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BMC Nephrology Jun 2023The association between serum β-microglobulin (βM) levels and the risk of all-cause and cardiovascular disease (CVD) mortality and the incidence of cardiovascular...
BACKGROUND
The association between serum β-microglobulin (βM) levels and the risk of all-cause and cardiovascular disease (CVD) mortality and the incidence of cardiovascular events (CVEs) in patients undergoing maintenance hemodialysis (MHD) is inconclusive. Furthermore, no study has been performed in China on the significance of serum βM levels in MHD patients. Therefore, this study investigated the aforementioned association in MHD patients.
METHODS
In this prospective cohort study, 521 MHD patients were followed at Dalian Municipal Central Hospital affiliated with Dalian University of Technology from December 2019 to December 2021. The serum βM levels were categorized into three tertiles, and the lowest tertile served as the reference group. Survival curves were calculated by the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. Sensitivity analysis was performed by excluding patients with CVD at baseline.
RESULTS
During the follow-up period of 21.4 ± 6.3 months, there were 106 all-cause deaths, of which 68 were caused by CVD. When excluding CVD patients at baseline, there were 66 incident CVEs. Kaplan-Meier analysis revealed that the risk of all-cause and CVD mortality in the highest tertile of serum βM levels was significantly higher than that in the lowest tertile (P < 0.05), but not for the CVEs (P > 0.05). After adjusting for potential confounders, serum βM levels were positively associated with the risk of all-cause (HR = 2.24, 95% CI = 1.21-4.17) and CVD (HR = 2.54, 95% CI = 1.19-5.43) mortality, and a linear trend was evident (P < 0.05). Besides, the results of sensitivity analysis were consistent with the main findings. However, we didn't observed the significant association between serum βM levels and CVEs (P > 0.05).
CONCLUSION
The serum βM level may be a significant predictor of the risk of all-cause and CVD mortality in MHD patients. Further studies are needed to confirm this finding.
Topics: Humans; Asian People; Cardiovascular Diseases; East Asian People; Prospective Studies; Renal Dialysis; beta 2-Microglobulin
PubMed: 37312042
DOI: 10.1186/s12882-023-03191-5 -
Blood Purification 2015Standard low-flux haemodialysis (HD) is not very efficacious, and patient morbidity and mortality rates are still very high. According to the initial study design, the... (Review)
Review
BACKGROUND
Standard low-flux haemodialysis (HD) is not very efficacious, and patient morbidity and mortality rates are still very high. According to the initial study design, the MPO study reported that high-flux HD (hf-HD) showed a significant 37% relative risk reduction of mortality in patients with serum albumin ≤4 g/dl; online haemodiafiltration (HDF) is considered the most efficient technique of using high-flux membranes, as clearances of small solutes, like urea, are higher than in haemofiltration and clearances of middle solutes, like β2-microglobulin, are higher than in hf-HD.
SUMMARY
Three randomized trials have recently been published analysing the effect of online HDF on mortality. Two trials were unable to demonstrate a positive effect of HDF on survival, while 1 showed a significantly better survival in patients randomized to HDF in comparison to those randomized to hf-HD. It is intriguing that post hoc analyses of these 3 studies showed that the patients randomized to online HDF who received the highest convection volumes had a lower risk of mortality and cardiovascular events than those randomized to HD. Four very recently published meta-analyses have shown inconsistent results concerning the effect of convective treatments in improving patient general and cardiovascular survival, while they have consistently shown a significant reduction of the intradialytic symptomatic hypotension in patients treated with convective techniques in comparison with those treated with prevalent diffusive ones. Key Messages: The results of the randomized trials on the effect of HDF in improving patient survival are inconclusive. Moreover, trials specifically designed for testing the effect of increased convection of online HDF on patient survival and morbidity in comparison to patients treated with hf-HD are still awaited.
Topics: Aged; Blood Flow Velocity; Dialysis Solutions; Female; Hemodiafiltration; Humans; Kidney Failure, Chronic; Male; Membranes, Artificial; Randomized Controlled Trials as Topic; Rheology; Risk Factors; Survival Analysis; Urea; beta 2-Microglobulin
PubMed: 26344510
DOI: 10.1159/000437410 -
Medical Archives (Sarajevo, Bosnia and... Oct 2016Higher than expected cardiovascular mortality in hemodialysis patients, has been attributed to dyslipidemia as well as inflammation. Beta2-Microglobulin (β2M) is an...
BACKGROUND
Higher than expected cardiovascular mortality in hemodialysis patients, has been attributed to dyslipidemia as well as inflammation. Beta2-Microglobulin (β2M) is an independent predictor of outcome for hemodialysis patients and a representative substance of middle molecules.
RESULTS
In 40 patients in high-flux membrane hemodialysis, we found negative correlation of β2M with high density lipoprotein (r=-0.73, p<0.001) and albumin (r= -0.53, p<0.001) and positive correlation with triglycerides (r=0.69, p<0.001), parathyroid hormone (r=0.58, p < 0.05) and phosphorus (r= 0.53, p<0.001). There was no correlation of β2M with C- reactive protein (CRP) and interleukin-6 (IL-6). During the follow-up period of three years, 6 out of 40 patients have died from cardiovascular events.
CONCLUSION
In high-flux membrane hemodialysis patients, we observed a significant relationship of β2M with dyslipidemia and mineral bone disorders, but there was no correlation with inflammation.
Topics: Adult; Aged; Dyslipidemias; Female; Humans; Inflammation; Kidney Failure, Chronic; Lipoproteins, HDL; Male; Middle Aged; Renal Dialysis; Serum Albumin; Young Adult; beta 2-Microglobulin
PubMed: 27994294
DOI: 10.5455/medarh.2016.70.348-350 -
American Journal of Physiology. Lung... May 2017β-Microglobulin (βM), the light chain of the major histocompatibility complex class I (MHC I), has been identified as a proaging factor and is involved in the...
β-Microglobulin (βM), the light chain of the major histocompatibility complex class I (MHC I), has been identified as a proaging factor and is involved in the pathogenesis of neurodegenerative disorders by driving cognitive and regenerative impairments. However, little attention has focused on the effect of βM in the development of lung emphysema. Here, we found that concentrations of βM in plasma were significantly elevated in patients with lung emphysema than those in normal control subjects (1.89 ± 0.12 vs. 1.42 ± 0.06 mg/l, < 0.01). Moreover, the expression of βM was significantly higher in lung tissue of emphysema (39.90 ± 1.97 vs. 23.94 ± 2.11%, < 0.01). Immunofluorescence showed that βM was mainly expressed in prosurfactant protein C-positive (pro-SPC) alveolar epithelial cells and CD14 macrophages. Exposure to recombinant human βM and cigarette smoke extract (CSE) in vitro enhanced cellular senescence and inhibited proliferation of A549 cells, which was partially reversed by the presence of anti-βM antibody. However, anti-βM antibody did not attenuate the elevated production of IL-1β, IL-6, and TNF-α in A549 cells that were exposed to CSE. Immunofluorescence showed that colocalization of βM, and the hemochromatosis gene (HFE) protein was observed on A549 cells. These data suggest βM might participate in the development of lung emphysema through induction of lung epithelial cell senescence and inhibition.
Topics: A549 Cells; Antibodies; Cell Proliferation; Cellular Senescence; Demography; Epithelial Cells; Female; Humans; Lung; Male; Middle Aged; Phenotype; Pulmonary Emphysema; Smoking; beta 2-Microglobulin
PubMed: 28213472
DOI: 10.1152/ajplung.00516.2016 -
PloS One 2019Premature infants are at risk for severe sepsis and meningitis, both infections associated with high mortality and morbidity. Cerebro-spinal fluid (CSF) culture is the...
BACKGROUND
Premature infants are at risk for severe sepsis and meningitis, both infections associated with high mortality and morbidity. Cerebro-spinal fluid (CSF) culture is the gold standard method for meningitis diagnosis, but interpretation of biochemical parameters of CSF is essential at the moment of the analysis in order to start the appropriate treatment. The main objective of this study was to determine whether levels of CSF beta-2-microglobulin (B2M) were elevated in preterm infants with CNS infections or other inflammatory processes, and to establish if there were differences in B2M concentrations amongst various inflammatory settings (sepsis, meningitis, and progressive post-hemorrhagic ventricular dilatation (PHVD)).
METHODS
This is a retrospective study of all very preterm and extremely preterm infants (< 32 weeks of gestation) admitted to our NICU between 2012 and 2017. All those who underwent a lumbar puncture during their stay as part of a sepsis work-up or PHVD were considered for inclusion. CSF biochemical parameters and B2M were tested in all of the patients.
RESULTS
Fifty-nine patients were included in the study. In patients with CNS infections, the median value of B2M was 8.69 mg/L (3.92-18.5). B2M levels above 3.92 mg/L showed greater sensitivity and specificity than leukocyte levels in discriminating between patients with CNS infections or other inflammatory processes and those without CNS inflammation.
CONCLUSIONS
In this population, CSF B2M proved to be an effective biomarker to discriminate between patients with CNS infections and other inflammatory processes and those without CNS inflammation.
Topics: Biomarkers; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Inflammation; Intracranial Hemorrhages; Male; Meningitis; Prognosis; Retrospective Studies; Sepsis; beta 2-Microglobulin
PubMed: 31063510
DOI: 10.1371/journal.pone.0216498 -
Scientific Reports Sep 2015β-2-microglobulin (β2m) self-aggregates to form amyloid fibril in renal patients taking long-term dialysis treatment. Despite the extensive structural and mutation...
β-2-microglobulin (β2m) self-aggregates to form amyloid fibril in renal patients taking long-term dialysis treatment. Despite the extensive structural and mutation studies carried out so far, the molecular details on the factors that dictate amyloidogenic potential of β2m remain elusive. Here we report molecular dynamics simulations followed by the solvation thermodynamic analyses on the wild-type β2m and D76N, D59P, and W60C mutants at the native (N) and so-called aggregation-prone intermediate (IT) states, which are distinguished by the native cis- and non-native trans-Pro32 backbone conformations. Three major structural and thermodynamic characteristics of the IT-state relative to the N-state in β2m protein are detected that contribute to the increased amyloidogenic potential: (i) the disruption of the edge D-strand, (ii) the increased solvent-exposed hydrophobic interface, and (iii) the increased solvation free energy (less affinity toward solvent water). Mutation effects on these three factors are shown to exhibit a good correlation with the experimentally observed distinct amyloidogenic propensity of the D76N (+), D59P (+), and W60C (-) mutants (+/- for enhanced/decreased). Our analyses thus identify the structural and thermodynamic characteristics of the amyloidogenic intermediates, which will serve to uncover molecular mechanisms and driving forces in β2m amyloid fibril formation.
Topics: Amyloidogenic Proteins; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Mutation; Protein Conformation; Protein Stability; Solvents; Thermodynamics; beta 2-Microglobulin
PubMed: 26348154
DOI: 10.1038/srep13631 -
Rheumatology International Feb 2023A strong correlation between lupus nephritis (LN), disease activity, and serum beta 2-microglobulin (b2MG) was observed. The current study examines the correlation...
A strong correlation between lupus nephritis (LN), disease activity, and serum beta 2-microglobulin (b2MG) was observed. The current study examines the correlation between serum b2MG and renal involvement, damage score, and disease activity in systemic lupus erythematosus (SLE) patients. One hundred SLE patients from Ain Shams University Hospital were enrolled and categorized into two groups. Group I had 40 patients with negative b2MG, while Group II had 60 patients with positive b2MG levels. Medical history, clinical examination, and assessing disease activity based on SLE disease activity index (SLEDAI-2 K), and damage score were recorded for all patients. Laboratory examinations, such as serum b2MG, complete blood count, blood urea nitrogen (BUN), serum creatinine, glomerular filtration rate (GFR), urine analysis, 24 h urinary protein excretion, Antinuclear antibodies (ANA), anti-dsDNA antibody, and serum complement (C3, C4). BUN, 24 h urinary protein, serum creatinine, active urinary sediment, SLEDAI score, and damage score were all elevated in group II compared to group I (p < 0.001). There is a positive correlation between serum b2MG and 24 h urinary protein, BUN, serum creatinine, disease activity, and damage score (p < 0.001), while it was negatively correlated with GFR, C3, and C4 (p < 0.001). Serum b2MG has proven to be a predictor of LN in SLE patients (Sensitivity 92.45%, Specificity 74.47%), also being a predictor of the activity of the disease as well as damage index (Sensitivity 96.67%, Specificity 85%) (Sensitivity 92.45%, Specificity 74.47%), respectively. Serum b2MG level can be used as a valuable predictor for LN, clinical disease activity, and damage score.
Topics: Humans; Cross-Sectional Studies; beta 2-Microglobulin; Creatinine; Biomarkers; Lupus Erythematosus, Systemic; Lupus Nephritis
PubMed: 36205758
DOI: 10.1007/s00296-022-05221-1 -
Proceedings of the National Academy of... May 2017Relative to other extrinsic factors, the effects of hydrodynamic flow fields on protein stability and conformation remain poorly understood. Flow-induced protein...
Relative to other extrinsic factors, the effects of hydrodynamic flow fields on protein stability and conformation remain poorly understood. Flow-induced protein remodeling and/or aggregation is observed both in Nature and during the large-scale industrial manufacture of proteins. Despite its ubiquity, the relationships between the type and magnitude of hydrodynamic flow, a protein's structure and stability, and the resultant aggregation propensity are unclear. Here, we assess the effects of a defined and quantified flow field dominated by extensional flow on the aggregation of BSA, β-microglobulin (βm), granulocyte colony stimulating factor (G-CSF), and three monoclonal antibodies (mAbs). We show that the device induces protein aggregation after exposure to an extensional flow field for 0.36-1.8 ms, at concentrations as low as 0.5 mg mL In addition, we reveal that the extent of aggregation depends on the applied strain rate and the concentration, structural scaffold, and sequence of the protein. Finally we demonstrate the in situ labeling of a buried cysteine residue in BSA during extensional stress. Together, these data indicate that an extensional flow readily unfolds thermodynamically and kinetically stable proteins, exposing previously sequestered sequences whose aggregation propensity determines the probability and extent of aggregation.
Topics: Animals; Antibodies, Monoclonal; Cattle; Granulocyte Colony-Stimulating Factor; Humans; Hydrodynamics; Kinetics; Protein Aggregates; Protein Stability; Serum Albumin, Bovine; beta 2-Microglobulin
PubMed: 28416674
DOI: 10.1073/pnas.1702724114 -
International Journal of Molecular... Oct 2021Aggregation of β microglobulin (βm) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type...
Aggregation of β microglobulin (βm) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, ΔN6 βm, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the βm variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of β microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic lines expressing wild-type (WT) human βm, or the two highly amyloidogenic naturally occurring variants, D76N βm and ΔN6 βm, in the bodywall muscle. Nematodes expressing the D76N βm and ΔN6 βm variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both βm variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of βm reduces the capacity of to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/ transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all βm variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal βm toxicity and a disrupted ER secretory metabolism.
Topics: Animals; Caenorhabditis elegans; Endoplasmic Reticulum Stress; Heat-Shock Response; Humans; Longevity; Mutation; Protein Aggregates; Unfolded Protein Response; beta 2-Microglobulin
PubMed: 34639093
DOI: 10.3390/ijms221910752 -
International Journal of Molecular... May 2021Proteolytic enzymes are known to be involved in the formation and degradation of various monomeric proteins, but the effect of proteases on the ordered protein...
Proteolytic enzymes are known to be involved in the formation and degradation of various monomeric proteins, but the effect of proteases on the ordered protein aggregates, amyloid fibrils, which are considered to be extremely stable, remains poorly understood. In this work we study resistance to proteolytic degradation of lysozyme amyloid fibrils with two different types of morphology and beta-2-microglobulun amyloids. We showed that the proteolytic enzyme of the pancreas, trypsin, induced degradation of amyloid fibrils, and the mechanism of this process was qualitatively the same for all investigated amyloids. At the same time, we found a dependence of efficiency and rate of fibril degradation on the structure of the amyloid-forming protein as well as on the morphology and clustering of amyloid fibrils. It was assumed that the discovered relationship between fibrils structure and the efficiency of their degradation by trypsin can become the basis of a new express method for the analysis of amyloids polymorphism. Unexpectedly lower resistance of both types of lysozyme amyloids to trypsin exposure compared to the native monomeric protein (which is not susceptible to hydrolysis) was attributed to the higher availability of cleavage sites in studied fibrils. Another intriguing result of the work is that the cytotoxicity of amyloids treated with trypsin was not only failing to decline, but even increasing in the case of beta-2-microglobulin fibrils.
Topics: Amyloid; Amyloid beta-Peptides; Anilino Naphthalenesulfonates; Benzothiazoles; Fluorescent Dyes; HeLa Cells; Humans; Hydrogen-Ion Concentration; Hydrolysis; Muramidase; Proteolysis; Trypsin; beta 2-Microglobulin
PubMed: 34063223
DOI: 10.3390/ijms22094828