Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients
2012; Elsevier BV; Volume: 82; Issue: 12 Linguagem: Inglês
10.1038/ki.2012.301
ISSN1523-1755
AutoresSophie Liabeuf, Aurélie Lenglet, Lucie Desjardins, Nathalie Neirynck, Griet Glorieux, Horst‐Dieter Lemke, Raymond Vanholder, Momar Diouf, Gabriel Choukroun, Ziad A. Massy,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoSince beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD. Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD. Beta-2 microglobulin (B2M) is a polypeptide with a molecular weight of 11,800Da. It is present on the surface of nucleated human cells and thrombocytes and forms part of the major histocompatibility class I family.1.Vincent C. Revillard J.P. Beta-2-microglobulin and HLA-related glycoproteins in human urine and serum.Contrib Nephrol. 1981; 26: 66-88Crossref PubMed Google Scholar,2.Winchester J.F. Salsberg J.A. Levin N.W. Beta-2 microglobulin in ESRD: an in-depth review.Adv Ren Replace Ther. 2003; 10: 279-309Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Under physiological conditions, B2M is generated at a constant rate and is eliminated by kidneys. Elevated B2M levels are observed in a range of hematological, immunodeficiency, autoimmune, and renal diseases.3.Alexanian R. Barlogie B. Fritsche H. Beta 2 microglobulin in multiple myeloma.Am J Hematol. 1985; 20: 345-351Crossref PubMed Scopus (65) Google Scholar, 4.Chitra P. Bakthavatsalam B. Palvannan T. Beta-2 microglobulin as an immunological marker to assess the progression of human immunodeficiency virus infected patients on highly active antiretroviral therapy.Clin Chim Acta. 2011; 412: 1151-1154Crossref PubMed Scopus (26) Google Scholar, 5.Michalski J.P. Daniels T.E. Talal N. et al.Beta2 microglobulin and lymphocytic infiltration in Sjogren's syndrome.N Engl J Med. 1975; 293: 1228-1231Crossref PubMed Scopus (141) Google Scholar, 6.Drueke T.B. Massy Z.A. Beta2-microglobulin.Semin Dial. 2009; 22: 378-380Crossref PubMed Scopus (90) Google Scholar B2M levels are elevated in patients with kidney failure, especially in dialysis patients, in whom glomerular filtration is almost completely absent. Furthermore, it is known that an elevated concentration of circulating B2M is a potential risk factor for the development of dialysis-related amyloidosis.7.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: 701-706Crossref PubMed Scopus (867) Google Scholar Indeed, longstanding, the marked elevation of serum B2M is a prerequisite for the formation of B2M amyloid fibrils, which are associated with chronic arthropathy and spondylarthropathy after several years of renal replacement therapy.6.Drueke T.B. Massy Z.A. Beta2-microglobulin.Semin Dial. 2009; 22: 378-380Crossref PubMed Scopus (90) Google Scholar,7.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: 701-706Crossref PubMed Scopus (867) Google Scholar In addition, B2M is known to be a surrogate marker for the concentration and removal of other middle-molecular-weight uremic toxins in dialysis patients. In the HEMO study on 1704 hemodialysis patients, Cheung et al. reported that predialysis serum B2M predicted mortality, with an 11% increase in mortality for each 10mg/l increase in B2M level—even after adjustment for years on dialysis and residual kidney function.8.Cheung A.K. Rocco M.V. 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: 546-555Crossref PubMed Scopus (367) Google Scholar Hence, the amelioration of B2M clearance during dialysis might be an important factor for improving outcomes.8.Cheung A.K. Rocco M.V. 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: 546-555Crossref PubMed Scopus (367) Google Scholar,9.Locatelli F. Gauly A. Czekalski S. et al.The MPO Study: just a European HEMO Study or something very different?.Blood Purif. 2008; 26: 100-104Crossref PubMed Scopus (35) Google Scholar It is still unknown whether B2M is only a uremic toxin marker or also an active player in vascular damage, which is one of the main mortality factors in chronic kidney disease (CKD).10.Vanholder R. Massy Z. Argiles A. et al.Chronic kidney disease as cause of cardiovascular morbidity and mortality.Nephrol Dial Transplant. 2005; 20: 1048-1056Crossref PubMed Scopus (532) Google Scholar There is preclinical and clinical evidence in favor of an active role. B2M stimulates osteoclastogenesis, probably via upregulation of tumor necrosis factor α and interleukin-1 expression.11.Menaa C. Esser E. Sprague S.M. Beta2-microglobulin stimulates osteoclast formation.Kidney Int. 2008; 73: 1275-1281Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar An interesting proteomic profiling study in patients with peripheral arterial disease (PAD)12.Wilson A.M. Kimura E. Harada R.K. et al.Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies.Circulation. 2007; 116: 1396-1403Crossref PubMed Scopus (149) Google Scholar identified B2M as a potential biomarker of PAD. In patients with PAD, elevated B2M levels correlated with severity of the disease, independently of other risk factors. It has been suggested that B2M may damage vessels by participating in amyloid formation in the vessel wall.12.Wilson A.M. Kimura E. Harada R.K. et al.Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies.Circulation. 2007; 116: 1396-1403Crossref PubMed Scopus (149) Google Scholar More recently, B2M was found to be independently and significantly associated with adverse cardiovascular outcomes in patients with prevalent, asymptomatic carotid atherosclerosis.13.Amighi J. Hoke M. Mlekusch W. et al.Beta 2 microglobulin and the risk for cardiovascular events in patients with asymptomatic carotid atherosclerosis.Stroke. 2011; 42: 1826-1833Crossref PubMed Scopus (47) Google Scholar Given that uremic patients are known to be at a high risk for developing cardiovascular disease and atherosclerosis, we decided to study the potential impact of B2M on cardiovascular outcomes in CKD patients in general. Indeed, it remains unknown whether B2M has an impact on CKD patients who are not yet on dialysis. Hence, we studied B2M levels in a cohort of patients at different CKD stages, with special focus on the protein's relationships with surrogate markers of bone and vascular disease (including bone density, arterial stiffness, and vascular calcification) and hard clinical outcomes (such as cardiovascular events, cardiovascular mortality, and all-cause mortality). Figure 1 illustrates the distribution of B2M levels. The B2M level increased with CKD stages. In comparison with a control group, the increase became statistically significant from CKD stage 4 onward. When considering nondialyzed patients only (n=96), there was a significant, inverse association between B2M levels and estimated glomerular filtration rate (eGFR), as shown in Figure 2.Figure 2Exponential relationship between plasma beta-2 microglobulin level and estimated glomerular filtration rate, predialysis chronic kidney disease stages 2–5 (n=96, r2=0.789, P 8.34mg/l were more likely to be at a later CKD stage and to have a higher aortic calcification score, higher circulating phosphate, parathyroid hormone (PTH), and C-reactive protein (CRP) levels, and lower hemoglobin and albumin levels. Univariate correlations between plasma B2M levels and the clinical and biochemical characteristics of the study population are shown in Table 3. There was an inverse correlation of B2M with albumin and hemoglobin but a positive correlation with CRP, phosphate, and PTH.Table 1Clinical and demographic characteristics of the study populationBeta-2 microglobulinAll (n=142)≤8.34mg/l (n=71)>8.34mg/l (n=71)PAge, years67±1266±1268±120.466Male gender, n (%)86 (60)47 (66)39 (55)0.170Body mass index (kg/m2)28±629±627±60.080Diabetes mellitus, n (%)60 (42)30 (50)30 (50)0.999Smoking habit, n (%)56 (41)31 (45)25 (36)0.298Presence of CVD, n (%)43 (31)22 (31)23 (32)0.860Systolic arterial pressure, mmHg153±26150±23156±290.180Diastolic arterial pressure, mmHg81±1282±1081±130.578Pulse pressure, mmHg72±2369±2275±240.070CKD stage, n (%) 8.34mg/l (n=71)PCalcium, mmol/l2.30±0.182.32±0.142.26±0.210.062Phosphate, mmol/l1.30±0.461.14±0.31.43±0.5<0.0001Intact PTH, pg/ml137±138 (85)89±75 (63)184±165 (128)<0.0001Albumin, g/l38±639.9±634.9±6<0.0001C-reactive protein, mg/l10.7±23 (3.5)6.2±13.4 (2.2)16.2±30.3 (4.1)0.002Hemoglobin, g/dl12±1.712.7±1.611.4±1.6<0.0001GFR-epiaCalculated for patients at CKD stages 2–5 (n=96)., ml/minper1.73m235±1942.5±17.417.1±6.2<0.0001Total cholesterol, mmol/l4.9±1.24.9±1.14.8±1.30.535LDL cholesterol, mmol/l2.7±0.92.7±0.82.5±0.90.225Triglycerides, mmol/l2.0±1.31.8±1.022.2±1.50.071Beta-2 microglobulin, mg/l13.5±12.5 (8.3)4.7±1.9 (4.7)22.4±12.3 (19.6)<0.0001Abbreviations: GFR, glomerular filtration rate; LDL, low-density lipoprotein; PTH, parathyroid hormone.Data are expressed as the mean±s.d. and, for variables with a non-Gaussian distribution, median.a Calculated for patients at CKD stages 2–5 (n=96). Open table in a new tab Table 3Correlations between serum beta-2 microglobulin levels and selected clinical or biochemical characteristicsBeta-2 microglobulinrPAge-0.0370.661Systolic arterial pressure0.0750.378Body mass index-0.1230.145Albumin-0.437<0.0001C-reactive protein0.292<0.0001LDL cholesterol-0.1370.114Triglycerides0.2280.008Hemoglobin-0.387<0.0001Calcium-0.1810.032Phosphate0.347<0.0001Intact PTH0.459 8.34mg/l was a significant predictor of overall and cardiovascular mortality and cardiovascular events (P<0.0001, P 8.34 vs. B2M≤8.34mg/l). (B2M>8.34 vs. B2M≤8.34mg/l) or a continuous variablebPlasma B2M level entered as continuous variable.HR95% CIPOverall mortality (events n=44) Unadjusted B2MaPlasma B2M level entered as a categorical variable (B2M>8.34 vs. B2M≤8.34mg/l).3.871.95–7.67<0.0001 Ln B2MbPlasma B2M level entered as continuous variable.1.941.39–2.71 8.34 vs. B2M≤8.34mg/l).4.112.00–8.430.0001 Age1.051.02–1.090.001Cardiovascular mortality (events n=24) Unadjusted B2MaPlasma B2M level entered as a categorical variable (B2M>8.34 vs. B2M≤8.34mg/l).4.811.79–12.91 8.34 vs. B2M≤8.34mg/l).4.751.76–12.830.002 Age1.051.007–1.0910.02Cardiovascular event-free survival (events n=49) Unadjusted B2MaPlasma B2M level entered as a categorical variable (B2M>8.34 vs. B2M≤8.34mg/l).2.331.29–4.160.005 Ln B2MbPlasma B2M level entered as continuous variable.1.511.11–2.050.009 Model 1 including Ln B2M, age, Ln CRP, Hb and albumincLn CRP, hemoglobin, and albumin were not selected in the models. Ln B2MbPlasma B2M level entered as continuous variable.1.321.08–2.800.048 Age1.031.01–1.060.017 Model 2 including B2M, age and propensity scoreeB2M was not selected in the model. Age1.031.004–1.060.026 Propensity score7.302.29–23.230.0008Abbreviations: B2M, beta-2 microglobulin; CI, confidence interval; CRP, C-reactive protein; Hb, hemoglobin; HR, hazard ratio.P-values are stated for the trend across categories.a Plasma B2M level entered as a categorical variable (B2M>8.34 vs. B2M≤8.34mg/l).b Plasma B2M level entered as continuous variable.c Ln CRP, hemoglobin, and albumin were not selected in the models.d Propensity score (included albumin, CRP, hemoglobin and phosphate levels, and aortic calcification score) was not selected in the model.e B2M was not selected in the model. Open table in a new tab Abbreviations: B2M, beta-2 microglobulin; CI, confidence interval; CRP, C-reactive protein; Hb, hemoglobin; HR, hazard ratio. P-values are stated for the trend across categories. In the subgroup of predialysis patients, B2M levels were not associated with overall (P=0.27) or cardiovascular mortality (P=0.065); however, a B2M level >6.07mg/l (the median for predialysis patients) was a significant predictor of cardiovascular events (P=0.009) in univariate analysis. The plasma B2M level was still a predictor of cardiovascular events after adjustment for age, CRP, hemoglobin, albumin, and eGFR (Table 5).Table 5For predialysis patients: univariate and multivariate Cox regression analyses of risk factors at baseline for cardiovascular event-free survival, with the plasma B2M entered as either a categorical variableaPlasma B2M level entered as a categorical variable (B2M>6.07 vs. B2M≤6.07mg/l). (B2M>6.07 vs. B2M≤6.07mg/l) or a continuous variablebPlasma B2M level entered as continuous variable.Models of patient survival (event n=31)HR95% CIPUnadjusted B2MaPlasma B2M level entered as a categorical variable (B2M>6.07 vs. B2M≤6.07mg/l).2.641.24–5.640.009 Ln B2MbPlasma B2M level entered as continuous variable.2.011.09–3.690.024Model 1 including B2M, age, Ln CRP, Hb, albumin, and eGFRcIn model 1 and 2: Ln CRP, hemoglobin, albumin, and eGFR were not selected in the models. Ln B2MbPlasma B2M level entered as continuous variable.1.831.32–3.050.007 Age1.041.01–1.080.008Model 2 including B2M, and propensity scoredIn model 2: Propensity score (including age, albumin, CRP, hemoglobin, phosphate, aortic calcification score, and eGRF) was not selected in the model. B2MaPlasma B2M level entered as a categorical variable (B2M>6.07 vs. B2M≤6.07mg/l).3.131.37–7.180.007Abbreviations: B2M, beta-2 microglobulin; CI, confidence interval; HR, hazard ratio.a Plasma B2M level entered as a categorical variable (B2M>6.07 vs. B2M≤6.07mg/l).b Plasma B2M level entered as continuous variable.c In model 1 and 2: Ln CRP, hemoglobin, albumin, and eGFR were not selected in the models.d In model 2: Propensity score (including age, albumin, CRP, hemoglobin, phosphate, aortic calcification score, and eGRF) was not selected in the model. Open table in a new tab Abbreviations: B2M, beta-2 microglobulin; CI, confidence interval; HR, hazard ratio. More importantly, additional Cox models demonstrated that the B2M level was a better predictor of overall and cardiovascular mortality, but not of cardiovascular events, compared with a propensity score that includes CRP, albumin, hemoglobin, phosphate, and aortic calcification in the whole group (Table 4). When considering the predialysis patient group alone, B2M levels were a better predictor of cardiovascular events compared with age, CRP, albumin, hemoglobin, phosphate levels, aortic calcification score, and eGFR, which were regrouped in a propensity score variable (Figure 3 and Table 5). Our study confirms that plasma B2M levels are elevated in CKD patients and that these levels progressively increase with decreasing GFR and peak in hemodialysis patients. More interestingly, B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the entire cohort and with cardiovascular events in predialysis patients. Moreover, we show that circulating B2M is a better predictor of overall and cardiovascular mortality for the whole cohort and of cardiovascular events for predialysis patients, compared with well-established factors associated with outcomes in this population, including eGFR, inflammation biomarkers, and others factors included in a propensity score. It is well known that the normal serum B2M concentration is 1.5–3mg/l. B2M is usually eliminated by the kidney via glomerular filtration and subsequent tubular catabolism.6.Drueke T.B. Massy Z.A. Beta2-microglobulin.Semin Dial. 2009; 22: 378-380Crossref PubMed Scopus (90) Google Scholar Hence, one can expect (i) circulating B2M levels to be highly correlated with GFR and (ii) B2M to accumulate in chronic dialysis patients, in whom GFR is either very low or entirely absent. Interestingly, we found an association between plasma B2M levels and overall and cardiovascular mortality and cardiovascular outcomes in our patient cohort with different stages of CKD (including predialysis patients). Several studies have demonstrated that serum B2M is an independent, significant predictor of mortality in dialysis patients.8.Cheung A.K. Rocco M.V. 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: 546-555Crossref PubMed Scopus (367) Google Scholar,14.Okuno S. Ishimura E. Kohno K. et al.Serum beta2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients.Nephrol Dial Transplant. 2009; 24: 571-577Crossref PubMed Scopus (123) Google Scholar However, data on predialysis CKD patients are scarce. In line with our results, Amighi et al.13.Amighi J. Hoke M. Mlekusch W. et al.Beta 2 microglobulin and the risk for cardiovascular events in patients with asymptomatic carotid atherosclerosis.Stroke. 2011; 42: 1826-1833Crossref PubMed Scopus (47) Google Scholar recently showed a strong link between serum B2M levels and cardiovascular outcomes in a patient population with comorbidity severity similar to that in CKD patients. The authors studied 1005 patients with prevalent asymptomatic carotid atherosclerosis and found that B2M was independently and significantly associated with major adverse cardiovascular events, even after adjustment for eGFR and CRP. They suggested that B2M is a novel risk marker for adverse cardiovascular outcomes in patients with carotid atherosclerosis. Furthermore, Shinkai et al.15.Shinkai S. Chaves P.H. Fujiwara Y. et al.Beta2-microglobulin for risk stratification of total mortality in the elderly population: comparison with cystatin C and C-reactive protein.Arch Intern Med. 2008; 168: 200-206Crossref PubMed Scopus (86) Google Scholar identified serum B2M as an independent predictor of all-cause mortality in a population-based sample of older adults.15.Shinkai S. Chaves P.H. Fujiwara Y. et al.Beta2-microglobulin for risk stratification of total mortality in the elderly population: comparison with cystatin C and C-reactive protein.Arch Intern Med. 2008; 168: 200-206Crossref PubMed Scopus (86) Google Scholar They suggested that the predictive value of circulating B2M concentration is superior to that provided by established prognostic factors for mortality, such as eGFR, cystatin C, and CRP (threshold for B2M, 1.9mg/l). Interestingly, systematic proteomic profiling-based screening for PAD biomarkers led to the identification of B2M as the most relevant candidate. The authors suggested that B2M might damage vessels by participating in amyloid formation in the vascular wall.12.Wilson A.M. Kimura E. Harada R.K. et al.Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies.Circulation. 2007; 116: 1396-1403Crossref PubMed Scopus (149) Google Scholar In view of these data as a whole, the possibility that high levels of circulating B2M have a direct pathophysiological role in vascular disease deserves serious consideration. The association between B2M levels and aortic calcification found in our cohort suggests that this solute may also have a role in the development of uremia-related cardiovascular disorders. The involvement of B2M in the inflammatory process, as highlighted in previous reports, could explain the observed association between vascular calcification and circulating levels of this uremic toxin.11.Menaa C. Esser E. Sprague S.M. Beta2-microglobulin stimulates osteoclast formation.Kidney Int. 2008; 73: 1275-1281Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Several reports have suggested that the uremic milieu has a harmful influence on the vascular system. In an in vitro study, high serum levels of B2M and indole-3-acetic acid were associated with low counts of circulating CD34+CD133+ endothelial progenitor cells;16.Jourde-Chiche N. Dou L. Sabatier F. et al.Levels of circulating endothelial progenitor cells are related to uremic toxins and vascular injury in hemodialysis patients.J Thromb Haemost. 2009; 7: 1576-1584Crossref PubMed Scopus (91) Google Scholar the latter contribute to vessel repair and neovascularization and show a decrease in their migration ability in the presence of uremic serum.17.Herbrig K. Pistrosch F. Oelschlaegel U. et al.Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis.Am J Kidney Dis. 2004; 44: 840-849Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The uremic milieu may disturb vascular repair mechanisms in patients with kidney failure.18.de Groot K. Bahlmann F.H. Sowa J. et al.Uremia causes endothelial progenitor cell deficiency.Kidney Int. 2004; 66: 641-646Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Moreover, it has been demonstrated that other uremic toxins (such as indoxyl sulfate, p-cresyl sulfate, and guanidine compounds) inhibit endothelial proliferation and wound repair.19.Dou L. Bertrand E. Cerini C. et al.The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair.Kidney Int. 2004; 65: 442-451Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 20.Schepers E. Glorieux G. Dou L. et al.Guanidino compounds as cause of cardiovascular damage in chronic kidney disease: an in vitro evaluation.Blood Purif. 2010; 30: 277-287Crossref PubMed Scopus (45) Google Scholar, 21.Meijers B.K. Van Kerckhoven S. Verbeke K. et al.The uremic retention solute p-cresyl sulfate and markers of endothelial damage.Am J Kidney Dis. 2009; 54: 891-901Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar Our present data suggest that B2M should be added to the list of suspects. However, we did not find a correlation between B2M levels and arterial stiffness. Previous studies have found such an association in non-CKD patients.22.Saijo Y. Utsugi M. Yoshioka E. et al.Relationship of beta2-microglobulin to arterial stiffness in Japanese subjects.Hypertens Res. 2005; 28: 505-511Crossref PubMed Scopus (45) Google Scholar,23.Kals J. Zagura M. Serg M. et al.Beta2-microglobulin, a novel biomarker of peripheral arterial disease, independently predicts aortic stiffness in these patients.Scand J Clin Lab Invest. 2011; 71: 257-263Crossref PubMed Scopus (30) Google Scholar This discrepancy may be due to the different types of recruitment and techniques used for arterial stiffness measurement. One study recorded brachial PWV, which is not a ‘gold standard’ parameter, whereas we used carotid-femoral PWV. Moreover, the low degree of PWV variability in our cohort might have precluded the identification of such an association. A variety of reports have suggested that B2M may be involved in metabolic bone disease in CKD. B2M appears to upregulate TNFα and IL-1 expression in a concentration-dependent manner. A TNFα-neutralizing antibody blocked B2M-induced osteoclast formation, suggesting that B2M stimulates osteoclastogenesis and has a direc
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