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Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) is the fulminant glomerular diseases with poor renal prognosis. Activation of the complement system has recently been reported in the pathogenesis of AAGN, but it remains to be clarified as to which complement pathway is mainly involved. 20 patients with myeloperoxidase (MPO)-AAGN were retrospectively evaluated. Using serum samples, circulating immune-complexes (CICs) were assessed by the monoclonal rheumatoid factor assay, and C5a and C5b-9 were assessed by ELISA. Complement activation through the classical pathway was further evaluated by the WIESLAB® Complement System Classical Pathway kit. The affinities of ANCAs were evaluated by a competitive inhibition method using ELISA, and were classified into the high, and low-affinity group. Deposition of complement components, such as C3, C5, C4d, C5b-9, factor Bb, mannan-binding lectin serine peptidase (MASP)-1, MASP-2, and mannose/mannan-binding lectin (MBL), in frozen renal sections were analyzed by immunofluorescence staining. CICs were found to be positive in 65% of the patients. All CIC-positive patients belonged to the high-affinity group. Furthermore, serum C5a and C5b-9 were significantly increased in MPO-AAGN patients, and these levels positively correlated with CIC levels. A significant negative correlation was also found between levels of WIESLAB® classical pathway kit and CICs. By immunofluorescence staining, glomerular deposition of C4d, C5, and C5b-9 were observed in similar distributions in MPO-AAGN patients, whereas the deposition of MASP-1, MASP-2, MBL, and factor Bb were minimal. These results suggest the involvement of immune-complex induced complement activation through the classical pathway in the pathogenesis of MPO-AAGN.

Background Hereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with HAE, excess production of bradykinin causes acute unpredictable recurrent attacks of angioedema in localized regions, including the larynx and intestines. Given the fact that HAE is an autosomal dominant disease, C1-INH produced in patients with HAE is 50% of that produced in healthy individuals. However, most patients with HAE present plasma C1-INH function of < 25% owing to the chronic consumption of C1-INH by kallikrein–kinin, contact, complement, coagulation, and fibrinolysis cascades. Recently, several therapeutic options have been developed for acute attacks and prophylaxis in the treatment of HAE; however, currently, there is no curative therapy for HAE. Case presentation Here we report the case of a 48-year-old male patient who presented with a long-standing history of HAE and underwent bone marrow transplantation (BMT) for acute myeloid leukemia (AML) at the age of 39 years and has been in complete remission of AML and HAE thereafter. Notably, after BMT, his C1-INH function gradually increased as follows: < 25%, 29%, 37%, and 45.6%. Since his 20 s, he intermittently presented with an acute attack of HAE once every 3 months from the initial attack. Further, after undergoing BMT, the number of acute attacks decreased to twice within 4 years until the age of 45 years, and subsequently, the patient has been free of acute attacks. C1-INH is mainly synthesized by hepatocytes, but it is known to be partially produced and secreted from peripheral blood monocytes, macrophages, endothelial cells, and fibroblasts. We speculate that the C1-INH function may be increased by extrahepatic production of C1-INH, possibly synthesized by differentiated cells derived from hematopoietic and mesenchymal stem cells after BMT. Conclusions This case report supports efforts to focus on extrahepatic production of C1-INH in the next strategy of new treatment development for HAE.

Hereditary angioedema (HAE), caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease that leads to unpredictable recurrent attacks of angioedema in localized regions, including the larynx. As medical or dental procedures can trigger laryngeal edema, resulting in asphyxiation, major global guidelines recommend short-term prophylaxis prior to invasive procedures and long-term prophylaxis to prevent acute attacks and achieve near-normal lives. Here, we report the case of a 63-year-old male who experienced asphyxiation after tooth extraction. Emergency tracheotomy had saved his life at the age of 40 years, before the diagnosis of HAE. At the age of 63, when he had another opportunity for tooth extraction, he was definitively diagnosed with HAE. Administering short-term prophylaxis with ongoing long-term prophylaxis for HAE and perioperative multidisciplinary management for tooth extraction helped prevent recurrent fatal angioedema due to dental procedures and this can be useful when managing patients with HAE.

Background Carnitine is an essential substance for energy metabolism, mainly responsible for intracellular fatty acid transport. Patients undergoing hemodialysis (HD) are prone to carnitine deficiency owing to the removal of carnitine during HD and dietary restrictions. Various diseases caused by carnitine deficiency are treated with biologically active levocarnitine (LC) administration. Vascular cell adhesion molecule 1 (VCAM-1) is an important marker associated with cardiovascular disease, vascular access failure (VAF), and prognosis of patients undergoing HD. While acetyl- l -carnitine inhibits cell adhesion molecules, there are almost no reports that LC inhibits VCAM-1. This study aimed to investigate the inhibitory effect of LC on tumor necrosis factor alpha (TNF-α)-induced VCAM-1. Methods Human umbilical vein endothelial cells were cultured in a medium containing TNF-α and LC for 6 and 24 h, and soluble VCAM-1 (sVCAM-1) in the culture supernatant was measured by enzyme-linked immunosorbent assay. We also measured the expression levels of intracellular reactive oxygen species (ROS), nuclear, and cytoplasmic nuclear factor kappa B (NF-κB/p65) to clarify the site of LC inhibition. NF-κB/p65 translocation into the nucleus was evaluated in intranuclear concentration and the ratio of intranuclear to total NF-κB/p65. Results Cotreatment with LC and TNF-α significantly suppressed sVCAM-1 expression, nuclear NF-κB/p65, and NF-κB/p65 ratio in response to TNF-α-induced inflammation. However, intracellular ROS was not significantly induced by TNF-α. Conclusions LC suppresses TNF-α-induced sVCAM-1 by inhibiting NF-κB/p65 nuclear translocation. LC may reduce the risk of vascular complications and VAF in patients undergoing HD.

Background Long-term enzyme replacement therapy (ERT) may improve prognosis in the patients with Fabry disease (FD), however, detail psychosocial burden has not been focused on long life expectancy. We experienced a male case of FD under ERT, he was placed on hemodialysis and presented rapidly progressive cognitive function. Case presentation A 51-year-old male patient with FD has been receiving ERT from age of 38 years. Hemodialysis was initiated at the age of 47 years. The patient experienced several attacks of cerebral infarction, and brain images demonstrated wide-spread asymptomatic ischemic lesions. His behavior became problematic at the age of 51 years. He often exhibited restlessness during hemodialysis sessions and failure to communicate effectively. The patient experienced impairment of attention and executive function, topographical disorientation, and amnesia. Consequently, it was necessary for medical staff and family members to monitor his behavior for safe extracorporeal circulation and daily life activities. Annual standardized neuropsychiatric testing revealed worsening of cognitive performance. Conclusions Despite treating with long-term ERT, it is necessary to determine the psychosocial burden derived from the progression of cognitive impairment in patients with FD undergoing hemodialysis.

Background Glomerular damage in IgA nephropathy (IgAN) is mediated by complement activation via the alternative and lectin pathways. Therefore, we focused on molecules stabilizing and regulating the alternative pathway C3 convertase in urine which might be associated with IgAN pathogenesis. Methods Membrane attack complex (MAC), properdin (P), factor H (fH) and Complement receptor type 1 (CR1) were quantified in urine samples from 71 patients with IgAN and 72 healthy controls. Glomerular deposition of C5, fH and P was assessed using an immunofluorescence technique and correlated with histological severity of IgAN and clinical parameters. Fibrotic changes and glomerular sclerosis were evaluated in renal biopsy specimens. Results Immunofluorescence studies revealed glomerular depositions of C5, fH and P in patients with IgAN. Urinary MAC, fH and P levels in IgAN patients were significantly higher than those in healthy controls (p < 0.001), but CR1 was significantly lower than that in healthy controls (p < 0.001). Urinary MAC and fH levels were positively correlated with serum creatinine (sCr), urinary N-acetyl-β-D-glucosaminidase (u-NAG), urinary β2 microglobulin (u-Bm), urinary protein (p < 0.001), interstitial fibrosis (MAC: p < 0.01, fH: p < 0.05) and the percentage of global glomerular sclerosis (p < 0.01). Urinary P was positively correlated with u-NAG, u-Bm, and urinary protein (p < 0.01). Conclusions Complement activation occurs in the urinary space in IgAN and the measurement of levels of MAC and fH in the urine could be a useful indicator of renal injury in patients with IgAN.

Background The prognostic period and factors associated with coronavirus disease (COVID-19) in patients on hemodialysis (HD) with high mortality due to COVID-19 are important for the treatment and management of patients on HD after COVID-19 infection. In previous studies, the observation period of prognosis in patients on HD with COVID-19 was 1 year or less, and few reports have examined long-term prognoses of over 3 years or more. Moreover, few studies have examined patient prognosis based on clearly defined severity rather than on hospitalization. In this prospective observational study, we investigated the relationship between the severity of COVID-19 at disease onset and the long-term prognosis of COVID-19-infected patients on HD. Methods In total, 373 patients on HD diagnosed with COVID-19 were included in this study. The follow-up period ranged from onset up to 3 years. Patient background, blood samples and chest computerized tomography scans were examined. Severity was classified into four categories based on peripheral oxygen saturation and clinical status. Three categories, namely moderate I, moderate II, and severe, were defined as the moderate or severe group, and one category, namely mild, was defined as the mild group. Results There were 255 patients in the mild stage, 70 in the moderate I stage, 45 in the moderate II stage, and three in the severe stage; therefore, 118 patients were in the moderate or severe group. The prognosis in the moderate or severe disease group was lower than that in the mild disease group, according to Kaplan–Meier curves. Moderate or severe disease, older age, and lower levels of albumin were risk factors for mortality according to the Cox proportional hazards model of multivariate analysis. Only eight of the 373 patients died from a direct cause of COVID-19 within 7 days after COVID-19 diagnosis. Conclusions Moderate or severe COVID-19 worsens the prognosis of patients on HD up to 3 years.

Purpose Polycystic ovary syndrome (PCOS) significantly affects women. This study investigated the association between serum anti‐Müllerian hormone (AMH) levels and menstrual cycle disorders, and AMH for PCOS in a general cohort of young Japanese women. Methods We measured serum AMH levels in 528 healthy female students at two universities in Japan between 2014 and 2020. We investigated the association between serum AMH levels and hormone levels, menstrual cycle, and body mass index. Results The mean (±standard deviation) AMH level was 4.78 ± 2.88 ng/mL. Correlations were observed between serum AMH and luteinizing hormone (LH) or LH/follicle‐stimulating hormone (FSH) levels in women with irregular menstruation (LH: r = 0.542, p < 0.001; LH/FSH: r = 0.584, p < 0.001). The optimal serum AMH cutoff value that predicted LH ≥7.1 IU/L and LH/FSH ≥1.21 (PCOS diagnostic criteria revised by Japan Society of Obstetrics and Gynecology) in women with menstrual irregularities was 5.30 ng/mL (area under the curve: 0.815, sensitivity: 84.2%, specificity: 70.3%). Conclusions Serum AMH can be measured during annual health checkups and may be a useful biomarker for early and arcuate diagnosis and intervention in women with PCOS. This study shows the association between serum anti‐Müllerian hormone (AMH) levels and menstrual cycle disorders and AMH's usefulness for diagnosing PCOS in a general cohort of young Japanese women. Serum AMH can be measured during annual health checkups and may be a useful biomarker for early intervention in women with PCOS.

Lipopolysaccharides (LPS) induce inflammation by binding to the Toll-like receptor (TLR) 4 complex, including LPS-binding protein (LBP). The anti-inflammatory effects of linagliptin in LPS-induced inflammation in the TLR4-independent pathway have not been examined before. We examined the anti-inflammatory effects of linagliptin in the TLR4- and the LBP-independent pathway. U937 cells were cultured in the medium supplemented with 10% fetal bovine serum (FBS) and treated with 100 nM phorbol myristate acetate for 48 h. Cells were then left untreated or were treated with 10 μg/mL anti-TLR4 antibodies alone or in combination with linagliptin for 1 h in media supplemented with or without 10% FBS. The cells were divided into 5 groups: a) control cells (untreated) b) cells treated with LPS c) cells treated with 10 μg/mL anti-TLR4 antibodies d) cells treated with LPS and 10 μg/mL anti-TLR4 antibodies and e) cells treated with LPS, 10 μg/mL anti-TLR4 antibodies, and linagliptin. The LPS concentrations used were 50 pg/mL or 100 pg/mL for cells treated in the presence of 10% FBS and 100 pg/mL or 1 μg/mL for cells treated in the absence of FBS. Linagliptin concentrations of 1 nM, 10 nM, and 100 nM were used for treatment. The supernatants were analyzed for interleukin (IL)-6 production after 24 h of various treatments. LPS increased IL-6 production compared to the untreated control cells, and anti-TLR4 antibody suppressed LPS-induced increased IL-6 levels. Linagliptin suppressed LPS-induced IL-6 production in a concentration-dependent manner in the presence of FBS. However, only 100 nM linagliptin could suppress LPS-induced IL-6 production in the absence of FBS. Concentration-dependent and -independent inflammatory suppression was observed following linagliptin treatment after LPS induction in an experimental model of TLR4 inhibition by anti-TLR4 antibodies. Our results showed that linagliptin may inhibit inflammation through multiple mechanisms centered around the TLR-4-mediated pathway.

Atherosclerosis and inflammation are more common in patients with diabetes than in patients without diabetes, and atherosclerosis progression contributes to inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of patients with diabetes. Linagliptin is the only bile-excreted, anti-diabetic oral dipeptidyl peptidase-4 (DPP-4) inhibitor. Although the anti-inflammatory effects of DPP-4 inhibitors in vivo and in vitro have been reported, few in vitro studies have examined the effects of linagliptin using monocytes, which play a central role in arteriosclerosis-related inflammation. Herein, we assessed the anti-inflammatory effects of linagliptin in human U937 monocytes. U937 cells at densities of 1 × 10  cells/mL were cultured in Roswell Park Memorial Institute medium supplied with 10% fetal bovine serum and treated with 100 nM phorbol myristate acetate for 48 h for differentiation into macrophages. The media were replaced, and the cells were pretreated with 1, 5, 10, 50, and 100 nM linagliptin for 1 h or were left untreated. The media were then replaced again, and the cells were treated with 1 μg/mL lipopolysaccharide (LPS) or 10 nM interleukin (IL)-1β only, in combination with 1, 5, 10, 50, and 100 nM linagliptin or were left untreated. The extracted media were used to measure IL-6 and tumor necrosis factor (TNF)-α levels using enzyme-linked immunosorbent assay kits. LPS alone significantly increased IL-6 and TNF-α production compared with the control treatment. The treatment of cells with linagliptin at all concentrations significantly inhibited the LPS-stimulated IL-6 and TNF-α production. Meanwhile, IL-1β alone significantly increased IL-6 production compared with the control treatment. No significant difference in IL-6 production was noted between the cells treated with IL-1β and simultaneous treatment with IL-1β and linagliptin. Linagliptin inhibited LPS-induced inflammation in human monocytic U937 cells.