Β2-microglobulin Levels Research Articles

MO671COMPARASION OF EXPENDED HEMODIALYSIS USING A MEDIUM CUT-OFF DIALYZER VERSUS HEMODIAFILTRATION: AN OBSERVATIONAL PROSPECTIVE STUDY

Abstract Background and Aims Expended hemodialysis (HDx) with medium cut-off (MCO) membrane enables efficient depuration of middleweight uremic toxins, which play significant roles in inflammation and cardiovascular morbidity. Hemodiafiltration (HDF) is known for good removal of middle molecules but it requires more technical resources and well-functioning dialysis access. The aim of this study is to evaluate the efficacy of depuration of uremic toxins with a high-flux dialyzer during HDF session and with a MCO membrane (Theranova®) in HDx session and its impact on quality of life (QoL) in hemodialysis patients. Method In an open, single-centre, prospective observational clinical study, 28 adult stable HD patients without residual renal function were assigned to be treated by on-line HDF (HDF group) with the APS-21H dialyzer (polysulfone membrane, 2.1 m2, Asahi Kasei Medical Co., Japan) or by HDx (HDx group) with the Theranova® 400 (1.7 m2) and Theranova® 500 (2.0 m2) dialyzers (Baxter International Inc, USA). The study was conducted during 2019-2020 and completed after 12 months period. All patients were receiving maintenance high-flux membrane HDF treatment at least six months before they were enrolled in the study. Groups of patients were matched in age, sex, BMI, dialysis length and underlying disease. Complete blood count (CBC), renal function and inflammation, electrolytes, liver function tests, iron and nutritional status were evaluated at the beginning of the study and after 3, 6, 9 and 12 months. Pre and postdialysis levels for urea, creatinine, albumin, calcium, phosphorus, C-Reactive Protein, kappa and lambda free light chains (FLC), vitamin B12, β2 microglobulin levels were determined in each patient quarterly and reduction rate (RR) for uremic toxins were calculated. Furthermore single-pool Kt/V, dose of erythropoietin therapy (EPO) and vascular access were evaluated during the study, while bioimpedance analysis using Body composition monitor (Fresenius Medical Care, Germany) and QoL using SF-36 questionnaire (Kidney Disease Quality of Life Short Form-KDQOLTM-36) were evaluated at the end of observation period. The values have been reported as mean ±SD. Results There were 28 patients (14 in each group) mean age of 54.24 years (57.71±9.65 in HDx group vs 59.81±7.99 in HDF group). Median dialysis vintage was 4.77 years (5.33 in HDx group vs 6.46 in HDF group, p=0.55). Vascular access was native arteriovenous fistula in 23 patients, arteriovenous graft in 2 patients and tunnelled dialysis catheter in 3 patients (p=0.98). Kt/V was similar in both groups (1.57±0.31 vs 1.45±0.24, p=0.9), as well as weekly dose of EPO (4533.3±1922.3 vs 4233.3±1971.8, p=0.67). Patients in HDF group had a significantly higher interdialysis fluid overload (2,48±1,37 in HDx group vs 3,64±1,33 in HDF group, p=0.04), without difference in relation to the systolic and diastolic blood pressure values, as well as others BCM parameters. There were not significant differences in examined parameters of CBC, renal function and inflammation, electrolytes, liver function tests, iron and nutritional status at the beginning and at the end of the study. RR of small and middle molecules are presented in Table 1. Serum albumin level has decreased from 37.8 g/dL to 36.4 g/dL in 12 months during HDx treatment with maximal change of serum albumin level of -3.7% during that period (Figure 1). Evaluation of Kidney Disease Quality of Life Short Form at the end of study period in both groups is shown in Figure 2. Conclusion Compared to HDF, HDx with MCO membranes show greater RR for large middle molecules such as lambda FLC (45kD), while RRs for middle molecules- kappa FLC (23kD), β2 microglobulin (12kD) and small uremic toxins are similar. During one year of treatment with MCO membranes serum albumin levels remain stable. HDx treatment may improve quality of life, making an impact primarily in energy status and emotional satisfaction.

Frequency domain analysis and clinical outcomes of pulsatile and non-pulsatile blood flow energy during cardiopulmonary bypass.

The superiority of pulsatile perfusion during cardiopulmonary bypass remains controversial. We analyzed the frequency-domain characteristics and organ protection of pulsatile and nonpulsatile flow in adult patients with valvular disease. EEP and SHE were used to calculate blood flow energy in 60 patients. The Fast Fourier Transform was employed to analyze the power spectral density and power density ratio (Rvpd) of flow energy. Changes in endothelin-1, nitric oxide, interleukin-6,10, tumor necrotic factor, S100β, NSE, blood and urinary β2-microglobulin levels were investigated to assess the endothelial function, inflammatory reaction, kidney and brain injury during CPB. EEP and SHE in PP group at each time point were 1.52-1.62 times and 2.03-2.22 times higher respectively compared with NP group. Power spectral density analysis demonstrated that the blood flow energy frequencies in each group were all within 40 Hz and the low frequency energy (0-5 Hz) was dominant in physiological perfusion (>90%). The energy ratio of 0-5 Hz at radial artery was significantly decreased compared with that of post arterial filter in PP (81% vs 64%) and NP (63% vs 37%) group. The power density ratio (Rvpd) was higher than that of NP in all frequency ranges at the radial artery (9.51 vs 4.68 vs 3.59) and arterial filter (3.87 vs 2.69 vs 2.38). The S100β, NSE Urinary and plasma β2-microglobulin level were significantly increased at 6 and 24 hours after surgery in two group, and significantly higher in group NP. PP provided more energy than NP. The proportion of low frequency energy in the pulsatile or nonpulsatile flow is significantly reduced. The low-frequency energy is significantly attenuated during conduction to peripheral tissues in nonpulsatile flow. The surplus pulsatile energy influences the secretion of endothelial and inflammatory factors, and demonstrate better cerebral and kidney protective effect at the biological marker level.

The correlation between polycyclic aromatic hydrocarbons and idiopathic membranous nephropathy

Objective: To explore the relationship between polycyclic aromatic hydrocarbons (PAHs), the major component of atmospheric pollutant particulate matter 2.5 (PM2.5) and idiopathic membranous nephropathy (IMN) and its possible mechanisms. Methods: Thirty-five (24 males and 11 females) patients with IMN confirmed by renal biopsy pathology in the First Affiliated Hospital of Zhengzhou University from June to September 2020 were selected as the research group, with an age of (47.3±12.9) years. Meanwhile, patients with secondary membranous nephropathy (SMN, n=10) and minimal-change disease (MCD, n=10) were selected as control group. Blood samples were collected to detect PAHs and heme oxygenase-1 (HO-1), and the relationship of PAHs with clinical indicators and oxidative stress indicator HO-1 was analyzed. Results: Compared with SMN and MCD groups [(2.6±1.7) mg/L and (2.8±1.0) mg/L], the concentration of PAHs in IMN group [(4.1±1.9) mg/L] increased (both P<0.05). The concentration of PAHs was positively correlated with the levels of β2 microglobulin, total cholesterol and 24-hour urine total protein (r=0.509, 0.336, and 0.653, respectively, all P<0.05), but was negatively correlated with the levels of total protein and albumin (r=-0.499,-0.530, respectively, both P<0.05). Additionally, the concentration of PAHs was negatively correlated with the level of HO-1 (r=-0.358, P=0.017). Linear regression analysis showed that the concentration of HO-1 decreased by 1.737 μg/L when the concentration of PAHs increased by 1 mg/L (P=0.035). Conclusion: PAHs have a high level in IMN patients, and may be involved in the occurrence and development of IMN through oxidative stress.

Diagnostic Utility of Beta 2 Microglobulin in Patients with Irritable Bowel Syndrome and Ulcerative Colitis

Background: Inflammatory bowel disease (IBD) is a chronically relapsing disease. It includes ulcerative colitis (UC) and crohn's disease (CD). Symptoms of IBD could be conflicting sometimes with irritable bowel syndrome (IBS) of diarrheal type. The ideal marker for IBD/IBS diagnosis has not yet been identified. B2 microglobulin (B2-M) is a low molecular weight protein released by activated T and B lymphocytes. It has been shown to increase in several chronic inflammatory conditions. Objectives: Assessment of the diagnostic role of (B2-M) in IBS cases presented with diarrhea (IBS-D type) and UC cases. Methodology: This case control study was conducted at Gastroenterology Unit in Tropical Medicine Department, Ain- Shams University Hospitals, Cairo, Egypt. Forty patients with UC, and twenty patients with IBS in addition to twenty healthy persons as control were included. Results: There was a higher mean of B2-M values among U.C group (1.93)(mean B2-M in Active UC was 2.26 and 1.61 in inactive disease) compared to the other two groups(1.51 in IBS and 1.43 in control group) and the difference was highly statistically significant(P=0.000).Using ROC curve analysis of different cut off values of (B2-M) for detection of UC cases among IBS cases, we found that at a cut off value of &lt;1.5 , we got sensitivity, specificity, PPV, NPV and accuracy of 75 %, 70 %, 83.3%, 58.3 %, and 0.753% respectively and this was the best cut off value. Conclusion: B2-M level may have a diagnostic and differentiating utility between UC cases and IBS-D type as well as a potential indicator of disease activation in UC patients.

CXCR4 is a valuable poor prognostic marker for chronic lymphocytic leukemia

Background Chronic lymphocytic leukemia (CLL) is one of the common chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin. CLL is a heterogeneous disease; thus, in some cases, the disease progresses so slowly that treatment is not required, but in others, a more aggressive form of the disease develops. CXCR4 (CD184) is a chemokine and chemokine receptor pair playing critical roles in tumor genesis. It is overexpressed in many hematological malignancies including acute myeloid leukemia and non-Hodgkin's lymphoma and generally correlates with a poor prognosis. Aim To evaluate the clinical utility of CXCR4 expression in patients with CLL as a possible predictor of disease outcome. Patients and methods This is a prospective study conducted on 33 adult patients with newly diagnosed CLL. Expression of CXCR4 was determined by flow cytometry on either peripheral blood or bone marrow samples. Correlation with the course of the disease and the known CLL prognostic parameters was done initially and after 6 months of follow-up. Results CXCR4 expression was positively correlated with absolute lymphocytic count, Rai score, β2 microglobulin, and lactate dehydrogenase levels. It was negatively correlated with hemoglobin and platelet counts, overall response rate, and 6-month disease-free survival. Conclusion We conclude that CXCR4 is a valuable poor prognostic marker for CLL. Its higher level of expression is associated with inferior response to therapy and lower disease-free survival.

Elevated cadmium and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in residents living near electroplating industries.

This study aims to evaluate the body burdens of cadmium (Cd) associated with potential health impairment in residents living near electroplating industries. A total of 269 residents from exposure area and 106 from control area were recruited. We measured the blood and urinary Cd levels using an inductively coupled plasma mass spectrometer (ICP-MS); performed physical examinations; determined the urinary levels of β2-microglobulin (β2-MG), Nacetyl-β-D-glucosaminidase (NAG), and 8-hydroxy-2'-deoxyguanosine (8-OHdG); and evaluated the associations between Cd and these biomarkers. Blood and urinary Cd levels in exposure group were statistically higher than in control group (1.712 vs. 1.159 μg/L; 1.980 vs. 1.740 μg/L, respectively, p < 0.05). Urinary β2-MG and 8-OHdG levels in exposure group were also statistically higher (0.448 vs. 0.090 mg/L; 12.759 vs. 12.115 μg/L, respectively, p < 0.05), but urinary NAG levels showed no significant difference between the two groups (13.614 vs. 8.246 IU/L, p > 0.05). The proportion of abnormal nasal symptoms occurring in exposed subjects (88.8%) was much higher than in control subjects (78.2%, p < 0.05). Urinary Cd levels were positively correlated with blood Cd levels, urinary 8-OHdG, and NAG levels (r = 0.307, r = 0.185, r = 0.150, p < 0.05), but not correlated with urinary β2-MG levels (p > 0.05). In conclusion, our study revealed that residents living in close proximity to electroplating industries had elevated body burdens of Cd levels, as well as slight renal dysfunction and DNA oxidation damage.

CLINICOPATHOLOGICAL STUDY OF MULTIPLE MYELOMA WITH EXPRESSION OF CD56

Background: Multiple myeloma (MM) is a plasma cell neoplasm with spectrum of clinical presentation and multisystem involvement. CD56 (a neural cell adhesion molecule, NCAM) is a membrane glycoprotein belonging to the immunoglobulin superfamily. Normal plasma cells do not express CD56, but it is frequently expressed by malignant plasma cells in patients with MM. The present study was conducted to evaluate the expression of CD56 in MM and its association with disease characteristics. Methods: We analysed CD56 expression in 34 newly diagnosed MM cases using immunohistochemistry in bone marrow core biopsies processed routinely. Results: CD56 expression was found in 70.97% cases. The clinicopathological disease characteristics such as age, serum creatinine level, serum β2-microglobulin level and plasmablastic morphology showed no statistically signicant difference between CD56 positive and negative groups. Bone lesions were signicantly higher in positive cases than in negative cases. Conclusion: CD56 expression dene a unique clinicopathological entity in MM. Expression of CD56 correlate well with lytic bone lesion and may correlate with its pathogenesis.

Serum β2-microglobulin levels in Coronavirus disease 2019 (Covid-19): Another prognosticator of disease severity?

β2-microglobulin (β2-m), a 11.8 kDa protein, pairs non-covalently with the α3 domain of the major histocompatibility class (MHC) I α-chain and is essential for the conformation of the MHC class I protein complex. Shed β2-m is measurable in circulation, and various disorders are accompanied by increases in β2-m levels, including several viral infections. Therefore, we explored whether β2-m levels could also be elevated in Coronavirus disease 2019 (Covid-19) and whether they predict disease severity. Serum β2-m levels were measured in a cohort of 34 patients infected with SARS-CoV-2 on admission to a tertiary care hospital in Riyadh, Saudi Arabia, as well as in an approximately age-sex matched group of 34 uninfected controls. Mean β2-m level was 3.25±1.68 mg/l (reference range 0.8-2.2 mg/l) in patients (mean age 48.2±21.6) and 1.98±0.61 mg/l in controls (mean age 48.2±21.6). 17 patients (mean age 36.9± 18.0) with mean β2-m levels of 2.27±0.64 mg/l had mild disease by WHO severity categorization, 12 patients (mean age 53.3±18.1) with mean β2-m levels of 3.57±1.39 mg/l had moderate disease, and five patients (of whom 2 died; mean age 74.4±13.8) with mean β2-m levels of 5.85±1.85 mg/l had severe disease (P < = 0.001, by ANOVA test for linear trend). In multivariate ordinal regression β2-m levels were the only significant predictor of disease severity. Our findings suggest that higher β2-m levels could be an early indicator of severity of disease and predict outcome of Covid-19. As the main limitations of the study are a single-center study, sample size and ethnicity, these results need confirmation in larger cohorts outside the Arabian Peninsula in order to delineate the value of β2-m measurements. The role of β2-m in the etiology and pathogenesis of severe Covid-19 remains to be elucidated.

Lipid microsphere-coated PGE1 improves peritoneal transport and reduces inflammation in peritoneal dialysis: A randomized clinical pilot trial.

To evaluate the effects of lipid microspheres coated with prostaglandin E1 (lipo-PGE1) on peritoneal transport function and inflammation in patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis (CAPD). In total, 89 patients were randomly allocated to the lipo-PGE1 and control groups. All the patients received conventional treatment, and those in the lipo-PGE1 group received lipo-PGE1 intravenously for 2weeks. The levels of β2-microglobulin (β2-MG), cystatin C, albumin, urea, creatinine, interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), and high-sensitivity C-reactive protein (hs-CRP) were measured before and at 1 and 2weeks after treatment. In the lipo-PGE1 group, the peritoneal clearance rates of β2-MG, cystatin C, and albumin were significantly increased comparing with pre-treatment values, and the IL-6 appearance rate (AR) in the peritoneal dialysate and the serum levels of IL-6 and hs-CRP were markedly decreased (p<0.05). The lipo-PGE1 group had significantly higher peritoneal clearance rates of β2-MG and cystatin C and lower IL-6 AR in the peritoneal dialysate than the control group (p<0.05). Lipid microspheres coated with prostaglandin E1 may increase the peritoneal clearance of moderately sized molecules and macromolecules with insignificant effect on the clearance of small molecules. The reduction in IL-6 level following treatment with lipo-PGE1 may alleviate inflammation.

Elevated cerebrospinal fluid β2-microglobulin levels in patients with neuromyelitis optica spectrum disorders

Cerebrospinal fluid (CSF) β2-microglobulin (β2-MG) levels elevated in patients with multiple sclerosis (MS). We examined the levels of β2-MG in serum and cerebrospinal fluid (CSF) from 46 patients with neuromyelitis optica spectrum disorders (NMOSD), in serum from 21 healthy controls (HC), in CSF from 25 disease controls with non-inflammatory neurological diseases (NIND) with normal CSF results. CSF β2-MG levels were significantly higher in patients with NMOSD than controls and with weak association with the number of white blood cells, protein and lactate levels in CSF. CSF β2-MG is thus one more, non-specific indicator of inflammation in NMOSD.

Prostate Cancer Differentiation - Stromal Cell PENK and Stem Cell Transcription Factors

Prostate cancer cells from luminal-like (differentiated) adenocarcinoma to less luminal-like and more stem-like (undifferentiated) small cell carcinoma retain responsiveness to signaling by stromal cell factor proenkephalin (PENK). Stem-like cancer cells, like stem cells, express stem cell transcription factor (scTF) LIN28A, NANOG, POU5F1, SOX2 as well as a 10-fold lower level of β2-microglobulin (B2M). Forced expression of this scTF quartet can reprogram adenocarcinoma cells, as represented by LuCaP xenograft lines, to stem-, small cell carcinoma-like derivatives with the phenotypic change from scTF−B2Mhi to scTF+B2Mlo. Prostate stromal mesenchyme cells control organ development through secreted hormone factors and heterotypic cell contact. The highly expressed prostate stromal-specific PENK, when transfected into scTF+B2Mlo small cell carcinoma LuCaP 145.1, caused down-regulation of scTF and up-regulation of B2M to indicate differentiation. When transfected into scTF-reprogrammed adenocarcinoma-like LNCaP cells, PENK reversed the reprogramming through down-regulation of scTF with attendant changes in cell appearance and colony morphology. When transfected into adenocarcinoma LuCaP 70CR, PENK up-regulated the expression of anterior gradient 2 (AGR2), a marker associated with prostate cancer differentiation and better patient survival. Thus, PENK can induce differentiation to counter cancer de-differentiation due to activation of scTF. Loss of cancer differentiation leads to an untreatable disease. Patient survival would benefit if this can be reversed or prevented. Prostate cancer de-differentiation is likened to reprogramming. Cancer cells containing multiple mutations and being aneuploid can, like normal cells, still undergo differentiation.

Systemic Mastocytosis Associated with "Smoldering" Multiple Myeloma.

A 79-year-old woman presented with a long history of peripheral eosinophilia. Previous right hemicolectomy for colonic polyposis was reported. Laboratory tests were notable for mild macrocitic anaemia and eosinophilia. β2 microglobulin and serum tryptase levels were elevated. Serum immunofixation revealed IgA/kappa monoclonal protein. Bence-Jones protein was positive. Bone marrow (BM) biopsy revealed the coexistence of two neoplastic components. Cohesive clusters of bland-looking, spindle-shaped mast cells, representing 20% of marrow cellularity, were close to aggregates of mature plasma cells occupying 40% of marrow cellularity. Molecular analysis on marrow aspirate demonstrated KIT D816V mutation, TET2 mutation, monoallelic deletion of TP53/17p13 and trisomy of ATM/11q23. A bone density study revealed mild osteoporosis. Full skeletal X-rays and magnetic resonance imaging (MRI) of spine and hips showed multiple, small rarefaction areas and an old L1-L2 fracture, both ascribed to osteoporosis. The association of systemic mastocytosis (SM) and multiple myeloma (MM) is very uncommon. The coexistence of SM with MM placed our patient in the SM with associated clonal haematological non-mast-cell lineage disease (SM-AHN) subtype. Midostaurin therapy was started.

The Nitty-Gritties of Kt/Vurea Calculations in Hemodialysis and Peritoneal Dialysis.

In advanced Chronic Kidney Disease, patients require renal replacement therapy (dialysis or transplantation) for clearance of toxins, electrolyte and acid-base balance and removal of excess fluid. Dialysis adequacy should be taken into consideration in the adjustment of the dialysis prescription. Kt/Vurea is one method of measuring dialysis adequacy that is commonly used in clinical practice. Different formulae for calculating Kt/V are available. The appropriate Kt/V formula to be used depends on the clinical scenario, as well as parameters such as gender and size of patient, frequency of dialysis, mode of dialysis (ie hemodialysis vs, peritoneal dialysis), inter-dialysis weight gain, clinical symptoms, complications (fluid overload, hyperkalemia, intolerance to dialysis, etc), and residual kidney function. Nutrition parameters including serum protein and albumin levels, vitamin B12 and β2-microglobulin levels should be factored into the assessment of dialysis adequacy. In this review, we have described how Kt/Vurea is calculated in hemodialysis and peritoneal dialysis with examples. We reviewed the available literature by searching for papers related to calculating Kt/Vurea, single pool Kt/V, double pool Kt/V, weekly Kt/V, standard Kt/V, surface area normalized Kt/V, and various equations commonly practiced in clinical practice. We found several original articles, some review articles along with detailed information from manufacturers of different dialyzers published on their websites or as package inserts. Understanding the different equations available for calculating Kt/Vurea and the application of these results in the clinical setting is important for refining patient care and for designing clinical studies.

Zinc supplementation in neonatal bronchopulmonary dysplasia: Is it beneficial?

Background: Neonatal Broncho Pulmonary Dysplasia (BPD) is a chronic chest disease that is caused by prolonged ventilation and oxygenation, leading to sever neonatal disability. Patients and methods: Prospective Randomized Clinical Trial (RCT) study which was done at Tanta University Hospital (TUH) from July 2016 to March 2018 on 100 preterm neonates who had Respiratory Distress (RD) and were put on Mechanical Ventilation (MV). The studied neonates were divided into 2 groups: group 1, which received Zn supplementation, and group 2, which received placebo. Urinary β2-microglobulin (B2M) and serum Krebs van den Lungen-6 (KL-6) levels were estimated on the 3rd day and the10th day of presence in the hospital. Results: Significant decline in urinary B2M and serum KL-6 levels occurred in neonates of group 1 who were given Zn compared with those in group 2 neonates, who received placebo (P<0.05). There was a significant decline in the time of incubator stay in group 1 neonates, compared with that of group 2 neonates (P<0.05). Group 1 neonates showed a significant decline in the development of established cases of BPD if compared with group 2 (P<0.05). Conclusion: Zn supplementation is beneficial in the prevention of neonatal BPD.

Clinical Significance of CRP/ALB Ratio in Evaluating the Prognosis of Patients with DLBCL

Objective: Exploring the expression characteristics of CRP/ALB (CAR) in DLBCL patients and its value in prognostic judgment. Methods: We collected the basic information, clinical characteristics, laboratory examinations and follow-up prognosis of 142 newly diagnosed DLBCL patients with relatively complete data in our hospital and performed statistical analysis. We used X-tile analysis software to obtain the best cut-off value of CAR (0.33), compared the clinical characteristics and survival of patients in the high CAR group and the low CAR group, and compared the survival status with the IPI scoring system. Results: 1) There were significant differences in staging, grouping, IPI scores, extranodal involvement, LDH levels, β2-microglobulin, CA125, and Hb levels between the high CAR group and the low CAR group (all P P < 0.01), and the one-year, three-year and five-year survival conditions of high CAR group were all shorter than those of low CAR group. 3) COX analysis showed that high CAR is an independent poor prognostic factor for DLBCL patients. 4) A comparative analysis of OS, three-year and five-year survival showed that the combination of CAR and IPI was significantly better than the IPI system, and there was no significant difference in the evaluation value of the prognosis between CAR alone and IPI alone. Conclusion: High CAR value, like the IPI scoring system, is an independent poor prognostic factor of DLBCL, can be used as a reliable indicator of prognosis. And CAR can also be combined with IPI to evaluate the prognosis of DLBCL, of which the effect is better than that of IPI alone.

Renal tubular injury induced by glyphosate combined with hard water: the role of cytosolic phospholipase A2.

BackgroundThe combined effects of glyphosate and hard water on chronic kidney disease of unknown etiology (CDKu) have attracted much interest, but the mechanisms remain unknown. Cytoplasmic phospholipase A2 (cPLA2) plays a key role in the acute and chronic inflammatory reactions. This study explored the effect of glyphosate combined with hard water on renal tubules and the possible targets and mechanisms involved.MethodsIn vivo experiments were conducted to investigate the synergistic effects and potential mechanisms of glyphosate and hard water on renal tubular injury in mice.ResultsAdministration of glyphosate in mice resulted in elevated levels of β2-microglobulin (β2-MG), albumin (ALB), and serum creatinine (SCr) compared to control mice. This increase was more pronounce when glyphosate was combined with hard water. In the glyphosate-treated mice, small areas of the kidney revealed fibroblast proliferation and vacuolar degeneration, particularly at the higher dose of 400 mg/kg glyphosate. However, the combination of glyphosate and hard water induced an even greater degree of pathological changes in the kidney. Immunofluorescence and western blot analyses showed that glyphosate and hard water had a coordinated effect on calcium ions (Ca2+)-activated phospholipase A2 and the activation may play a key role in inflammation and renal tubular injury. Exposure to glyphosate alone or glyphosate plus hard water increased the levels of oxidative stress markers and inflammatory biomarkers, namely, thromboxane A2 (TX-A2), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), nitric oxide synthase (NOS), and nitric oxide (NO). Parameters of oxidative stress, including the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were decreased. Further analysis showed that the levels of these biomarkers were significantly different between the mice treated with glyphosate plus hard water and the mice treated with glyphosate alone.ConclusionsThese findings suggested that hard water combined with glyphosate can induce renal tubular injury in mice, and this may involve mitogen-activated protein kinases (MAPK)/cytosolic phospholipase A2 (cPLA2)/arachidonic acid (AA) and its downstream factors.

Enhanced β2-microglobulin binding of a "navigator" molecule bearing a single-chain variable fragment antibody for artificial switching of metabolic processing pathways.

Kidney dysfunction increases the blood levels of β2-microglobulin (β2-m), triggering dialysis-related amyloidosis. Previously, we developed a navigator molecule, consisting of a fusion protein of the N-terminal domain of apolipoprotein E (ApoE NTD) and the α3 domain of the major histocompatibility complex class I (MHC α3), for switching the metabolic processing pathway of β2-m from the kidneys to the liver. However, the β2-m binding of ApoE NTD-MHC α3 was impaired in the blood. In the current study, we replaced the β2-m binding part of the navigator protein (MHC α3) with an anti-β2-m single-chain variable fragment (scFv) antibody. The resultant ApoE NTD-scFv exhibited better β2-m binding than ApoE NTD-MHC α3 in buffer, and even in serum. Similar to ApoE NTD-MHC α3, in the mice model ApoE NTD-scFv bound to the liver cells' surfaces in vitro and accumulated mainly in the liver, when complexed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Both ApoE NTD-MHC α3 + DMPC and ApoE NTD-scFv + DMPC significantly switched the β2-m accumulation in mice from the kidneys to the liver, but only the ApoE NTD-scFv + DMPC group showed a significantly higher ratio of β2-m accumulation in the liver versus the kidneys, compared with the control group. These results suggest that the enhanced β2-m binding activity of the navigator molecule increased the efficiency of switching the metabolic processing pathway of the etiologic factor.

Environmental cadmium exposure induces kidney tubular and glomerular dysfunction in the Myanmar adults.

Cadmium is an environmental toxic metal and its exposure has become a worldwide public health threat. We aimed to evaluate the exposure assessment of cadmium in people living in Ta Zin Yae Kyaw village of Nyaung Don Township in Ayeyarwady Division, Myanmar and adverse effects of cadmium on the kidneys. Subjects (18-40 years) residing in this village were selected as the exposed group (n = 65) and those living in Kamayut Township in Yangon Division, Myanmar as the control group (n = 65). Spot urine samples were taken for determination of urinary cadmium concentration using graphite-furnace atomic absorption spectrometry (GFAAS) method and adjusted to the concentration of creatinine in urine. To assess the kidney function, urinary β2-microglobulin level was determined by ELISA, serum creatinine was measured by colorimetric Jaffe method and estimated glomerular filtration rate (eGFR) was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Urine cadmium concentrations were significantly higher in the exposed group (median (Interquartile range): 0.96 (0.19-1.77) μg/g Creatinine) compared to the control (p = 0.036). Urinary β2-microglobulin levels were significantly higher (p = 0.000) and eGFR was significantly lower in the exposed group (p = 0.013) compared to the control. In addition, urine cadmium level showed significant positive correlation with urinary β2-microglobulin in all study population (p < 0.01). Positive correlation becomes stronger (p < 0.01) in the exposed group only. For eGFR, significant negative correlation was found in all study population (p < 0.01) and exposed group (p < 0.01). Our findings suggested that environmental cadmium exposure can induce renal dysfunction in both tubular and glomerular functions in apparently healthy human adults.

Tubular Injury Causing Protracted Glycosuria Following Withdrawal of a Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor: A Possible Role in the Development of Protracted Hypoglycemia and Ketoacidosis.

We herein present the case of a 45-year-old diabetic woman who developed diabetic ketoacidosis following the administration of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. The patient had been diagnosed with diabetes three years previously and was being treated with multiple daily injections of insulin. Metformin hydrochloride and dapagliflozin were added seven months and 11 months later, respectively. Her clinical course was uneventful until the onset of influenza. She then discontinued insulin and oral medications voluntarily. On arrival at the hospital, she was found to be in a state of ketoacidosis, and promptly received insulin and saline infusion. In retrospect, the initial amount of glucose infused was insufficient, and the hypoglycemia was thought to have been prolonged. This phenomenon may also have affected her long-term urinary glucose excretion. Her urinary L-type fatty acid-binding protein (L-FABP) level was found to be markedly elevated (48.8 μg/g·Cr, reference value < 8.4 μg/g·Cr) as was her urinary β2-microglobulin level (9,230 μg/L, reference value < 230 μg/L). Patients with SGLT-2 inhibitor-associated diabetic ketoacidosis often exhibit protracted hyperglycosuria, in which acute proximal renal tubular dysfunction is considered to be etiologically implicated.

Prognostic Stratification of Patients with Burkitt Lymphoma Using Serum β2-microglobulin Levels.

PurposeWe aimed to investigate the prognostic value of serum β2-microglobulin for patients with Burkitt lymphoma (BL) and to propose a risk-stratifying classification system.Materials and MethodsA prospective registry-based cohort study of BL patients treated with dose-intensive or effective dose-adjusted chemotherapies (n=81) was conducted. Survival outcomes were compared based on previously reported risk groups and/or serum β2-microglobulin levels. A risk-stratifying classification system incorporating serum β2-microglobulin levels was proposed and validated in an independent validation cohort (n=60).ResultsThe median age was 47 years, and 57 patients (70.4%) were male. Patients with high serum β2-microglobulin levels (> 2 mg/L) had significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.01 for both). Serum β2-microglobulin levels further stratified patients in the low-risk and high-risk groups in terms of PFS (p=0.010 and p=0.044, respectively) and OS (p=0.014 and p=0.026, respectively). Multivariate analyses revealed that a high serum β2-microglobulin level (> 2 mg/L) was independently associated with a shorter PFS (hazards ratio [HR], 3.56; p=0.047) and OS (HR, 4.66; p=0.043). The new classification system incorporating the serum β2-microglobulin level allowed the stratification of patients into three distinct risk subgroups with 5-year OS rates of 100%, 89.5%, and 62.5%. In an independent cohort of BL, the system was validated by stratifying patients with different survival outcomes.ConclusionSerum β2-microglobulin level is an independent prognostic factor for BL patients. The proposed β2-microglobulin–based classification system could stratify patients with distinct survival outcomes, which may help define appropriate treatment approaches for individual patients.