M per session was 20–30% higher with online haemodiafiltration than that with high-flux haemodialysis (72.7 versus 49.7%), and that regular use of online haemodiafiltration significantly reduced circulating levels of predialysis β2-M (median value 20 mg/L) [27]. Recently, high-efficiency haemodiafiltration patients were shown to have a significantly lower mortality risk than those receiving low-flux haemodialysis [28,29]. Taken together, removal of middle-molecule uraemic toxins, as represented by β2-M as a surrogate marker, by the use of high-flux membrane or haemodiafiltration may improve the survival of dialysis patients.

Our study, which demonstrated significantly improved survival in patients with lower serum β2-M may also indicate that removal of middle-molecule uraemic toxins is important in dialysis practice. Middle-molecular uraemic toxins may impact nutritional status or have immunosuppressive effects [30,31]. Indeed, in our present study, serum albumin levels were significantly lower and serum CRP were significantly higher in patients with higher serum β2-M, compared to those with lower serum β2-M. The HEMO study also demonstrated a negative correlation between serum β2-M levels and serum albumin. This may also indicate that serum levels of β2-M, and/or middle-molecular uraemic toxins, are associated with nutritional status and inflammation. Although poor nutritional status and chronic inflammation have been reported to be associated with cardiovascular mortality [32,33], they were also reported to be significantly related to non-cardiovascular mortality [34]. In an earlier study by Canaud et al. [21], it was reported that patients with high values of β2-M were observed in patients presenting with severe intercurrent disease, such as cancer. Taken together, these facts may explain why serum β2-M levels were associated significantly with non-cardiovascular mortality in the present study. In a recently published article by Cheung et al. [35], a significant association between serum β2-M levels and infectious mortality in haemodialysis patients were reported. In their article, they could not demonstrate significant association between serum β2-M levels and cardiovascular mortality in haemodialysis patients. Our results studying Japanese haemodialysis patients, who relatively live longer and have longer periods of haemodialysis due to less chances to receive kidney transplantation, compared to other countries [10], are consistent with the recent results reported by Cheung et al.

There were some limitations in this study. First, at the start of this study, we could not obtain data regarding serum lipids, smoking history, residual urine or history of cardiovascular or non-cardiovascular disease, which may affect survival of haemodialysis patients. Second, we could not include the information regarding medications, such as lipid-lowering drugs, calcium carbonate or calcium acetate and vitamin D, which could affect patient survival. In the analyses excluding these data, our data may reflect inadequate adjustments for these known risk or beneficial factors. However, serum β2-M levels in dialysis patients have not been reported to be associated with the above-noted clinical history or medications [3,7,36]. Although we analysed a cohort of prevalent haemodialysis patients who may have a limitation in elucidating the effect of β2-M on survival, we found that, after adjustment for several variables that were significant in univariate Cox proportional hazards analysis, serum β2-M levels remained associated significantly with both all-cause and non-cardiovascular mortality in multivariate Cox proportional analysis. Influence of β2-M on mortality should be examined in incident haemodialysis patients in future studies, to clearly confirm the results of our findings.

In conclusion, in an observational study on prevalent haemodialysis patients, we demonstrated that serum β2-M levels were a significant predictor of mortality in haemodialysis patients with relatively longer haemodialysis durations of 87.4 ± 75.7 months, independent of haemodialysis duration, diabetes, malnutrition and chronic inflammation, suggesting the clinical importance of lowering serum β2-M in these patients.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 31. 3.08
Accepted in revised form: 25. 8.08


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E. L. Penne, T. van Berkel, N. C. van der Weerd, M. P. C. Grooteman, and P. J. Blankestijn
Optimizing haemodiafiltration: tools, strategy and remaining questions
Nephrol. Dial. Transplant., December 1, 2009; 24(12): 3579 - 3581.
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